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Luca RONCUCCI

Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto


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Pubblicazioni

2023 - A West Nile Virus infection expressed as unilateral limb paralysis and complicated by Parsonage–Turner syndrome: a case report [Articolo su rivista]
Scarciglia, Antonella; Roncucci, Luca; Benatti, Piero
abstract

BackgroundWest Nile Virus is a single-stranded Ribonucleic Acid arbovirus of the Flaviviridae family that is transmitted to humans by Culex species mosquitoes. West Nile Virus infection is asymptomatic in the majority of affected people. Of those who develop symptoms, the usual manifestation is a febrile syndrome, while only 1% develop neurological symptoms due to a neuroinvasive form of infection, including encephalitis, meningitis, asymmetrical flaccid paralysis, or a combination of all these features. Parsonage-Turner syndrome is a rare disorder characterized by sudden painful symptoms and subsequent paralysis, involving a shoulder or one of the upper limbs due to post-infective brachial plexopathy. The etiology is unknown, although it can be considered a multifactorial process: a predisposing factor, such as viral infection or strenuous upper-extremity exercise, can trigger an immune-mediated process localized in the brachial plexus.Clinical presentationIn late summer, a 79-year-old male Italian patient was admitted to the emergency department for acute right upper limb weakness and high fever, without any mental status impairment, pain, sensory alterations, or signs of meningeal irritation. Laboratory tests confirmed acute West Nile Virus infection, expressed as a unilateral upper limb flaccid paralysis. After a few days, the patient reported an acute pain in the right upper limb scarcely responsive to nonsteroidal anti-inflammatory drug therapy and a subsequent wider distribution of flaccid paralysis. After multiple examinations, Parsonage-Turner syndrome could be suspected. Patient was treated with steroids and reported an improvement of clinical condition after 2 months, with complete pain remission but partial strength recovery in the affected limb.ConclusionsWest Nile Virus disease has a broad spectrum of neurological manifestations, among which the most common are signs of meningeal irritation or cognitive impairment. We report an unusual presentation of neuroinvasive West Nile Virus infection with arm weakness as expression of unilateral viral neuritis, followed by a post-infective brachial plexopathy consistent with Parsonage-Turner syndrome diagnosis. We diagnosed Parsonage-Turner syndrome after excluding the most common causes of atraumatic acute upper limb pain, through a challenging differential diagnosis in a patient with several comorbidities.


2022 - Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features [Articolo su rivista]
Pedroni, Monica; Ponz de Leon, Maurizio; Reggiani Bonetti, Luca; Rossi, Giuseppina; Viel, Alessandra; Urso, Emanuele Damiano Luca; Roncucci, Luca
abstract

: We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G>T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents-c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother-as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.


2022 - Colon cancer in a 12-year-old girl with hypertriglyceridemia [Articolo su rivista]
Pedroni, Monica; Leon, Maurizio Ponz de; Bonetti, Luca Reggiani; Viel, Alessandra; Noto, Davide; Nascimbeni, Fabio; Sena, Paola; Roncucci, Luca
abstract


2022 - DIFFERENZE DI GENERE NELLA COMORBILITÀ TRA SINTOMATOLOGIA ANSIOSO-DEPRESSIVA, SINDROME METABOLICA E ADENOMI COLORETTALI [Abstract in Atti di Convegno]
Rioli, Giulia; Bonamici, Caterina; Mancini, Stefano; Mattei, Giorgio; Alboni, Silvia; Sena, Paola; Roncucci, Luca; Fiore, Gianluca; Pingani, Luca; Ferrari, Silvia; Galeazzi, Gian Maria
abstract


2022 - Differenze di genere nella comorbilità tra sintomatologia ansioso-depressiva, sindrome metabolica e adenomi colorettali [Abstract in Rivista]
Rioli, G.; Bonamici, C.; Mancini, S.; Mattei, G.; Alboni, S.; Sena, P.; Roncucci, L.; Fiore, G.; Pingani, L.; Ferrari, S.; Galeazzi, G. M.
abstract


2022 - Expression of Autophagic and Inflammatory Markers in Normal Mucosa of Individuals with Colorectal Adenomas: A Cross Sectional Study among Italian Outpatients Undergoing Colonoscopy [Articolo su rivista]
Sena, Paola; Mancini, Stefano; Pedroni, Monica; Reggiani Bonetti, Luca; Carnevale, Gianluca; Roncucci, Luca
abstract

: Colorectal cancer (CRC) ranks among the three most common cancers in terms of both cancer incidence and cancer-related deaths in Western industrialized countries. Lifetime risk of colorectal cancer may reach 6% of the population living in developed countries. In the current era of personalized medicine, CRC is no longer considered as a single entity. In more recent years many studies have described the distinct differences in epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and outcome depending on the anatomical site. The aim of our study is to assess in a multidimensional model the association between metabolic status and inflammatory and autophagic changes in the normal colorectal mucosa classified as right-sided, left-sided and rectum, and the presence of adenomas. One hundred and sixteen patients undergoing colonoscopy were recruited and underwent a complete serum lipid profile, immunofluorescence analysis of colonic biopsies for MAPLC3 and myeloperoxidase expression, matched with clinical and anthropometric characteristics. Presence of adenomas correlated with cholesterol (total and LDL) levels, IL-6 levels, and MAPLC3 tissue expression, especially in the right colon. In conclusion, serum IL-6 amount and autophagic markers could be good predictors of the presence of colorectal adenomas.


2022 - Gender differences in Anxious-depressive symptomatology, Metabolic Syndrome and Colorectal Adenomas among outpatients undergoing colonoscopy: a cross-sectional study according to a PNEI perspective [Articolo su rivista]
Rioli, Giulia; Mattei, Giorgio; Bonamici, Caterina; Mancini, Stefano; Alboni, Silvia; Cannazza, Giuseppe; Sena, Paola; Roncucci, Luca; Pingani, Luca; Ferrari, Silvia; Galeazzi, Gian Maria
abstract


2022 - IL RUOLO DELL’INFIAMMAZIONE SISTEMICA CRONICA E DELLA VIA METABOLICA DELLE CHINURENINE NELLA COMORBIDITÀ TRA ANSIA, DEPRESSIONE E SINDROME METABOLICA: RISULTATI DI UNO STUDIO CROSS-SECTIONAL [Abstract in Atti di Convegno]
Rioli, Giulia; Bonamici, Caterina; Macini, Stefano; Mattei, Giorgio; Alboni, Silvia; Sena, Paola; Roncucci, Luca; Fiore, Gianluca; Pingani, Luca; Ferrari, Silvia; Galeazzi, Gian Maria
abstract


2022 - Il ruolo dell'infiammazione sistemica cronica e della via metabolica delle chinurenine nella comorbidilità tra ansia, depressione e sindrome metabolica: risultati di uno studio cross-sectional [Abstract in Rivista]
Rioli, G.; Bonamici, C.; Macini, S.; Mattei, G.; Alboni, S.; Sena, P.; Roncucci, L.; Fiore, G.; Pingani, L.; Ferrari, S.; Galeazzi, G. M.
abstract


2021 - Autoimmunity profiles as prognostic indicators in patients with colorectal cancer versus those with cancer at other sites: A prospective study [Articolo su rivista]
Sena, P.; Mancini, S.; Bertacchini, J.; Carnevale, G.; Pedroni, M.; Roncucci, L.
abstract

Colorectal cancer represents a paradigmatic model of inflammatory carcinogenesis accom-panied by the production of several kinds of tumor-associated autoantibodies (TAABs). The specific aim of this study is to define the clinical impact of the presence of non-specific circulating TAABs in a cohort of cancer patients and to establish whether significant differences were present between colorectal cancer and cancers at other sites. For this aim a prospective study was developed and a five-year survival analysis performed. Indirect immunofluorescence on rat tissues for non-organ specific autoantibodies (NOSAs: liver-kidney-stomach), on rat colon substrates (colon-related autoantibodies, CAAs) and on HEp-2 cell lines was performed. NOSA positivity was more frequent in patients with colorectal cancer than in those with cancer at other sites. Survival analysis demonstrated a significantly worse prognosis in cancer patients positive for TAABs. CAA positivity is a predictor of survival, independently from the presence of comorbidities, and HEp-2 reactivity was a strong predictor of survival in a stepwise Cox-regression model, including stage at diagnosis. Overall overproduction of TAABs is associated with advanced oncological disease, the presence of metastasis, and poorer prognosis of cancer patients.


2021 - Automated capture-based NGS workflow: one thousand patients experience in a clinical routine framework [Articolo su rivista]
Tenedini, E; Celestini, F; Iapicca, P; Marino, M; Castellano, S; Artuso, L; Biagiarelli, F; Cortesi, L; Toss, A; Barbieri, E; Roncucci, L; Pedroni, M; Manfredini, R; Luppi, M; Trenti, T; Tagliafico, E
abstract

Objectives: The Next Generation Sequencing (NGS) based mutational study of hereditary cancer genes is crucial to design tailored prevention strategies in subjects with different hereditary cancer risk. The ease of amplicon-based NGS library construction protocols contrasts with the greater uniformity of enrichment provided by capture-based protocols and so with greater chances for detecting larger genomic rearrangements and copy-number variations. Capture-based protocols, however, are characterized by a higher level of complexity of sample handling, extremely susceptible to human bias. Robotics platforms may definitely help dealing with these limits, reducing hands-on time, limiting random errors and guaranteeing process standardization.Methods: We implemented the automation of the CE-IVD SOPHiA Hereditary Cancer Solution (TM) (HCS) libraries preparation workflow by SOPHiA GENETICS on the Hamilton's STARlet platform. We present the comparison of results between this automated approach, used for more than 1,000 DNA patients' samples, and the performances of the manual protocol evaluated by SOPHiA GENETICS onto 240 samples summarized in their HCS evaluation study.Results: We demonstrate that this automated workflow achieved the same expected goals of manual setup in terms of coverages and reads uniformity, with extremely lower standard deviations among samples considering the sequencing reads mapped onto the regions of interest.Conclusions: This automated solution offers same reliable and affordable NGS data, but with the essential advantages of a flexible, automated and integrated framework, minimizing possible human errors and depicting a laboratory's walk-away scenario.


2021 - Automation of a capture-based NGS workflow: one thousand patients experience in a diagnostic clinical routine framework [Abstract in Rivista]
Tenedini, E.; Celestini, F.; Iapicca, P.; Marino, M.; Castellano, S.; Artuso, L.; Biagiarelli, F.; Cortesi, L.; Toss, A.; Barbieri, E.; Roncucci, L.; Pedroni, M.; Manfredini, R.; Luppi, M.; Trenti, T.; Tagliafico, E.
abstract


2021 - Preliminary results of a multidisciplinary italian study adopting a psycho-neuro-endocrine-immunological (Pnei) approach to the study of colorectal adenomas [Articolo su rivista]
Mancini, S.; Alboni, S.; Mattei, G.; Rioli, G.; Sena, P.; Marchi, M.; Sacchetti, A.; Boarino, V.; Roncucci, L.; Galeazzi, G. M.; Ferrari, S.
abstract

Background and aim of the work: Colorectal mucosal precancerous lesions, metabolic syndrome (MetS) and psychiatric disorders may share a common low-grade local and systemic inflammation. Aim is to report on preliminary data concerning a research adopting a psycho-neuro-endocrine-immune (PNEI) approach to study outpatients undergoing colonoscopy. Methods: A sample of patients undergoing colonosco-py was cross-sectionally investigated. Data on colorectal adenomas, MetS, early atherosclerosis, anxious-de-pressive symptoms, personality traits, and inflammatory markers were statistically analyzed. Results: Sixty-two patients were recruited (female 50%, mean age: 60.8±9.4 years). The prevalence of adenomas and MetS was respectively of 45.2% and 41.9%. Anxiety and depressive symptoms were detected in 16 (32.7%) and 9 (18.4%) subjects, respectively. The presence of adenomas positively correlated with male sex (p=0.01), age (p<0.01), IL-6 (p=0.03), hsCRP (p=0.04), and MetS (p=0.03); it was also associated with hsCRP concentra-tion (aOR=3.81, p=0.03). Conclusions: Proinflammatory atherogenic status, psychological traits, increased mucosal inflammation, and metabolic parameters may share a common a pathogenic mechanism, worth studying.


2021 - Risk factors in acute diabetic foot syndrome: analysis of 75 consecutive patients referred to a tertiary center in Modena, Italy [Articolo su rivista]
Maurantonio, M.; Gabrielli, F.; Castellano, C.; Carla, A.; Andreone, P.; Roncucci, L.
abstract

Aim: Diabetic foot syndrome (DFS) is a complication of diabetes in which the presence of infections, ulceration and/or destruction of deep tissue associated with neuropathy, peripheral atherosclerosis and comorbidity affect the prognosis, the need for limb amputation and quality of life. Purpose of the present study is to report the features of patients with acute DFS admitted to our Diabetic Foot Unit tertiary Center in 2019. Methods: In all patients admitted, the approach was performed through a multidisciplinary team (Diabetic Foot Care Team) and described in a specific diagnostic-therapeutic-assistance program. Criteria of inclusion were presence of sepsis and/or suspected osteomyelitis and/or critical limb ischemia. Clinical features and interventions performed were registered. Primary endpoints were mortality and amputation (major, minor). Secondary endpoints were length of hospitalization, type of revascularization and duration of antibiotic therapy. Results: Among 75 consecutive patients (mean age 70.9 years) enrolled, prevalence of acute DFS was higher among men (M/F 3:1). Poor glycemic control [mean hemoglobin A1c (HbA1c) 67.9 ± 22.3 mmol/mol], long duration of diabetes (mean 19 ± 16.3 years), high low-density lipoprotein-cholesterol (mean 89.5 ± 45.1 mg/ dL) and obesity (mean Body Mass Index 30.2 ± 7.6 kg/m2) were common. Diabetes-related complications as peripheral arterial disease (PAD) (76%), ischemic heart disease (48%), retinopathy (40.5%), hepatic steatosis (50%), heart failure (17.8%) were present. During hospitalization, 21 subjects (28.4%) underwent lower limb amputations (overall rate of major amputation 4%), and 41.3% underwent percutaneous angioplasty. Long period of hospitalization (18.4 ± 7.9 days) and prolonged antibiotic therapy (23.9 ± 15.9 days) were observed. Major amputation was associated with C-reactive protein > 6.5 mg/dL (P = 0.03), osteomyelitis (P = 0.001), prior insulin therapy (P = 0.015). Conclusions: Male sex, co-morbidity, PAD, systemic inflammation and poor glycemic control are major features of acute hospitalized DFS. An approach through a multidisciplinary team is recommended in order to treat vascular and extra-vascular complications aimed at reducing mortality and at improving quality of life.


2021 - The Combination of AHCC and ETAS Decreases Migration of Colorectal Cancer Cells, and Reduces the Expression of LGR5 and Notch1 Genes in Cancer Stem Cells: A Novel Potential Approach for Integrative Medicine [Articolo su rivista]
Paganelli, F.; Chiarini, F.; Palmieri, A.; Martinelli, M.; Sena, P.; Bertacchini, J.; Roncucci, L.; Cappellini, A.; Martelli, A. M.; Bonucci, M.; Fiorentini, C.; Ferri, I. H.
abstract

The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with im-munomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.


2019 - Deep learning techniques for detecting preneoplastic and neoplastic lesions in human colorectal histological images [Articolo su rivista]
Sena, P.; Fioresi, R.; Faglioni, F.; Losi, L.; Faglioni, G.; Roncucci, L.
abstract

Trained pathologists base colorectal cancer identification on the visual interpretation of microscope images. However, image labeling is not always straightforward and this repetitive task is prone to mistakes due to human distraction. Significant efforts are underway to develop informative tools to assist pathologists and decrease the burden and frequency of errors. The present study proposes a deep learning approach to recognize four different stages of cancerous tissue development, including normal mucosa, early preneoplastic lesion, adenoma and cancer. A dataset of human colon tissue images collected and labeled over a 10-year period by a team of pathologists was partitioned into three sets. These were used to train, validate and test the neural network, comprising several convolutional and a few linear layers. The approach used in the present study is ‘direct’; it labels raw images and bypasses the segmentation step. An overall accuracy of >95% was achieved, with the majority of mislabeling referring to a near category. Tests on an external dataset with a different resolution yielded accuracies >80%. The present study demonstrated that the neural network, when properly trained, can provide fast, accurate and reproducible labeling for colon cancer images, with the potential to significantly improve the quality and speed of medical diagnoses.


2019 - Personality traits and physical activity may be involved in colorectal carcinogenesis: preliminary data from a cross-sectional study on patients undergoing colonoscopy [Articolo su rivista]
Marchi, Mattia; Mattei, Giorgio; Mancini, Stefano; Roncucci, Luca; Galeazzi, Gian M.; Ferrari, Silvia
abstract

The preliminary results of a study aiming at assessing potential risk factors for carcinogenesis, including metabolic and inflammatory parameters, life-style, psychosocial and personality traits, according to a holistic approach are here reported and briefly described. The presence of at least one adenoma was significantly associated to the TCI Self Transcendence (ST) domain (OR=1.36, p=0.04) and to the absence of regular physical activity (OR=0.14, P=0.03), that may suggest pathways to definition of high risk for metabolic syndrome and carcinogenesis.


2019 - The Association Between Symptoms of Anxiety, Depression, and Cardiovascular Risk Factors: Results From an Italian Cross-Sectional Study [Articolo su rivista]
Rioli, Giulia; Tassi, Silvia; Mattei, Giorgio; Ferrari, Silvia; Galeazzi, Gian Maria; Mancini, Stefano; Alboni, Silvia; Roncucci, Luca
abstract

Cardiovascular diseases, anxiety, and depression are among the most frequent clinical conditions in the Western world, often in comorbidity. Evidence regarding a shared pathophysiology suggests a mediating role by chronic systemic inflammation. The aims of this study were to measure the association between anxiety and depressive symptoms, cardiovascular risk factors, and inflammatory markers. Outpatients aged 40 years or more undergoing colonoscopy after positive fecal occult blood test were enrolled; the following data were collected: body mass index, blood pressure, blood glucose, lipid profile, C-reactive protein (CRP) level, carotid thickness, Hospital Anxiety and Depression Scale, Temperament and Character Inventory, INTERdisciplinary MEDicine Self-Assessment, and 36-Item Short-Form Health Survey scores. Fifty-four patients were enrolled; 30.2% had anxiety symptoms, 18.9% depressive symptoms, and 9.4% concomitant anxiety-depressive symptoms. Anxiety symptoms were associated with low high-density lipoprotein levels. Depressive symptoms were associated with CRP levels, providing supporting evidence for the role of inflammation in the pathophysiology of depression.


2018 - LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells [Articolo su rivista]
Gibellini, L; Losi, L; De Biasi, S; Nasi, M; Lo Tartaro, D; Pecorini, S; Patergnani, S; Pinton, P; De Gaetano, A; Carnevale, G; Pisciotta, A; Mariani, F; Roncucci, L; Iannone, A; Cossarizza, A; Pinti, M.
abstract

Mitochondrial Lon protease (LonP1) is a multi-function enzyme that regulates mitochondrial functions in several human malignancies, including colorectal cancer (CRC). The mechanism(s) by which LonP1 contributes to colorectal carcinogenesis is not fully understood. We found that silencing LonP1 leads to severe mitochondrial impairment and apoptosis in colon cancer cells. Here, we investigate the role of LonP1 in mitochondrial functions, metabolism, and epithelial-mesenchymal transition (EMT) in colon tumor cells and in metastasis. LonP1 was almost absent in normal mucosa, gradually increased from aberrant crypt foci to adenoma, and was most abundant in CRC. Moreover, LonP1 was preferentially upregulated in colorectal samples with mutated p53 or nuclear β-catenin, and its overexpression led to increased levels of β-catenin and decreased levels of E-cadherin, key proteins in EMT, in vitro. LonP1 upregulation also induced opposite changes in oxidative phosphorylation, glycolysis, and pentose pathway in SW480 primary colon tumor cells when compared to SW620 metastatic colon cancer cells. In conclusion, basal LonP1 expression is essential for normal mitochondrial function, and increased LonP1 levels in SW480 and SW620 cells induce a metabolic shift toward glycolysis, leading to EMT.


2018 - Metformin induces apoptosis and alters cellular responses to oxidative stress in Ht29 colon cancer cells: Preliminary findings [Articolo su rivista]
Sena, P; Mancini, S; Benincasa, M; Mariani, Francesco; Palumbo, C; Roncucci, L
abstract

Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.


2018 - Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes [Articolo su rivista]
Ponz de Leon, Maurizio; Pedroni, Monica; Pezzi, Annalisa; Sulce, Blerta; Roncucci, Luca; Domati, Federica; Rossi, Giuseppina; Reggiani Bonetti, Luca
abstract

Objective: Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis. Material and Methods: Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis. They were informed of the cancer risk and surveillance was suggested. As controls, 113 nongene carriers (Mut−) in the same Lynch families were identified. Results: About one-fourth of the mutation carriers developed polyps, mostly adenomas; polyps were less (12%, p <.05) in Mut − subjects, and hyperplastic lesions were the prevalent histology. More polyps were detected in MLH1 vs. MSH2 mutation carriers. In Mut+, 21 malignant tumours developed in 14 carriers vs. 4 tumours in 3 patients among Mut− (p <.001). Tumours were mostly of the Lynch spectrum; however, three glioblastomas were developed, together with neoplasms of various organs (duodenum, thyroid, skin, lung and cervix). Mean age of tumour occurrence was 43.0 years in Mut + vs. 53.0 among Mut−. Conclusions: Cancer developed more often in Mut+, with no consistent difference between MLH1 and MSH2 carriers. More polyps (mostly adenomas) were detected in MLH1 carriers. The majority (13 of 21) of malignant tumours occurred in organs for which there is no recommended surveillance, and were lethal in three patients.


2017 - An Italian observational study on subclinical cardiovascular risk factors and depressive symptomatology. A suggestion for the potential utility of a sinergic cardio-psychiatric perspective [Abstract in Rivista]
Tassi, S.; Rioli, Giulia; Mattei, Giorgio; Mancini, Stefano; Alboni, Silvia; Roncucci, Luca; Sena, Paola; Mariani, Francesco; Marchi, Mattia; Fabbrizi, Andrea; Feltri, L.; Visentini, Chiara; Pollutri, Gabriella; Artoni, Cecilia; Saraceni, Serena; Galli, Giacomo; Spiga, Giulia; Minarini, Alessandro; Perrone, Daniela; Galletti, Martina; Giambalvo, Nina; Montardi, Giulia; Galeazzi, Gian Maria; Ferrari, Silvia
abstract

Introduction Growing evidence has been collected over the complex, intertwined pathophysiological connection among subclinical cardiovascular (CV) disease, i.e. atherosclerosis, systemic low pro-inflammatory states and psychiatric disorders/symptomatology (anxiety, depression), with controversial results. Aim Aim of this study was to investigate the possible link between subclinical CV risk factors (atherosclerosis), depressive symptoms, and inflammation. Methods Cross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C reactive protein), LPS (bacterial lipopolysaccharide), ultrasound carotid intima-media thickness (c-IMT). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13. Results The 54 patients enrolled were equally distributed by gender. CV risk factors were common in the study population, with 33 patients (61.11%) with hypertension, 14 (25.93%) with hyperglycaemia, 20 (37.4%) with hypertriglyceridemia, 19 (35.19%) with low HDL and 64.81% with overweight. High levels of PCR were found in 24 subjects (44.44%). Right c-IMT was increased in 26.41% of the sample, and 11.32% had an atheromatous plaque. Left c-IMT was increased in 24.53% of patients, with a plaque in 7.55% of them. Clinically relevant depressive symptoms were found in the 18.87% of the sample and were statistically significantly associated with PCR (OR = 28.63; P = 0.01). Conclusions Evidence contributing to the so-called “inflammation theory” of depression and supporting the association between mood and CV disorders was here collected, supporting the need for a multidisciplinary approach to the diagnosis and treatment of such conditions, assuming a clinically-translated PNEI (psycho-neuro-endocrino-immunological) perspective.


2017 - Attenuated adenomatous polyposis of the large bowel: Present and future [Articolo su rivista]
Roncucci, Luca; Pedroni, Monica; Mariani, Francesco
abstract

Attenuated adenomatous polyposis (AAP) is a poorly understood syndrome, that can be defined as the presence of 10-99 synchronous adenomas in the large bowel, and it is considered a phenotypic variant of familial adenomatous polyposis (FAP). This definition has the advantage of simplicity, but it may include sporadic multiple adenomas of the large bowel at an extreme, or FAP cases on the other side. AAP shows a milder phenotype than FAP, with an older age of onset of adenomas and cancer, and less frequent extracolonic manifestations. AAP may be diagnosed as a single case in a family or, less frequently, it may be present in other family members, and it shows distinct pattern of inheritance. In less than 50% of cases, it may be caused by adenomatous polyposis coli (APC) or MUTYH mutations, referred to as APC-associated polyposis, inherited as an autosomal dominant trait, or MUTYH - associated polyposis, which shows an autosomal recessive mechanism of inheritance, respectively. Surveillance should rely on colonoscopy at regular intervals, with removal of adenomas and careful histological examination. When removal of polyps is not possible or advanced lesions are observed, the surgical approach is mandatory, being subtotal colectomy with ileo-rectal anastomosis the treatment of choice. Studies on this syndrome are lacking, and controversies are still present on many issues, thus, other clinical and genetic studies are requested.


2017 - Attenuated polyposis of the large bowel: a morphologic and molecular approach [Articolo su rivista]
PONZ DE LEON, Maurizio; Pedroni, Monica; Roncucci, Luca; Domati, Federica; Rossi, Giuseppina; Magnani, Giulia; Pezzi, Annalisa; Fante, Rossella; Bonetti, Luca Reggiani
abstract

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex.


2017 - Cardiovascular risk factors, anxiety symptoms and inflammation markers: Evidence of association from a cross-sectional study [Abstract in Rivista]
Rioli, Giulia; Tassi, S.; Mattei, Giorgio; Alboni, Silvia; Mancini, Stefano; Artoni, Cecilia; Galletti, Martina; Giambalvo, Nina; Galli, Giacomo; Marchi, Mattia; Minarini, Alessandro; Montardi, Giulia; Perrone, Daniela; Pollutri, Gabriella; Roncucci, Luca; Saraceni, Serena; Spiga, Giulia; Visentini, Chiara; Galeazzi, Gian Maria; Ferrari, Silvia
abstract

Introduction Anxiety disorders and Cardiovascular (CV) diseases, among the most common disorders in Western World, are often comorbid. A chronic systemic inflammatory state might be a shared underlining pathophysiological mechanism. Aims To investigate the association between anxiety symptoms, CV risks factors and inflammatory markers in an outpatient sample. Methods Cross-sectional study. Inclusion criteria: outpatients aged ≥40 years, attending colonoscopy after positive faecal occult blood test, negative medical history for cancer. Collected data: blood pressure, glycaemia, lipid profile, waist circumference, BMI, PCR (C Reactive Protein), LPS (bacterial Lipopolysaccharide). Psychometric tests: HADS, TCI, IMSA, SF36. Statistical analysis performed with STATA13. Results Fifty four patients enrolled (27 males, 27 females). Sixteen patients (30.19%) were positive for anxiety symptoms. Thirty-three patients (61.11%) had hypertension, 14 (25.93%) hyperglycaemia and 64.81% were overweight, with frank obesity (BMI≥ 30) in 11 subjects (20.37%). Anxiety symptoms were associated with low hematic HDL values (OR = 0.01; P = 0.01) and high concentration of triglycerides (OR = 0.023; P = 0.02) at the multiple regression model. At the univariate logistic analysis, anxiety was associated with LPS (OR = 1.06; P = 0.04). Conclusions Further evidence over the epidemiological link between common mental disorders and CV diseases was collected, with possible hints on pathophysiology and causative mechanisms related to inflammation. The importance of screening for anxiety and depression in medical populations is confirmed. Suggestions on future availability of screening tools based on inflammatory-related indicators should be the focus of future research.


2017 - Myeloperoxidase expression in human colonic mucosa is related to systemic oxidative balance in healthy subjects [Articolo su rivista]
Mancini, Stefano; Mariani, Francesco; Sena, Paola; Benincasa, Marta; Roncucci, Luca
abstract

Objectives: To improve understanding of the preclinical stage of colonic inflammation by exploring the existence of a link between early inflammatory changes in the colonic mucosa and the systemic redox balance. Methods: Clinical characteristics, a fasting blood draw, and mucosal biopsies from the right, left, and sigmoid-rectum colonic tracts collected from 28 healthy individuals (14/14 males/females) who underwent colonoscopy. Myeloperoxidase (MPO) positive cells infiltrating colonic mucosa specimens were assessed by immunohistochemistry, and patients divided into high or low MPO expressing cells/optical field groups (MPOhighor MPOlow, respectively).The systemic oxidative balance has been studied through derived-Reactive Oxygen Metabolites (d-ROMs), Biological Antioxidant Potential (BAP), and Lipoperoxide-cholesterol Oxidizing (LP-CHOLOX) tests on serum. Results: MPOhighpatients demonstrated an increased systemic oxidative stress compared to MPOlowindividuals (P = 0.035), especially when MPO is referred to the left-sided colonic mucosa (P = 0.007). MPOlowsubjects in the sigmoid-rectum showed a significant higher antioxidant capacity in the serum (P < 0.02). Sex-specific differences in MPO expression (male and female: 4.6 ± 3.2 and 2.6 ± 1.5 MPO-positive cells/optical field, respectively, P = 0.044), and a decreasing gradient in MPO expression moving from the cecum to the rectum (ascendant, descendant, and sigmoid-rectum: 3.7 ± 2.8, 3.1 ± 1.7, and 1.4 ± 0.5, respectively, P = 0.012) were also found and discussed. Discussion: The study is the first demonstrating a connection between systemic redox balance and MPO expression in the colonic mucosa, according to the colonic tract and patient gender. Further research evaluating the MPO expression in the human colon and its relationship with pathological conditions could benefit from these results.


2017 - Myeloperoxidase-positive cell infiltration of normal colorectal mucosa is related to body fatness and is predictive of adenoma occurrence [Articolo su rivista]
Mariani, F.; Boarino, V.; Bertani, A.; Merighi, A.; Pedroni, M.; Rossi, G.; Mancini, S.; Sena, P.; Benatti, P.; Roncucci, L.
abstract

Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (±s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63±0.20 vs 2.06±0.18, P=0.03), and in subjects with BMI equal or above 25 kg m ' 2 (2.54±0.18 vs 1.97±0.20, P=0.03). A Cox proportional hazard model showed that mean MPO-positive cell count in normal colorectal mucosa was the only factor independently related to occurrence of adenomas in follow-up colonoscopies. Though preliminary, these results show that MPO-positive cell infiltration in normal colorectal mucosa is related with body fatness, as evaluated by WC and BMI, and it may be considered a useful and simple marker to estimate adenoma occurrence risk.


2017 - Prevalence of metabolic syndrome and of symptoms of anxiety and depression in patients undergoing colonoscopy [Abstract in Rivista]
Marchi, Mattia; Alboni, Silvia; Fabbrizi, Andrea; Feltri, L.; Galli, Giacomo; Guicciardi, Alessia; Mancini, Stefano; Mattei, Giorgio; Minarini, Alessandro; Perrone, Daniela; Rioli, Giulia; Roncucci, Luca; Sena, Paola; Ferrari, Silvia
abstract

Introduction Metabolic syndrome (MetS) is defined by metabolic and cardio-vascular impairments and is frequently associated with anxiety and depressive disorders. Both MetS and anxiety-depressive syndromes feature similar systemic inflammatory alterations. Inflammation of the large bowel is also a key factor for the development of colorectal cancer (CRC). Objective To measure the prevalence of MetS and symptoms of anxiety and depression among patients undergoing colonoscopy. Methods Cross-sectional study. Patients undergoing colonoscopy aged 40 or more, with negative history for neoplasia or inflammatory bowel disease, were enrolled. Data collected: colonoscopy outcome, presence/absence of MetS (IDF and ATP III criteria), presence/absence of depressive and anxiety symptoms assessed with HADS. Results The sample was made up of 53 patients (female 24, 45.3%). Mean age was 60.66 ± 9.08. At least one adenoma was found to 23 patients (43.3%). Prevalence of MetS ranged from 34% to 36% (ATP III and IDF criteria, respectively). Prevalence of depressive and anxiety symptoms was 20% and 33%, respectively. Conclusion Prevalence of MetS, anxiety and depressive symptoms among patients undergoing colonoscopy was higher than in the general population.


2017 - Role of the vanins-myeloperoxidase axis in colorectal carcinogenesis [Articolo su rivista]
Mariani, Francesco; Roncucci, Luca
abstract

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α.


2016 - Prognostic significance of the presence of circulating non-orga specific autoantibodies in a cohort of cancer patients: A five-year follow-up study [Abstract in Rivista]
Mancini, Stefano; Mariani, Francesco; Sena, Paola; Muratori, Paolo; Muratori, Luigi; Degli Esposti, Claudia; Roncucci, Luca
abstract

Serum non-organ specific autoantibodies are indicative of a worse prognosis in cancer patients


2016 - Role of metabolic, atherogenic and psychological factors in patients with colorectal adenomas [Abstract in Rivista]
Boarino, Valentina; Merighi, Alberto; Mancini, Stefano; Bertani, Angela; Marocchi, Margherita; Marsico, Maria; Olivetti, Giampiero; Primerano, Anna Maria; Mattei, Giorgio; Ferrari, Silvia; Roncucci, Luca; Villa, Erica
abstract

Some metabolic, atherogenic, and psychological risk factors are related to the growth of colorectal adenomas


2016 - Subclinical inflammation of colorectal mucosa is related to systemic oxidative balance in healthy adult subjects [Abstract in Rivista]
Mancini, Stefano; Mariani, Francesco; Sena, Paola; Benincasa, Marta; Roncucci, Luca
abstract

Oxidative balance is related to myeloperroxidase-positive cell count in normal colorectal mucosa


2015 - Autophagy is upregulated during colorectal carcinogenesis, and in DNA microsatellite stable carcinomas [Articolo su rivista]
Sena, Paola; Mariani, Francesco; Mancini, Stefano; Benincasa, Marta; Magnani, Giulia; Pedroni, Monica; Palumbo, Carla; Roncucci, Luca
abstract

Cancer cells are exposed to a wide range of stress sources, such as nutrient deprivation and hypoxia, as well as cytotoxic chemotherapy and radiotherapy. Certain forms of stress can also promote survival activating the metabolic autophagy pathway in cancer cells. Autophagy is dramatically increased in cancer cells. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. Its role in tumorigenesis is more controversial and both the presence and the absence of autophagy have been implicated. Autophagy is known to be associated with the poor outcome of patients with various types of cancers, and its effectiveness as a prognostic marker in colorectal cancer was demonstrated by several studies. The inhibition of autophagy may be a potential therapeutic target in colorectal cancer. In vitro experiments have shown that the inhibition of autophagy increases 5-FU-induced apoptosis. There are two trials currently investigating the addition of chloroquine to 5-FU-based chemotherapy and bevacizumab. In the present study, we evaluated the expression of LC3B-II in samples of human colorectal microadenomas (i.e., dysplastic aberrant crypt foci) and carcinomas compared to normal mucosa. Furthermore, the expression pattern of LC3B-II was assessed in carcinomas classified as DNA microsatellite stable (MSS) and unstable (MSI). Thus, immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments were performed. The results clearly showed a significant increase in expression of the autophagic key factor in microadenomas and carcinomas with respect to normal mucosa. In MSS carcinomas, the level of LC3B-II expression was higher than that in the MSI carcinomas.


2015 - Chemerin/chemR23 axis in inflammation onset and resolution [Articolo su rivista]
Mariani, Francesco; Roncucci, Luca
abstract

Chemerin is an adipokine secreted by adipocytes and associated with obesity, insulin resistance and metabolic syndrome. Different chemerin fragments with pro- or anti-inflammatory action can be produced, depending on the class of proteases predominating in the microenvironment. Chemerin binds to three receptors, especially to chemR23, expressed on various cells, as dendritic cells, macrophages and natural killer cells, regulating chemotaxis towards the site of inflammation and activation status. Recently, the chemerin/chemR23 axis has attracted particular attention for the multiple roles related to the control of inflammation, metabolism and cancerogenesis in different organs and systems as lung (allergy and cancer), skin (psoriasis, lupus, cancer, wound repair), cardiovascular system (lipid profile and atherosclerosis), reproductive apparatus (polycystic ovary syndrome, follicular homoeostasis), and digestive tract (inflammatory bowel diseases and cancer). This pathway may regulate immune responses by contributing both to the pathogenesis of inflammatory diseases and to the resolution of acute inflammation. Thus, chemerin-derived peptides or other substances that may affect the chemerin/chemR23 axis could be used in the future for the treatment of many diseases, including cancer at different sites.


2015 - High prevalence of fragility vertebral fractures in patients hospitalised in Internal Medicine Units. Results of the POINT (Prevalence of Osteoporosis in INTernal medicine) study [Articolo su rivista]
Vitali, Claudio; Gussoni, Gualberto; Bianchi, Gerolamo; Albanese, Carlina V.; Diacinti, Daniele; Sinigaglia, Luigi; Nuti, Ranuccio; Muzzulini, Carlo Lorenzo; Pintaudi, Carmelo; Scanelli, Giovanni; Magni, Giovanna; Valerio, Antonella; Iori, Ido; Mazzone, Antonino; Campanini, Mauro; Muzzulini, C. L.; Pintaudi, C.; Scanelli, G.; Grandi, M.; Sacchetti, C.; Pieralli, F.; D'Angelo, A.; Fazio, M.; Cagnoni, C.; Occhipinti, L.; Campanini, M.; Bobbio, F.; Mazzone, A.; Rondena, M.; Stefani, I.; Sgnaolin, E.; De Sandre, P.; Mattiello, K.; Vescovo, G.; Parisi, D.; Di Michele, D.; Zullo, A.; Stucchi, M.; Franchi, T.; Gasparini, M.; Gerini, S.; Landini, G.; Fattorini, L.; Roncucci, Luca; Mancini, Stefano; Paradiso, A.; Leandri, P.; Reta, M.; Nardi, R.; Vitali, C.; Palombi, G.; Frediani, R.; Traballi, G.; Andreoli, A.; Errico, M.; Molinaro, F.; Fusconi, L.; Tucci, V.; Nocera, M.; Zanardi, M.; Maselli, A.; Bulfoni, A.; Vitale, C.; Cipriani, M.; Montagnani, A.; Occhipinti, G.; Costantino, S.; Cortiggiani, M.; Porciello, G.; Anastasio, L.; Manno, V.; Massarelli, L.; Sposito, P.; Stobbione, P.; Tancredi, M.; Medico, P.; Giorgi, R.; Nuzzi, A. M.; Mauro, G.; Migliore, A.; Vacca, F.; Scarpato, S.
abstract

Background: Osteoporotic vertebral fractures (VFs) often go unrecognised in both healthy individuals and in pathological conditions. Few data exist on VFs in patients hospitalised in Internal Medicine Units (IMUs), who often suffer from multiple concomitant chronic disorders. Aim of the study: This multicentre cross-sectional study was aimed at assessing the prevalence of VFs in an unselected population of patients referring to IMUs. Correlations between VFs and the main coexisting diseases were also investigated. Methods: Information on demographic, clinical and laboratory findings, and on the presence of known risk factors for osteoporosis was recorded. The Genant's semi-quantitative method was used to evaluate, in a central reading centre, the presence and severity of VFs in the thoracic and lumbar spine. Results: A cohort of 995 patients was evaluated. At least one VF of any grade was found in 47.5% of patients, with similar prevalence between females (48.1%) and males (46.7%). Older age, chronic obstructive pulmonary disease, and previous diagnosis of osteoporosis showed a significant association with VFs in multivariable analysis. However, 79.7% of the VFs were observed in patients without previous diagnosis of osteoporosis. Moreover, a VF of grade 2 or greater was found in 20.8% of patients. Conclusions: Fragility VFs is a very frequent finding in patients hospitalised in IMUs. Consequently, more attention should be devoted in this clinical setting to this comorbidity, which is known to be an additional factor for mortality and, when localised in the thoracic part of the spine, may negatively influence a concomitant respiratory insufficiency.


2015 - Prevention of colorectal cancer: How many tools do we have in our basket? [Articolo su rivista]
Roncucci, Luca; Mariani, Francesco
abstract

Prevention is the main strategy in order to reduce colorectal cancer incidence and mortality. It can be accomplished through primary prevention, using measures affecting factors known to confer higher risk of colorectal cancer, or through secondary prevention, aimed at early diagnosis of cancer or preneoplastic lesions in groups of subjects at increased risk of cancer. Although primary prevention should be the goal for future years, because it acts on the probable causes of colorectal cancer, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the approaches which have yielded the most satisfying results, in terms of reduced mortality for cancer, are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of colorectal cancer. These groups are subjects aged 50 years or older, affected individuals (gene carriers) or family members of hereditary colorectal cancer syndromes (i.e., Lynch syndrome and familial adenomatous polyposis), and patients with inflammatory bowel diseases. The most effective procedures used, though with some drawbacks, are fecal occult blood tests and colonoscopy. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the population, and more cost-effective.


2014 - Incidence, clinical features and possible etiology of early onset (≤40 years) colorectal neoplasms. [Articolo su rivista]
Domati, Federica; Maffei, Stefania; Kaleci, Shaniko; Di Gregorio, C; Pedroni, Monica; Roncucci, Luca; Benatti, Piero; Magnani, Giulia; Marcheselli, Luigi; Bonetti, Lr; Mariani, Francesco; Alberti, Am; Rossi, V; PONZ DE LEON, Maurizio
abstract

The aim of the study was to investigate the clinical features, including survival, of patients with colorectal malignancies developed at a very early age (≤40 years), together with possible factors involved in the pathogenesis of these rare neoplasms. The study took advantage of the existence of a specialized colorectal cancer Registry active from 1984. 57 patients met the criteria of early onset cancer; main epidemiological data, morphology, stage, familial aggregation, possible role of inheritance and survival were analyzed. Despite the relevant increase over time of all registered patients, joiningpoint analysis of crude incidence rate of early onset colorectal neoplasms revealed a certain stability of these tumors (EAPC: 2.4, CI 14-22) with a constant prevalence of the male sex. Stage at diagnosis did not show significant variations between early onset and maturity onset colorectal neoplasms. Hereditary as well as familial cases were significantly (P &lt; 0.005 and 0.03) more frequent among patients with early onset tumors, although in the majority of them no specific etiological factor could be identified. Survival was more favorable in patients with early onset tumors, though this had to be attributed to the higher presence of some histological types in early onset cases. Survival was significantly more favorable for patients of all ages registered in the last decade. Incidence of early onset colorectal cancer was relatively stable between 1984 and 2008. A male preponderance was evident through the registration period. Hereditary and familial cases were significantly more frequent among early onset case. A well defined etiology could be observed in 16% of the cases (versus 2-3% in older individuals). Five-year survival showed a significant improvement over time.


2014 - Increased expression of autophagy-related proteins in human colorectal cancer development, and correlation with DNA Microsatellite Stable and Unstable [Abstract in Rivista]
Sena, Paola; Mancini, Stefano; Mariani, Francesco; Pedroni, Monica; Magnani, Giulia; Benincasa, Marta; Roncucci, Luca
abstract

Autophagy is upregulated during human colorectal carcinogenesis


2014 - Induction of altered cellular response to oxydative stress in HT29 colon cancer cells treated with metformin [Abstract in Rivista]
Sena, Paola; Mancini, Stefano; Mariani, Francesco; Pedroni, Monica; Benincasa, Marta; Roncucci, Luca
abstract

Metformin induces oxydative stress in HT29 colon cancer cells


2014 - Inflammatory pathways in the early steps of colorectal cancer development [Articolo su rivista]
Mariani, Francesco; Sena, Paola; Roncucci, Luca
abstract

Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal.


2014 - Italian cancer figures, report 2014: Prevalence and cure of cancer in Italy [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Arciprete, C; Artioli, Me; Autelitano, M; Baili, P; Balducci, C; Baracco, M; Baracco, S; Battisti, W; Bella, F; Bellatalla, C; Bellini, A; Belluardo, C; Benatti, P; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bordini, M; Bovo, E; Bozzani, F; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabrese, A; Calabretta, L; Caldarella, A; Candela, G; Cannone, G; Canu, L; Caparelli, M; Capocaccia, R; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cavalieri d'Oro, L; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Coviello, V; Crapanzano, G; Cremone, L; Crocetti, E; Cuccaro, F; Curatella, S; Cusimano, R; D'Alò, D; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Davini, C; De Dottori, M; De Angelis, R; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigili, E; Di Felice, E; di Grazia, L; Di Gregorio, C; di Norcia, R; Di Prima, A; Dinaro, Y; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, F; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Foschi, R; Francisci, S; Frasca, G; Frassoldi, E; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatta, G; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, Ma; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gigli, A; Gilardi, F; Giorgetti, S; Giorgi Rossi, P; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Le Rose, L; Leone, A; Leone, R; Lonati, F; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mallone, S; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Marchesi, C; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Merlo, E; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Negrino, L; Nemcova, L; Nicita, C; Ocello, C; Pala, F; Palumbo, M; Panciroli, E; Panico, M; Pannozzo, F; Pascucci, C; Pasolini, A; Pastore, G; Patriarca, S; Pedroni, M; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Pezzuto, L; Piffer, S; Pinon, M; Pinto, A; Pintori, N; Pirani, M; Pirino, D; Pironi, V; Ponz de Leon, M; Prandi, R; Prazzoli, R; Puleio, M; Puppo, A; Quarta, F; Quattrocchi, M; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ricci, P; Rinaldi, E; Rizzello, R; Rognoni, M; Rollo, Pc; Roncaglia, F; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossi, S; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacchetto, L; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Santucci, C; Scheibel, M; Sciacca, S; Sciacchitano, C; Sciacchitano, S; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Spinosa, S; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sutera Sardo, A; Tagliabue, G; Tamburo, L; Tamburrino, S; Taranto, V; Terracini, B; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A;
abstract

This Report intends to estimate the total number of people still alive in 2010 after cancer diagnosis in Italy, regardless of the time since diagnosis, and to project these estimates to 2015. This study is also aimed to estimate the number of already cured cancer patients, whose mortality rates have become undistinguishable from that of the general population of the same age and sex.


2014 - Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis. [Articolo su rivista]
Sena, Paola; Mariani, Francesco; Benincasa, Marta; PONZ DE LEON, Maurizio; Di Gregorio, C; Mancini, Stefano; Cavani, Francesco; Smargiassi, Alberto; Palumbo, Carla; Roncucci, Luca
abstract

The aim of the present study was to determine whether BCL6 is expressed during malignant transformation of the large bowel and to assess whether, and to what extent, immunoreactivity is related to the different stages of neoplastic progression. Samples of normal colorectal mucosa (n=22), microadenomas (n=22) and colorectal cancer (n=22), were analyzed by immunohistochemistry, immunofluorescence coupled with confocal microscopy and western blotting. Our results clearly outlined the marked increase occurring in both intensity and density of BCL6 protein expression in the normal mucosa-microadenoma-carcinoma sequence. Immunohistochemistry and immunofluorescence analyses showed that BCL6 is expressed at low levels in normal mucosa and increases in microadenoma and in cancer with statistical significance. These results were confirmed by western blotting data. The increasing expression of BCL6 in human colorectal cancer development suggests the involvement of BCL6 in tumor progression, from the earliest stages of carcinogenesis with significant increase in cancer. The enhanced understanding of the biological role of BCL6, previously shown to exert a key role in lymphomagenesis, may lead to a re-evaluation of this protein and may highlight the importance of performing further studies in order to identify novel therapeutic targets for colorectal cancer.


2013 - Clinical and molecular features of attenuated adenomatous polyposis in northern Italy. [Articolo su rivista]
PONZ DE LEON, Maurizio; Urso, Ed; Pucciarelli, S; Agostini, M; Nitti, D; Roncucci, Luca; Benatti, Piero; Pedroni, Monica; Kaleci, S; Balsamo, A; Laudi, C; Di Gregorio, C; Viel, A; Rossi, G; Venesio, T.
abstract

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10-99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. METHODS: During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. RESULTS: MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the "no mutation" group). Clinical features rendered the "no mutation" group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. CONCLUSIONS: AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30-40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.


2013 - Duodenal carcinoma in a 37-year-old man with Cowden/Bannayan syndrome. [Articolo su rivista]
PONZ DE LEON, Maurizio; Di Gregorio, C; Giunti, L; Roncucci, Luca; Pedroni, Monica; Tinca, Ac; Crucianelli, F; Tricarico, R; Genuardi, M.
abstract

A 37-year-old man was hospitalised because of anaemia and fatigue due to an infiltrating adenocarcinoma of the Treitz angle (duodenum), together with gastric, duodenal and colorectal polyps. After the operation, removal of colorectal lesions revealed the presence of ganglioneuromatosis of the large bowel. Further investigations showed lack of MLH1 protein expression and microsatellite instability in the duodenal neoplasm, while the gene was normally expressed in the polyps. MLH1 sequence and Multiple Ligation-dependent Probes Amplification analysis (from constitutional DNA) were normal. Analysis of the PTEN gene revealed the presence of a constitutional mutation (c.510 T&gt;A; p.Ser170Arg) which had been associated with the Cowden phenotype. Further detailed clinical investigations revealed macrocephaly (63cm), melanotic spots of the penis, small angiomas, millimetric trichilemmomas in the nose and multiple lipomas, which led to the diagnosis of Cowden/Bannayan disease. The unusual appearance of a duodenal carcinoma as the first symptom rendered the identification of the syndrome extremely difficult.


2013 - Italian cancer figures, report 2013: Multiple tumours [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Antonini, S; Artioli, Me; Autelitano, M; Balducci, C; Balottari, P; Baracco, M; Battisti, W; Bella, F; Bellatalla, C; Belluardo, C; Benatti, Piero; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bovo, E; Bozzani, F; Bozzeda, A; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabretta, L; Caldarella, A; Candela, G; Canu, L; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Carone, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Civaschi, A; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Cremone, L; Crocetti, E; Curatella, S; Cusimano, R; D'Alò, D; D'Angelo, S; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Dall'Acqua, M; Dalsasso, F; Davini, C; De Dottori, M; De Maria, V; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigli, E; Di Felice, E; di Grazia, L; Di Gregorio, C; Di Prima, A; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Frasca, G; Frassoldi, E; Frizza, J; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, M; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gilardi, F; Giorgetti, S; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Grandi, L; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Leone, A; Leone, R; Lonati, F; Lottero, B; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Nemcova, L; Nicita, C; Ocello, C; Paci, E; Pala, F; Palumbo, M; Panico, M; Pannozzo, F; Pascucci, C; Pastore, G; Patriarca, S; Pedroni, Monica; Pellegri, C; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Piffer, S; Pintori, N; Pirani, M; Pirino, D; Pironi, V; PONZ DE LEON, Maurizio; Prandi, R; Prazzoli, R; Preto, L; Puleio, M; Puppo, A; Quaglia, A; Quarta, F; Quattrocchi, M; Raho, Am; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ribaudo, M; Rinaldi, E; Ricci, P; Rizzello, R; Rollo, Pc; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Sandrini, M; Santucci, C; Scheibel, M; Schiacchitano, S; Sciacca, S; Sciacchitano, C; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sigona, A; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sardo, As; Tagliabue, G; Tamburo, L; Tamburrino, S; Tanzarella, M; Terracini, B; Tessandori, R; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A; Trapani, C; Tschugguel, B; Tumino, R; Usala, M; Vacirca, S; Valerio, O; Valla, K; Varvarà, M; Vasquez, E; Vassante, B; Vattiato, R; Vercelli, M; Vercellino, Pc; Vicentini, M; Villa, M; Vitale, F; Vital
abstract

OBJECTIVES: This collaborative study, based on data collected by the network of Italian association of cancer registries (AIRTUM), provides updated estimates on the incidence risk of multiple primary cancer (MP). The objective is to highlight and quantify the bidirectional associations between different oncological diseases. The quantification of the excess or decreased risk of further cancers in cancer patients, in comparison with the general population, may contribute to understand the aetiology of cancer and to address clinical follow-up. MATERIAL AND METHODS: Data herein presented were provided by AIRTUM population-based cancer registries, which cover nowadays 48% of the Italian population. This monograph utilizes the AIRTUM database (December 2012), considering all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to ICD-O-3. Non-melanoma skin cancer cases, cases based on death certificate only, cases based on autopsy only, and cases with follow-up time equal to zero were excluded. To define multiple primaries, IARC-IACR rules were adopted (http://www.iacr.com.fr/MPrules_july2004.pdf). Data were subjected to standard quality control procedures (described in the AIRTUM data management protocol) and specific quality control checks defined for the present study. A cohort of cancer patients was followed over time from first cancer diagnosis until the date of second cancer diagnosis, death, or the end of follow-up, to evaluate whether the number of observed second cancer cases was greater than expected. Person years at risk (PY) were computed by first cancer site, geographic area (North, Centre, South and Islands), attained age, and attained calendar-year group. All second cancers diagnosed in the cohort's patients were included in the observed numbers of cases. The expected number of cancer cases was computed multiplying the accumulated PY by the expected rates, calculated from the AIRTUM database stratified by cancer site, geographic area, age, and calendar-year group. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cancer cases. The Excess Absolute Risk (EAR) beyond the expected amount were calculated subtracting the expected number of subsequent cancers from the observed number of cancer cases; the difference was then divided by the PY and the number of cancer cases in excess (or deficit) was expressed per 1,000 PY. Confidence intervals were stated at 95%. The two months (60 days) after first cancer diagnosis were defined as "synchronicity period", and in the main analysis observed and expected cases during this period were excluded. It was estimated the excess risk in the period after first diagnosis (≥ 0 months), excluding the synchronicity period (≥ 2 months), and during the following periods: 2-11, 12-59, 60-119 and 120 months after diagnosis. First-cancer-site-and-gender-specific sheets are presented, reporting both SIRs and EARs. RESULTS: For 5,979,338 person-years a cohort of 1,635,060 cancer patients (880,361 males and 754,699 females) diagnosed between 1976 and 2010 was followed. The mean follow-up length was 14 years. Overall, 85,399 metachronous (latency ≥2 months) cancers were observed, while 77,813 were expected during the study period: SIR: 1.10 (95%CI 1.09-1.10), EAR: 1.32 x 1,000 person-years (95%CI 1.19 - 1.46). The SIR was 1.08 (95%CI 1.08-1.09) for men (54,518 observed and 50,260 expected) and 1.12 (95%CI 1.11-1.13) for women (30,881/27,553), and the EAR 1.61 (95%CI 1.37-1.84) and 1.08 x 1,000 person-years (95%CI 0.93-1.24), respectively.Moreover, during the first two months after first cancer diagnosis (synchronous period) 14,807 cancers were observed while 3,536 were expected (SIR: 4.16; 95%CI 4.09-4.22); the SIR was 4.08 (95%CI 4.00-4.16) for men and 4.32 (95%CI 4.20-4.45) for women.The mean age of patients at first cancer diagnosis was 67.0 years among males and


2013 - PLZF expression during colorectal cancer development and in normal colorectal mucosa according to body size, as marker of colorectal cancer risk. [Articolo su rivista]
Mariani, Francesco; Sena, Paola; Magnani, Giulia; Mancini, Stefano; Palumbo, Carla; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Promyelocytic leukemia zinc finger protein (PLZF) is a protein involved in various signaling, growth regulatory, and differentiation pathways, including development/function of some T cells. Here, we aimed at the detection of PLZF during colorectal carcinogenesis, using immunofluorescence, and at the evaluation of the colocalization of PLZF with CD2 and CD56 positive cells (T, γδ, NK, and NKT cells), using confocal-microscopy, along colorectal carcinogenesis, since its earliest stages, that is, dysplastic aberrant crypt foci (ACF). Furthermore, we analyzed PLZF in the normal colonic mucosa (NM) according to anthropometric parameters of the subject. NM exhibited strong CD56 fluorescent staining. This infiltration was lost in both ACF and colorectal carcinoma (CRC), while PLZF presence increased from NM to ACF and CRC. Strong association was found between CD56+ colonic mucosa cell infiltration and body mass index. Interestingly, an increased stromal PLZF-reactivity was present in NM of obese subjects. This study shows that overexpression of PLZF and exclusion of NK cells in dysplastic microenvironment are very early events in the stepwise sequence leading to CRC and that lower levels of CD56+ cells in NM, together with increased levels of PLZF+ cells, can be a reflection of colon cancer risk due to obesity.


2013 - Th Inducing POZ-Kruppel Factor (ThPOK) Is a Key Regulator of the Immune Response since the Early Steps of Colorectal Carcinogenesis [Articolo su rivista]
Mariani, Francesco; Sena, Paola; Pedroni, Monica; Benatti, Piero; Manni, Paola; Di Gregorio, C; Manenti, Antonio; Palumbo, Carla; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

We purposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity in colorectal carcinogenesis. The amounts of CD4+, CD8+ and CD56+ and ThPOK+ cells infiltrate in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA), the earliest detectable lesions in colorectal carcinogenesis, and in colorectal carcinomas (CRC), were measured, and the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, in carcinomas, too. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development, decreasing the immune response against cancer cells.


2012 - Italian cancer figures, report 2011: survival of cancer patients in italy. [Curatela]
AIRTUM Working, Group; Roncucci, Luca
abstract

AIRTUM Working Group


2012 - Matrix metalloproteinases 15 and 19 are stromal regulators of colorectal cancer development from the early stages [Articolo su rivista]
Sena, Paola; Mariani, Francesco; Marzona, Laura; Benincasa, Marta; PONZ DE LEON, Maurizio; Palumbo, Carla; Roncucci, Luca
abstract

Matrix metalloproteinases (MMPs) have been well characterized for their ability to degrade extracellular matrix proteins and, thus, they have been studied to elucidate their involvement in both tumor development and progression. In the present study, attention was focused on MMP-15 and MMP-19, two less known members of the MMP family. The expression profile of MMP-15 and -19 was assayed in samples of normal colorectal mucosa, microadenomas and cancer using confocal analysis, western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Both qRT-PCR and western blotting showed that MMP-15 and MMP-19 appeared to be upregulated during colorectal tumorigenesis, with different expression patterns: MMP-15 expression level increases from normal mucosa to microadenomas, with a reduced level in cancer with respect to microadenomas; the semiquantitative immunofluorescence analysis showed a stromal localization of this protein in the early phases of neoplastic transformation. Increasing amount of MMP-19 mRNA and protein levels were observed in the progression of colonic lesions; MMP-19 staining increased in the normal mucosa-microadenoma-carcinoma sequence. Such different expression patterns, are probably due to the different roles played in colorectal tumorigenesis by these two molecules. Conflicting data on the role of these proteins in tumor progression have been reported, thus, an improved understandingof the biological roles of MMPs, in particular the lesser known members such as MMP-15 and 19, in colorectal cancer may lead to a re-evaluation of the use of MMP inhibitors and suggests the need of integrated translational studies on MMP expression patterns.


2012 - Overweight, inflammation of normal colorectal mucosa, and cancer risk [Abstract in Rivista]
Roncucci, Luca; Mariani, Francesco; Sena, Paola; Palumbo, Carla; Pedroni, Monica
abstract

Myeloperoxidase-positive cell infiltration of normal colorectal mucosa is related to body fatness and colorectal cancer risk.


2012 - Prevalence of differentiated thyroid cancer is relevant in patients with familial adenomatous polyposis: a case-control, prospective study [Abstract in Rivista]
Diazzi, Chiara; Benatti, Piero; Zirilli, Lucia; Gnarini, Valentina; Madeo, Bruno; Romano, Stefania; Rossi, Giuseppina; Carani, Cesare; PONZ DE LEON, Maurizio; Roncucci, Luca; Rochira, Vincenzo
abstract

Studio sulla prevalenza dei tumori differenziati della tiroide in pazienti con poliposi adenomatosa famigliare. Lo studio ha permesso di stabilire che la prevalenza di tumori della tiroide è aumentata in questi pazienti in confronto alla popolazione normale.


2012 - Proposed roles of the immune response regulator-ThPOK in human colorectal cancer progression [Abstract in Rivista]
Sena, Paola; Mariani, Francesco; Roncucci, Luca; Benincasa, Marta; PONZ DE LEON, Maurizio; Palumbo, Carla
abstract

Solid tumours are commonly infiltrated by several immune cells [1-3]. In cancer, immune cells play conflicting roles with both the potentials to eliminate or to promote malignancy. In contrast to infiltration of cells responsible for chronic inflammation, the presence of high numbers of lymphocytes, especially T cells, has been reported to be important as indicator of good prognosis in many types of cancer [4-7]. The thorough knowledge of both manners and pathways with which tumors are able to evade immune-mediated attack, once established, is therefore of crucial importance. The strategies to escape anti-tumor immune responses include the limited priming or differentiation of antitumor T cells and the role of tumor microenvironment in order to prevent infiltration or activation of effector phase functions. We proposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity during colorectal carcinogenesis. Data were collected on the amounts of CD4+, CD8+ and CD56+ as well as on ThPOK+ cells infiltrated in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA, the earliest detectable lesions in colorectal carcinogenesis) and in colorectal carcinomas (CRC); moreover, the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, also in carcinomas. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development. The novelty of the present study is the proposed role of ThPOK in influencing the immune response against cancer cells. References [1] Dunn et al. (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21: 137-148. [2] Knaapen et al. (2006) Neutrophils and respiratory tract DNA damage and mutagenesis: a review. Muta-genesis 21: 225-236. [3] Coussens and Werb (2002) Inflammation and cancer. Nature 420: 860-867. [4] Watt and House (1978) Colonic carcinoma: a quantitative assessment of lymphocyte infiltration at the periphery of colonic tumors related to prognosis. Cancer 41: 279-282. [5] Galon et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960-1964. [6] Pagès et al. (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27: 5944-5951. [7] Mlecnik et al. (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal. Gastroenterology 138: 1429-1434.


2011 - EXPRESSION PROFILES OF MATRIX METALLOPROTEINASES 15 AND 19 IN HUMAN COLORECTAL CARCINOGENESIS [Abstract in Rivista]
Sena, Paola; Mariani, Francesco; Marzona, Laura; Roncucci, Luca; Palumbo, Carla
abstract

INTRODUCTION: The matrix metalloproteinases (MMPs) have been well characterized for their ability to degrade extracellular matrix proteins and thus they have been extensively studied to elucidate their involvement in both tumour development and progression. In the present study the attention were focused on two members of MMP family, i.e. MMP-15 and MMP-19.METHODS: The expression profile of MMP-15 and 19 were assayed from samples of normal mucosa, microadenomas and cancer using confocal analysis, Western blotting and quantitative reverse transcription polymerase chain reaction (Q-PCR).RESULTS: The semiquantitative immunofluorescence analysis showed that MMP-15 expression level increases from normal mucosa to microadenomas, with a reduced level in cancer respect to microadenomas, while MMP-19 staining increases in normal mucosa-microadenoma-carcinoma sequence.Both Q-PCR and Western blot methods correlate with immunofluorescence behaviour of MMP-15 and 19, showing a significantly higher expression of MMP-15 in microadenomas compared to normal mucosa, and indicating an increasingly amount of MMP-19 levels in the progression of colon lesions.CONCLUSIONS: MMP-15 and 19 appear to be up-regulated during tumorigenesis, with different expression patterns, that are probably due to the different roles played by these two molecules. The literature up to now reported show conflicting data regarding the role of these proteins in tumor progression so that the improved understanding of the biological roles of MMPs in colorectal cancer should lead to a re-evaluation of the use of MMP inhibitors and highlight the importance of integrated translational studies on the MMP expression patterns.


2011 - I numeri dell'AIRTUM: I giovani italiani che convivono con un tumore sono quasi duecentomila [AIRTUM numbers: 200,000 young Italians live with cancer] [Articolo su rivista]
Dal Maso, L; De Angelis, R; Guzzinati, S; AIRTUM Working, Group; Roncucci, Luca
abstract

no abstract


2011 - I tumori in Italia. Rapporto 2011: La sopravvivenza dei pazienti oncologici in Italia [Articolo su rivista]
Fusco M, AIRTUM Working G. r. o. u. p.; Buzzoni, C; Coviello, E; Rashid, I; Bianconi, F; Cuccaro, F; Castaing, M; De Angelis, R; Giacomin, A; Guzzinati, S; Mosso, Ml; Pisani, P; Quaglia, A; Randi, G; Ramazzotti, V; Russo, A; Senatore, G; Stracci, F; Traina, A; Vercelli, M; Zarcone, M; Ferretti, S; Mazzoleni, G; Bellú, F; Tschugguel, B; De Valiere, E; Facchinelli, G; Falk, M; Dal Cappello, T; Vercellino, Pc; Andreone, S; Busato, A; Marzola, L; Migliari, E; Carletti, N; Nenci, I; Crocetti, E; Caldarella, A; Corbinelli, A; Giusti, F; Intrieri, T; Manneschi, G; Nemcova, L; Romeo, G; Sacchettini, C; Zappa, M; Paci, E; Serraino, D; Angelin, T; Bidoli, E; Dal Maso, L; de Dottori, M; De Paoli, A; De Santis, E; Forgiarini, O; Lise, M; Zucchetto, A; Zanier, L; Orengo, Ma; Casella, C; Marani, E; Puppo, A; Celesia, Mv; Cogno, R; Manenti, S; Garrone, E; Pannozzo, F; Busco, S; Cercato, Mc; Battisti, W; Sperduti, I; Macci, L; Bugliarello, E; Bernazza, E; Tamburo, L; Rossi, M; Curatella, S; De Francesco, C; Tamburrino, S; Bisanti, L; Autelitano, M; Ghilardi, S; Leone, R; Filipazzi, L; Bonini, A; Giubelli, C; Federico, Massimo; Artioli, Me; Valla, K; Braghiroli, B; Cirilli, C; Luminari, Stefano; Pirani, M; Ferrari, L; Bellatalla, C; Fusco, M; Panico, M; Perrotta, C; Vassante, B; Vitale, Mf; Michiara, M; Bozzani, F; Sgargi, P; Tumino, R; La Rosa, Mg; Cascone, G; Frasca, G; Giurdanella, Mc; Martorana, C; Morana, G; Nicita, C; Rollo, Pc; Ruggeri, Mg; Sigona, A; Spata, E; Vacirca, S; Mangone, L; Di Felice, E; Pezzarossi, A; Caroli, S; Pellegri, C; Vicentini, M; Storchi, C; Cavuto, S; Costa, J; Falcini, F; Colamartini, A; Bucchi, L; Balducci, C; Ravegnani, M; Vitali, B; Cordaro, C; Caprara, L; Giuliani, O; Giorgetti, S; Salvatore, S; Palumbo, M; Vattiato, R; Ravaioli, A; Foca, F; Rinaldi, E; Mancini, S; Tonelli, C; Amadori, M; Cremone, L; Iannelli, A; Zevola, A; Budroni, M; Cesaraccio, R; Pirino, D; Carboni, D; Fiori, G; Soddu, M; Mameli, G; Mura, F; Contrino, Ml; Madeddu, A; Tisano, F; Sciacca, S; Muni, A; Mizzi, M; Russo, M; Sacco, G; Aletta, P; Colanino Ziino, A; Tessandori, R; Fanetti, Ac; Maspero, S; Annulli, Ml; Moroni, E; Sanoja Gonzalez, Me; Zanetti, R; Rosso, S; Patriarca, S; Prandi, R; Sobrato, I; Gilardi, F; Busso, P; Piffer, S; Gentilini, Ma; Battisti, L; Rizzello, R; Cappelletti, M; Moser, M; La Rosa, F; D'Alò, D; Scheibel, M; Costarelli, D; Spano, F; Rossini, S; Santucci, C; Petrinelli, Am; Solimene, C; Brunori, V; Crosignani, P; Tagliabue, G; Contiero, P; Preto, L; Tittarelli, A; Maghini, A; Codazzi, T; Frassoldi, E; Gada, D; Costa, E; di Grazia, L; Zambon, P; Baracco, M; Bovo, E; Dal Cin, A; Fiore, Ar; Greco, A; Monetti, D; Rosano, A; Stocco, C; Tognazzo, S; Donato, F; Limina, Rm; Adorni, A; Andreis, P; Zani, G; Piovani, F; Salvi, O; Puleio, M; Vitarelli, S; Antonini, S; Candela, G; Pappalardo, G; Scuderi, T; Lottero, B; Ribaudo, M; Ricci, P; Guarda, L; Gatti, L; Bozzeda, A; Dall'Acqua, M; Pironi, V; Sutera Sardo, A; Mazzei, A; Sirianni, N; Lavecchia, Am; Mancuso, P; Usala, M; Pala, F; Sini, Gm; Pintori, N; Canu, L; Demurtas, G; Doa, N; PONZ DE LEON, Maurizio; Domati, Federica; Rossi, Giuseppina; Goldoni, Ca; Rossi, F; De Gaetani, C; Benatti, Piero; Roncucci, Luca; Di Gregorio, C; Pedroni, Monica; Pezzi, A; Maffei, Stefania; Mariani, Francesco; Borsi, E; Carruba, G; Cusimano, R; Amodio, R; Dolcemascolo, C; Staiti, R; Pastore, G; Magnani, C; Terracini, B; Cena, T; Alessi, D; Baussano, I; Merletti, F; Maule, M; Macerata, V; Cocchioni, M; Pascucci, C; Gennaro, V; Lazzarotto, A; Benfatto, L; Mazzucco, G; Montanaro, F.
abstract

INTRODUCTION: population-based survival analyses are fundamental to assess the impact of public health interventions and new therapies in cancer control. This monograph updates previous reports on cancer patient survival in Italy up to the year 2007. MATERIAL AND METHODS: we extracted from the Network of Italian Cancer Registries (AIRTUM) database over 1,490,000 records of tumours diagnosed during 1990-2007 and followed up to the end of 2008, including all multiple tumours. We used the Ederer II method to estimate relative survival (RS) for 29 different types of neoplasm. Five-year relative survival rates were analysed by gender and macroarea. Trends in 5-, 10- and 15-year RS were studied by gender over six 3-year diagnostic periods, from 1990 to 2007. Conditional 5-year RS was also computed by gender and macroarea. Hybrid approaches were applied to exploit the recent survival experiences of cases diagnosed up to 2007. Adjustment for age was performed using EUROCARE weights. Additional sections describe cancer patient survival in childhood and in elderly patients and provide a comparison of cancer patient survival rates in Italy with those of other countries. RESULTS: Standardized 5-year RS for all tumours but skin in 52% for men and 61% for women. Patient survival has improved for almost all types of cancer: from 1990 to 2007 5-year RS has increased by 15% for all cancers but skin; the exceptions are some cancers with poor prognosis, where patient survival has remained basically unchanged. In males, RS was usually lower than in females, but trend analysis shows that the gap is narrowing. We also report persisting lower RS in southern Italy: 5-year RS in the South is usually from 4% to 10% lower than in the North and Centre. CONCLUSION: this study provides valuable information for all stakeholders in cancer control, both in Italy and elsewhere. Increasing survival reflects improvements in various areas of cancer control. On the other hand, delayed diagnosis and suboptimal management are consistent with the reported differences in survival within the country.


2011 - Long-term survey of patients with curable colorectal cancer with specific reference to the quality of life. [Articolo su rivista]
Domati, Federica; Rossi, Giuseppina; Benatti, Piero; Roncucci, Luca; Cirilli, C; PONZ DE LEON, Maurizio
abstract

Colorectal cancer can be a painful event, generally associated with changes in lifestyle for many patients. We studied the quality of life of the patients operated for colorectal malignancies 5 years after the diagnosis. Using detailed questionnaires, we investigated 220 patients of both sexes (mean age 66.5 years) 5 years (or more) after a curative operation for cancer of the large bowel. The short form 36 (SF-36) questionnaire took into consideration several aspects concerning work activity, physical activity, psychological attitude, alimentation, familial relationships, and other relevant components of lifestyle. Moreover, we compared the perception of the so-called SF-36 score between our patients and a comparison group in the general population. Both univariate and multivariate analysis were used. The obtained results revealed that familial and social relations were equally unchanged or tended to improve. Sexual activity declined in only 61(31.3%) subjects. Rather surprisingly (because of the average age at diagnosis), work activity remained unchanged in about half of the patients. Using the SF-36 questionnaire, the main differences from the general Italian population were seen in bodily pain (especially in the few individuals in whom a permanent stoma was necessary), social functioning and general physical health. In conclusion the results seem to suggest that the majority of patients who survive for more than 5 years after an operation for colorectal malignancy return to an almost normal life. The awareness among individuals about their disease, the improvements in surgical techniques and medical treatments are among the factors responsible for these positive results.


2011 - Lymph node micrometastasis and survival of patients with Stage I (Dukes' A) colorectal carcinoma. [Articolo su rivista]
REGGIANI BONETTI, Luca; Di Gregorio, C; DE GAETANI, Carmela; Pezzi, A; Barresi, G; Barresi, V; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Objective. Although patients with Stage I colorectal cancer show an excellent prognosis, a few of them die of metastatic disease. In this subgroup of individuals, the search of occult metastasis might reveal that early dissemination of tumor cells could be the cause of cancer progression. Material and methods. Through a Cancer Registry, we selected all patients with Stage I disease who died of metastatic tumor; a total of 32 patients were identified and in 25 of them paraffin-embedded material was available. The group was matched to 70 Stage I patients with favorable prognosis (controls). In cases and controls resected lymph nodes were cut, and micrometastases were searched using pan-cytokeratin antibodies. Results. Micrometastases were detected in 18 of 25 (72%) Stage I patients who died of the disease, while they were almost absent among controls (1 of 70, p < 0.001 by χ2 test). Vascular invasion and tumor budding were more frequent among Stage I patients with an unfavorable prognosis than in controls. By regression analyses, micrometastases (HR 12.3, CI 4.8–32) and vascular invasion (HR 3.5, CI 1.4–8.5) maintained an independent association with prognosis (cancer-specific survival). Conclusion. Micrometastasis in the lymph nodes can be revealed in the majority of patients with early colorectal cancer who die of tumor progression, while they appear extremely rare in Stage I individuals with good prognosis. The selection of patients through histology (vascular invasion) and search of occult metastatic cells might represent a way to identify individuals who might benefit from adjuvant chemotherapy.


2011 - Primary adrenal gland carcinosarcoma associated with metastatic rectal cancer: a hitherto unreported collision tumor [Articolo su rivista]
Bertolini, F; Fiocchi, Federica; Giacometti, Marco; Fontana, A; Giberti, Mc; Roncucci, Luca; Luppi, G; Torricelli, Pietro; Rossi, Aldo; Conte, Pierfranco
abstract

A collision tumor between renal cancer and adrenal carcinoma is described


2011 - Quantification and localization of matrix metalloproteinases (MMP15 and MMP19) in human colorectal carcinogenesis. [Abstract in Rivista]
Sena, Paola; Mariani, Francesco; Marzona, Laura; Roncucci, Luca; Palumbo, Carla
abstract

Matrix metalloproteinases (MMPs) are capable of degrading all kinds of extracellular matrix proteins, but they also can process a number of other bioactive molecules. They are well known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (as FAS ligand) and chemokine/cytokine activation/de-activation. MMPs are also thought to play a pivotal role on cell processes like proliferation, migration (adhesion/dispersion), differentiation, apoptosis and host defence; thus they have been extensively studied to elucidate their involvement in both tumour development and progression. In the present study the attention was focused on two members of MMP family, i.e. MMP-15 and MMP-19, not jet well investigated as far as their role is concerned in the onset of colorectal neoplastic pathologies.The expression profile of MMP-15 and MMP-19 was assayed from samples of: a) normal mucosa, b) microadenomas and c) cancer, using confocal analysis, Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blot and qRT-PCR showed that MMP-15 expression level increases from normal mucosa to microadenomas, with a reduced level in cancer respect to microadenomas. The semiquantitative immunofluorescence analysis correlate with these data showing a localization exclusively at the stromal level of this protein, suggestive of an important role of stromal compartment, especially in the early phases of neoplastic transformation.Increasingly amount of MMP-19 mRNA and protein levels were instead recorded in the progression of colon lesions both in epithelial and stromal compartments. MMP-19 staining increases in parallel to normal mucosa ® microadenoma® carcinoma sequence; in particular this protein was showed to be expressed at the epithelial level only at the end of the sequence, indicating an intriguing epithelial involvement of MMP-19 production only in the late stages of carcinogenesis.In conclusion, MMP-15 and MMP-19 appear to be up-regulated during tumorogenesis, with different expression patterns, which in turn are probably due to the different roles played by these two molecules. The results reported up to now in literature show conflicting data regarding the specific role of these proteins in tumour progression so that the improved understanding of the biological roles of MMPs in colorectal cancer suggests a re-evaluation of the use of MMP inhibitors and highlights the importance of integrated translational studies on the MMP expression patterns.


2010 - Altered Expression of Apoptosis Biomarkers in Human Colorectal Microadenomas [Articolo su rivista]
Sena, Paola; Roncucci, Luca; Marzona, Laura; Mariani, Francesco; Maffei, Stefania; Manenti, Antonio; DE POL, Anto
abstract

Human colorectal microadenomas are considered the earliest detectable premalignant lesions in the colon. They can be identified as aggregates of enlarged crypts with thicker epithelial linings and elongated luminal openings on the colonic mucosal surface after methylene blue staining and observation under a dissecting microscope. Multiple lines of evidence suggest that a central role in neoplastic development is played by the inhibition of apoptosis, followed by disruption of DNA repair. Understanding the early mechanisms of colorectal carcinogenesis may help develop new approaches of colorectal cancer prevention and treatment. The aim of the present study was to quantify poly-ADP ribose polymerase 1 (PARP-1)-positive cells and to evaluate apoptotic control mechanisms through Caspase-3 active and Bcl-2 protein expression in human microadenomas and in normal colorectal mucosa using immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments. The mean percentage of PARP-1-positive epithelial cells was 3.0 +/- 0.37% (SD) and 15.67 +/- 0.40% in microadenoma and in normal mucosa, respectively. Proteins involved in programmed cell death were differently expressed in microadenoma and in normal mucosa. Indeed, by semiquantitative immunoflourescence analysis, confirmed byWestern blot, microadenoma showed high levels of Caspase-3 active and low levels of Bcl-2 expression, whereas the opposite was true for normal colorectal mucosa. In the stroma of normal colorectal mucosa, fibroblast-like cells and neutrophils were the cells that underwent apoptosis to a greater extent. In conclusion, malfunction of the control mechanisms of programmed cell death seems present in the early stages of colorectal cancer development. Cancer Epidemiol Biomarkers Prev; 19(2); 351-7. (C) 2010 AACR.


2010 - Altered expression of apoptosis biomarkers in human colorectal microadenomas (Cancer Epidemiology, Biomarkers & Prevention (2010) 19, (351-357)) [Articolo su rivista]
Sena, P.; Roncucci, L.; Marzona, L.; Mariani, F.; Maffei, S.; Manenti, A.; De Pol, A.
abstract


2010 - Clinical features and colorectal cancer survival: an attempt to explain differences between two different Italian regions. [Articolo su rivista]
Fusco, M; Pezzi, A; Benatti, Piero; Roncucci, Luca; Chiodini, P; Di Maio, G; Di Napoli, R; PONZ DE LEON, Maurizio
abstract

AIMS OF THE STUDY AND METHODS: Recent studies suggested the existence of significant regional variations, in Italy, for cancer survival. For most neoplasms, survival rates tended to be lower in Southern regions versus Northern areas; for colorectal tumours, 5-year survival was 60% in Northern regions, but ranged between 40% and 50% in the South. Main purpose of the present study was to find out possible reasons which might explain such differences. To reach this objective, we compared the main epidemiological and clinical data in two areas covered by cancer registration: Modena, in the North, and Naples in the South of Italy.RESULTS: The results of the study suggest that differences in colorectal cancer survival can be mainly attributed to a different stage at diagnosis, which was less favourable in a larger fraction of cases diagnosed in Southern Italy. This could be the consequence of an insufficient diffusion of screening procedures. Type of surgery, medical treatment and follow-up seem to play little or no role. The study also shows that incidence rates of colorectal cancer are significantly higher in the North than in the South of the country, and that the excess of cases seen in Modena is limited to the age group 55-75+ years, while age-specific incidence is virtually identical in the younger age classes.CONCLUSION: This high-resolution study confirms the paramount importance of stage at diagnosis in the management of colorectal cancer, and suggests that social and economic factors are of relevance, even in Western countries, for reducing inequalities in cancer care.


2010 - Infliximab-related hepatitis: discussion of a case and review of the literature. [Articolo su rivista]
Mancini, S; Amorotti, E; Vecchio, S; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.


2010 - [Italian cancer figures, report 2010: Cancer prevalence in Italy. Patients living with cancer, long-term survivors and cured patients] [Articolo su rivista]
AIRTUM Working, Group; Guzzinati, S.; Dal Maso, L.; De Angelis, R.; De Paoli, A.; Buzzoni, C.; Crocetti, E.; Bucchi, L.; Casella, C.; Cuccaro, F.; Fusco, M.; Luminari, Stefano; Madeddu, A.; Mangone, L.; Patriarca, S.; Piffer, S.; Stracci, F.; Tagliabue, G.; Tumino, R.; Zappa, M.; Capocaccia, R.; Ferretti, S.; Mazzoleni, G.; Bellú, F.; Tschugguel, B.; De Valiere, E.; Facchinelli, G.; Falk, M.; Dal Cappello, T.; Giacomin, A.; Vercellino, P. C.; Andreone, S.; Busato, A.; Marzola, L.; Migliari, E.; Carletti, N.; Nenci, I.; Caldarella, A.; Corbinelli, A.; Giusti, F.; Intrieri, T.; Manneschi, G.; Nemcova, L.; Romeo, G.; Sacchettini, C.; Paci, E.; Serraino, D.; Angelin, T.; Bidoli, E.; de Dottori, M.; De Santis, E.; Forgiarini, O.; Zucchetto, A.; Zanier, L.; Vercelli, M.; Orengo, M. A.; Marani, E.; Puppo, A.; Celesia, M. V.; Cogno, R.; Manenti, S.; Garrone, E.; Quaglia, A.; Pannozzo, F.; Busco, S.; Rashid, I.; Ramazzotti, V.; Cercato, M. C.; Battisti, W.; Sperduti, I.; Macci, L.; Bugliarello, E.; Bernazza, E.; Tamburo, L.; Rossi, M.; Curatella, S.; De Francesco, C.; Tamburrino, S.; Bisanti, L.; Autelitano, M.; Randi, G.; Ghilardi, S.; Leone, R.; Filipazzi, L.; Bonini, A.; Giubelli, C.; Federico, Massimo; Artioli, M. E.; Valla, K.; Braghiroli, B.; Cirilli, C.; Pirani, M.; Ferrari, L.; Bellatalla, C.; Fusco, M.; Panico, M.; Perrotta, C.; Vassante, B.; Traina, A.; Carruba, G.; Cusimano, R.; Amodio, R.; Dolcemascolo, C.; Staiti, R.; Zarcone, M.; Michiara, M.; Bozzani, F.; Sgargi, P.; Cilia, S.; La Rosa, M. G.; Cascone, G.; Frasca, G.; Giurdanella, M. C.; Martorana, C.; Morana, G.; Nicita, C.; Rollo, P.; Ruggeri, M. G.; Sigona, A.; Spata, E.; Vacirca, S.; Di Felice, E.; Pezzarossi, A.; Caroli, S.; Pellegri, C.; Vicentini, M.; Storchi, C.; Cavuto, S.; Costa, J.; Falcini, F.; Colamartini, A.; Balducci, C.; Ravegnani, M.; Vitali, B.; Cordaro, C.; Caprara, L.; Giuliani, O.; Giorgetti, S.; Salvatore, S.; Palumbo, M.; Vattiato, R.; Ravaioli, A.; Foca, F.; Rinaldi, E.; Donato, A.; Iannelli, A.; Senatore, G.; Zevola, A.; Budroni, M.; Cesaraccio, R.; Pirino, D.; Carboni, D.; Fiori, G.; Soddu, M.; Mameli, G.; Mura, F.; Contrino, M. L.; Tisano, F.; Sciacca, S.; Muni, A.; Mizzi, M.; Russo, M.; Tessandori, R.; Ardemagni, G.; Gianola, L.; Maspero, S.; Annulli, M. L.; Moroni, E.; Roberto, G.; Zanetti, R.; Rosso, S.; Prandi, R.; Sobrato, I.; Gilardi, F.; Busso, P.; Franchini, S.; Gentilini, M. A.; Battisti, L.; Cappelletti, M.; Moser, M.; La Rosa, F.; D'Alò, D.; Scheibel, M.; Costarelli, D.; Spano, F.; Rossini, S.; Santucci, C.; Petrinelli, A. M.; Solimene, C.; Bianconi, F.; Brunori, V.; Crosignani, P.; Contiero, P.; Preto, L.; Tittarelli, A.; Maghini, A.; Codazzi, T.; Frassoldi, E.; Gada, D.; Costa, E.; di Grazia, L.; Zambon, P.; Baracco, M.; Bovo, E.; Dal Cin, A.; Fiore, A. R.; Greco, A.; Monetti, D.; Rosano, A.; Stocco, C.; Tognazzo, S.; Donato, F.; Limina, R. M.; Adorni, A.; Andreis, P.; Zani, G.; Piovani, F.; Salvi, O.; Puleio, M.; Vitarelli, S.; Antonini, S.; Candela, G.; Pappalardo, G.; Scuderi, T.; Lottero, B.; Ribaudo, M.; Ricci, P.; Guarda, L.; Gatti, L.; Bozzeda, A.; Dall'Acqua, M.; Pironi, V.; Sutera Sardo, A.; Mazzei, A.; Sirianni, N.; Lavecchia, A. M.; Mancuso, P.; Usala, M.; Pala, F.; Sini, G. M.; Pintori, N.; Canu, L.; Demurtas, G.; Doa, N.; Pisani, P.; Pastore, G.; Magnani, C.; Terracini, B.; Cena, T.; Alessi, D.; Baussano, I.; Merletti, F.; Maule, M.; Mosso, M. L.; Nonnato, M.; Rasulo, A.; Richiardi, L.; Zuccolo, L.; Pivetta, E.; Dalmasso, P.; Macerata, V.; Ponz De Leon, Maurizio; Domati, F.; Rossi, G.; Goldoni, C. A.; Rossi, F.; De Gaetani, C.; Benatti, Piero; Roncucci, Luca; Di Gregorio, C.; Pedroni, Monica; Pezzi, A.; Maffei, S.; Mariani, F.; Borsi, E.; Cocchioni, M.; Pascucci, C.; Gennaro, V.; Lazzarotto, A.; Benfatto, L.; Mazzucco, G.; Montanaro, F.
abstract

OBJECTIVES: the aim of the present monograph is to update the estimation of the number of people living with cancer in Italy, to describe geographic variability, and estimate the number of long-term survivors, i.e., people living five years or more after a cancer diagnosis. MATERIALS AND METHODS: the study included the data of the AIRTUMdatabase. Twenty-four Cancer Registries (CRs) (covering 27% of the Italian population) collected information on the incidence and vital status of 1,275,353 cases diagnosed between 1978 and 2005. For each CR, the observed prevalence was calculated up to the maximum observable duration. To estimate the complete prevalence (all living patients, independently from time since diagnosis) and the prevalence for lengths of time exceeding the CR maximum duration of registration, the observed prevalence was corrected through a completeness index. Completeness indices, gender, age and site specific, were estimated by means of statistical regression models using cancer incidence and survival data available from CRs with more than 15 years of observation. As of 1 January 2006, the prevalence was estimated (as absolute numbers and as a proportion per 100,000 inhabitants) for 46 cancer sites, by gender, age class, years since diagnosis and geographic areas. RESULTS: as of 2006, 2,244,000 persons (4%of the Italian population) were alive with a cancer diagnosis. A relevant geographic variability emerged, with proportions between 4%-5% among CRs in the Centre and North of Italy, and proportions between 2%-3% in the South. Forty-four percent of prevalent subjects (988,000) were males and 56% (1,256,000) females. Fifty-seven percent (1,285,680 people, 2.2% of total population) of these patients was represented by long-term survivors. In patients aged 75 years or more, the proportions of prevalent cases were 19%in males and 13%in females, and 10%between 60 and 75 years of age in both genders.More than half a million Italian women were alive with a breast cancer diagnosis (42%of women with a neoplasm), followed by women with cancers of the colonrectum (12%), corpus uteri (7%), thyroid (5%), and cervix uteri (4%). In men, 22%of prevalent cases (216,716) included patients with prostate cancer, 18% with bladder cancer, and 15%with colon-rectum cancer. Percentages of long-term survivors higher than 70% were reported for cancers of the cervix uteri (82% at five years, and 55% at 15 years from diagnosis), Hodgkin lymphoma, testis, brain and central nervous system, bone and connective tissue. Many patients with these types of cancers (often occurring in young people) can be considered "cured", i.e., with a life expectancy overlapping that of the general population.The estimated proportions of prevalent cases emerging from this study in Italy were quite similar to those reported in Northern Europe, but at least 15%lower than those in the United States. CONCLUSIONS: in 2006, the number of prevalent cases nearly doubled compared to 1992. The increase over time in the proportion of elderly patients, related to population ageing, requires adequate health policies. Knowing the number of people alive many years after cancer diagnosis (either cured or long-term survivors) provides the scientific bases for the definition of health policies focusing on them. Furthermore, it promotes the conduction of studies aimed at improving the present knowledge on the quality of life of these patients during and after the active phase of treatments, in addition to studies on the long-term effects of treatments.


2009 - Cyclooxygenase-2 and Hypoxia-Inducible Factor-1 alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis [Articolo su rivista]
Mariani, Francesco; Sena, Paola; Marzona, Laura; Riccio, Massimo; Fano, Rita Adriana; Manni, Paola; C., Di Gregorio; A., Pezzi; PONZ DE LEON, Maurizio; Monni, Sebastiano Graziano; DE POL, Anto; Roncucci, Luca
abstract

Chronic mucosal inflammation is considered a risk factor for colorectal cancer. Neutrophils are a major source of oxidants, whereas cyclooxygenase 2 (COX-2) and Hypoxia Inducible Factor-1 alpha (HIF-1 alpha) protein expression levels are increased in inflammatory and malignant lesions. The main purpose of the present study was to evaluate myeloperoxidase (MPO) positive cell infiltration, COX-2 and HIF-1 alpha protein expression in colorectal carcinogenesis, especially in its early phases, using immunohistochemistry and immunofluorescence confocal microscopy techniques. MPO, COX-2 and HIF-1 alpha proteins were expressed at higher rates in the normal colorectal mucosa of patients with inflammatory bowel diseases and colorectal tumours than in patients with normal colonoscopy. A gradual increase in COX-2 and HIF-1 alpha protein expression was observed in dysplastic aberrant crypt foci, adenomas and carcinomas, showing a strong relation to dysplasia. In conclusion, the present study supports the hypothesis of a key role of inflammation in malignant transformation of colorectal mucosa. The evaluation of some early markers related to inflammation in the mucosa of the large bowel may serve as potential tool for prognosis and therapeutic strategies. (C) 2009 Elsevier Ireland Ltd. All rights reserved.


2009 - Differentiated Thyroid Carcinoma (DTC) in a Young Woman with Peutz-Jeghers Syndrome: are these Two Conditions Associated? [Articolo su rivista]
Zirilli, Lucia; Benatti, Piero; Romano, Stefania; Roncucci, Luca; Rossi, Giuseppina; Diazzi, Chiara; Carani, Cesare; PONZ DE LEON, Maurizio; Rochira, Vincenzo
abstract

AIMS: Peutz-Jeghers Syndrome (PJS) is a rare dominantly inherited disease characterized by hamartomatous small bowel polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer. Differentiated thyroid cancers (DTCs) present mainly as sporadic, but they may have also a familial component. We present a case of PJS in a caucasian 25 years-old woman, who developed a DTC. METHODS: The patient had a palpable nodule in the right side of the thyroid region and an endocrinological evaluation, including hormonal assays, neck ultrasound (US) and fine needle aspiration (FNAB) of the nodule was performed. RESULTS: US confirmed a single nodular lesion in the right thyroid lobe (14 mm). Cytological analysis at FNAB revealed a pattern compatible with papillary thyroid carcinoma. The histological analysis after total thyroidectomy confirmed the diagnosis of a Hurtle cell variant of papillary thyroid carcinoma, with follicular architecture. CONCLUSION: Even though rare, the association between PJS and DTC can be possible. In clinical practice it must be borne in mind that the wide spectrum of possible cancer diseases occurring in PJS could also include DTC, that the latter can occur earlier in life in PJS population and with a more aggressive histological pattern. Furthermore, in patients with PJS, US of the thyroid should be performed whenever thyroid disease is suspected at physical examination or based on patient's medical history. Due to lack of established data allowing for a real esteem of the association between PJS and DTC, US of the thyroid, should not be recommended as a routine screening for all subjects with PJS.


2009 - New incidence and mortality data. 2003-2005 [Articolo su rivista]
Crocetti E, AIRTUM Working G. r. o. u. p.; Buzzoni C., Collaborators:Serraino D; Vicario, G; Angelin, T; Bessega, G; Bidoli, E; Brunetti, D; de Dottori, M; Forgiarini, O; French, S; Stanta, G; Zaina, L; Zanier, L; Zambon, P; Baracco, M; Bovo, E; Dal Cin, A; Fiore, Ar; Greco, A; Guzzinati, S; Monetti, D; Rosano, A; Stocco, Cf; Tognazzo, S; Egarter Vigl, E; Bellù, F; Vittadello, F; Bulatko, A; Lüthy, M; Facchinelli, G; De Valiere, E; Tschugguel, B; Dorfmann, H; Giacomin, A; Vercellino, Pc; Andreone, S; Ferretti, S; Marzola, L; Migliari, E; Carletti, N; Nenci, I; Vitarelli, S; Antonini, S; Federico, Massimo; Artioli, Me; Cirilli, C; Fracca, A; Rashid, I; Valla, K; De Lisi, V; Sgargi, P; Bozzani, F; Donato, A; Iannelli, A; Mari, C; Senatore, G; Zevola, A; Abbamonte, B; Alfano, Ia; Annunziato, L; Barone, S; Ferrante, A; Budroni, M; Cesaraccio, R; Pirino, D; Sechi, O; Piras, D; Sechi, A; Oggiano, M; Piffer, S; Franchini, S; Gentilini, Ma; Battisti, L; Cappelletti, M; Falcini, F; Amadori, D; Balducci, C; Benericetti, E; Bucchi, L; Caprara, L; Colamartini, A; Cordaro, C; Desiderio, F; Fabbri, C; Foca, F; Giorgetti, S; Montanari, E; Naldi, S; Nannini, R; Ravaioli, A; Ravegnani, M; Rinaldi, E; Salvatore, S; Serafini, M; Vattiato, R; Vitali, B; Pannozzo, F; Busco, S; Natali, M; Ramazzotti, V; Macci, L; Bugliarello, E; Bernazza, E; Tamburo, L; Rossi, M; Curatella, S; Sperduti, I; Fusco, M; Bellatalla, C; Fusco, M; Panico, M; Perrotta, C; Vassante, B; Crosignani, P; Tagliabue, G; Contiero, P; Fabiano, S; Maghini, A; Tittarelli, A; Codazzi, T; Frassoldi, E; Costa, E; Nobile, S; Vigano, C; Berrino, F; Mangone, L; Pezzarossi, A; Pellegri, C; Caroli, S; Valentini, M; Cavuto, S; De Felice, E; Vercelli, M; Orengo, Ma; Casella, C; Marani, E; Puppo, A; Celesia, Mv; Cogno, R; Grondona, Am; Giachero, G; Manenti, S; Quaglia, A; Garrone, E; Paci, E; Crocetti, E; Buzzoni, C; Caldarella, A; Corbinelli, A; Dainelli, G; Guadagni, M; Intrieri, T; Manneschi, G; Miccinesi, G; Nemcova, L; Sacchettini, C; Giusti, F; La Rosa, F; Stracci, F; Petrinelli, Am; Costarelli, D; Cassetti, T; Scheibel, M; Romagnoli, C; Mastrandrea, V; Zanetti, R; Rosso, S; Patriarca, S; Vicari, P; Sobrato, I; Gilardi, F; Maglietta, G; Gallesio, L; Tumino, R; Cilia, S; La Rosa, Mg; Cascone, G; Cianciolo, G; Frasca, G; Giurdanella, Mc; Martorana, C; Morana, G; Nicita, C; Rollo, P; Ruggeri, Mg; Sigona, A; Spata, E; Vacirca, S; Bisanti, L; Autelitano, M; Ghilardi, S; Bovini, A; Giubelli, C; Tessandori, R; Ardemagni, G; Traina, A; Candela, P; Contrino, Ml; Tisano, F; Madeddu, A; Ponz de Leon, M; di Gregorio, C; Roncucci, Luca; Benfatti, P; Losi, Lorena; Ponti, Giovanni; Pedroni, Monica; Rossi, G; Roncari, B; Maffei, S; Menigatti, M; Rossi, F; Pecone, L; Domati, F; Pastore, G; Magnani, C; Terracini, B; Alessi, D; Dal masso, P; Dama, E; Macerata, V; Maule, M; Mosso, Ml; Nonnato, M; Zuccolo, L; Merletti, F; Pannelli, F; Pascucci, C; Gennaro, V; Benfatto, L; Bianchelli, M; Lazzarotto, A; Viarengo, P.
abstract

In Italy cancer incidence and mortality rates are similar to those in northern European countries and in USA among males, but they are still lower than women.


2009 - Relative role of APC and MUTYH mutations in the pathogenesis of familial adenomatous polyposis. [Articolo su rivista]
Pezzi, A; Roncucci, Luca; Benatti, Piero; Sassatelli, R; Varesco, L; Di Gregorio, C; Venesio, T; Pedroni, Monica; Maffei, S; Reggiani Bonetti, L; Borsi, E; Ferrari, M; Martella, P; Rossi, G; PONZ DE LEON, Maurizio
abstract

OBJECTIVE: Familial adenomatous polyposis (FAP) is an interesting model for the study of colorectal tumour. Two genes contribute to the FAP phenotype - APC and MUTYH - but their relative role is still undefined. The objective of this study was to evaluate the contribution of the two genes to the pathogenesis of FAP by means of a series of FAP families. MATERIAL AND METHODS: Sixty-one unrelated families with a diagnosis of FAP and a total of 187 affected individuals were evaluated. After extracting DNA, APC and MUTYH genes were sequenced. RESULTS: In the whole series of patients, colectomy with ileorectal anastomosis was the most frequent surgery, although the number of patients treated by total proctocolectomy and ileoanal anastomosis was increasing. Duodenal and jejunal-ileal adenomas were present in more than half of the patients. Constitutional mutations were detected in 37 of the 45 families (82.2%); there were 33 families with APC and 4 with MUTYH alterations. Age at onset of polyposis and age at surgery were 10-15 years delayed for carriers of MUTYH mutations; cancer at diagnosis was frequent, and extracolonic manifestations were diagnosed in the majority of MUTYH-positive families. MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations). CONCLUSIONS: At least two genes are associated with the FAP phenotype. APC mutations account for the majority of cases, while MUTYH mutations can be observed in 10% of patients. There are few but definite differences between APC- and MUTYH-associated FAP, such as age at diagnosis and pattern of transmission.


2009 - Survival, surgical management and perioperative mortality of colorectal cancer in the 21-year experience of a specialised registry [Articolo su rivista]
PONZ DE LEON, Maurizio; Pezzi, A; Benatti, Piero; Manenti, Antonio; Rossi, Giuseppina; Di Gregorio, C; Roncucci, Luca
abstract

BACKGROUND AND AIMS:A general improvement of colorectal cancer prognosis has been observed. Reasons of this more favourable trend are diffusion of screening, advancements in molecular biology, new developments in chemotherapy and surgical techniques. Through the data of a colorectal cancer registry, we purposed to evaluate changes in surgical procedures for colorectal neoplasms and to analyse trends of perioperative mortality.PATIENTS AND METHODS:Patients with colorectal cancer were registered from 1984 to 2004. The main surgical procedures were recorded and classified. Perioperative mortality was defined as death of patients within 1 month since the operation.RESULTS:Regression analysis showed an increase over time of right and left hemicolectomy. Both colectomy and endoscopic polypectomy showed significant rise over time. In contrast, abdominoperineal operations dropped during the study period. A similar decrease was observed for palliative surgery. Perioperative mortality declined from 7-11% to 3-6% of all operations; main factors associated with perioperative mortality were presence of comorbidities, increasing age and advanced stage.CONCLUSION:The better prognosis of patients with colorectal cancer was associated with changes of surgical techniques, with a tendency to prefer large operations over limited resections. Perioperative mortality showed a gradual decrease and is at present in the order of 3% to 6% of all operations.


2008 - Higher prevalence of nodular goiter and thyroid carcinoma in patients with familial adenomatous poliposis (FAP) [Abstract in Rivista]
Zirilli, Lucia; Romano, Stefania; Madeo, Bruno; Carani, Cesare; Benatti, Piero; PONZ DE LEON, Maurizio; Roncucci, Luca; Rochira, Vincenzo
abstract

The evaluation of 46 patients with familial adenomatous poliposis showed that nodular goiter is very common and the prevalence of thyroid cancer is higher than that of a control group


2008 - Higher prevalence of nodular goiter and thyroid carcinoma in patients with familial adenomatous poliposis (FAP) [Abstract in Atti di Convegno]
Zirilli, Lucia; Romano, Stefania; Roncucci, Luca; Benatti, Piero; Madeo, Bruno; Diazzi, Chiara; Scaltriti, Sara; Carani, Cesare; PONZ DE LEON, Maurizio; Rochira, Vincenzo
abstract

The evaluation of 46 patients with familial adenomatous poliposis showed that nodular goiter is very common, and the prevalence of thyroid cancer is higher than that of a control group.


2008 - Identification of mucin depleted foci in the human colon [Articolo su rivista]
Femia, Ap; Giannini, A; Fazi, M; Tarquini, E; Salvadori, M; Roncucci, Luca; Tonelli, F; Dolara, P; Caderni, G.
abstract

Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the β-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm2) and at a much lower density in CRC patients (average of 0.0006 lesions/cm2). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.


2008 - Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk. [Articolo su rivista]
Roncucci, Luca; Mora, E; Mariani, F; Bursi, S; Pezzi, A; Rossi, G; Pedroni, Monica; Luppi, D; Santoro, L; Monni, Sebastiano Graziano; Manenti, Antonio; Bertani, A; Merighi, A; Benatti, Piero; Di Gregorio, C; PONZ DE LEON, Maurizio
abstract

Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.


2007 - A mononucleotide markers panel to identify hMLH1/hMSH2 germline mutations. [Articolo su rivista]
Pedroni, Monica; Roncari, B; Maffei, S; Losi, Lorena; Scarselli, A; Di Gregorio, C; Marino, M; Roncucci, Luca; Benatti, Piero; Ponti, Giovanni; Rossi, G; Menigatti, M; Viel, A; Genuardi, M; PONZ DE LEON, Maurizio
abstract

Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome) is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI). MSI is present in 85-90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the "Bethesda panel"). Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites. The Bethesda panel detected more MSI(+) tumors than the mononucleotide panel (49.5% and 28.6%, respectively). However, the mononucleotide panel was more efficient to detect MSI(+) tumours with lack of expression of Mismatch Repair proteins (93% vs 54%). Germline mutations were detected in almost all patients whose tumours showed MSI and no expression of MLH1/MSH2 proteins. No germline mutations were found in patients with MSI(+) tumour defined only through dinucleotide markers. In conclusion, the proposed mononucleotide markers panel seems to have a higher predictive value to identify hMLH1 and hMSH2 mutation-positive patients with Lynch syndrome. Moreover, this panel showed increased specificity, thus improving the cost/effectiveness ratio of the biomolecular analyses.


2007 - Epidemiology of colorectal cancer: the 21-year experience of a specialised registry. [Articolo su rivista]
PONZ DE LEON, Maurizio; Rossi, G; di Gregorio, C; De Gaetani, C; Rossi, F; Ponti, Giovanni; Pecone, L; Pedroni, Monica; Roncucci, Luca; Pezzi, A; Benatti, Piero
abstract

Cancer registries can be viewed as one of the main strategies for improving our understanding of cancer, as they may reveal the importance of specific trends in cancer incidence and survival; in addition, the information obtained from the registries can be translated into preventive measures that might lead to a better control of neoplasms. A colorectal cancer registry was instituted in Northern Italy in 1984. The purpose of this study is to provide a description of the main findings observed in a 21-year period of continuous registration. RESULTS: A total of 3951 malignancies of the large bowel were registered in 3817 patients, for a crude incidence rate of 75.1/100 000/year in men and 59.0 in women. Overall incidence (crude and age-adjusted) of colorectal tumours increased remarkably throughout the registration period. This increase was mainly due to early (Stage I and II) tumours and to lesions with lymph nodal involvement (Stage III). There was a tendency over time towards a progressive increase of colonic tumours, whereas the fraction of rectal neoplasms tended to decline. Colorectal cancer-specific survival increased significantly over time in each of the main TNM/Dukes classes (p<0.006 and <0.001 for Stage II and III tumours). Finally, surgery for colorectal tumours showed a tendency towards large operations (colectomy and hemicolectomy), which was parallel to a definite improvement of pathological staging. CONCLUSIONS: Despite the increasing incidence of colorectal cancer, there are several reasons for cautious optimism. Most of the lesions are now diagnosed at an early stage, and this is associated with a significant increase of survival. The disease is undoubtedly cured better than in the past; the main challenge for future years is to achieve a sustained reduction of mortality for colorectal neoplasms.


2007 - Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC. [Articolo su rivista]
Roncari, Barbara; Pedroni, Monica; Maffei, S; Di Gregorio, C; Ponti, Giovanni; Scarselli, A; Losi, Lorena; Benatti, Piero; Roncucci, Luca; De Gaetani, C; Camellini, L; Lucci Cordisco, E; Tricarico, E; Genuardi, M; PONZ DE LEON, Maurizio
abstract

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC.


2007 - Genotype-phenotype correlations in individuals with a founder mutation in the MLH1 gene and hereditary non-polyposis colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, P; Di Gregorio, C; Losi, Lorena; Pedroni, Monica; Ponti, Giovanni; Genuardi, M; Lucci Cordisco, E; Roncucci, Luca
abstract

The results of the study underline the difficulty in discriminating between Lynch I and Lynch II syndromes on the basis of specific molecular changes.


2007 - O6-methylguanine-DNA methyltransferase promoter hypermethylation in colorectal carcinogenesis [Articolo su rivista]
Menigatti, Mirco; Pedroni, Monica; Verrone, Am; Borghi, F; Scarselli, A; Benatti, Piero; Losi, L; Di Gregorio, C; Schär, P; Marra, G; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Epigenetic alterations have been reported in colorectal neoplasia which can either complement or in some cases be predisposed to genetic alterations such as K-ras mutations. We examined the promoter methylation status of the CDKN2A and O6-methylguanine-DNA methyltransferase (MGMT) genes, after sodium bisulfite conversion and DNA amplification with methylation specific PCR. Moreover, we searched for G to A transitions in codons 12 and 13 of the K-ras oncogene in normal colorectal mucosae, aberrant crypt foci (ACF, early premalignant lesions) and carcinomas. CDKN2A hypermethylation was an infrequent event in ACF (2 of 26, 7.7%). On the contrary, MGMT hypermethylation was found in the normal mucosae (3 of the 12 samples, 25%), in 14 of the 26 ACF (53.8%) and in 7 of the 9 (77.8%) carcinomas examined. K-ras mutations were evident in 6 ACF (23%) and in 3 carcinomas (33.3%), mostly associated with MGMT promoter hypermethylation. These findings strongly support the hypothesis that epigenetic mechanisms play an important role in the early steps of colorectal carcinogenesis.


2007 - Preventive war and chemoprevention of cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

WITHOUT ABSTRACT


2006 - Carcinoma papillare e Sindrome di Peutz-Jeghers: una rara associazione [Abstract in Atti di Convegno]
Rochira, Vincenzo; Romano, Stefania; Zirilli, Lucia; Madeo, Bruno; Caffagni, Giovanni; Diazzi, Chiara; Valeria, Pugni; Pignatti, Elisa; Roncucci, Luca; PONZ DE LEON, Maurizio; Carani, Cesare; Benatti, Piero
abstract

Case report of a patient with Peutz-Jeghers syndrome and concomitant papillary thyroid cancer that indicates that thyroid cancer might be more frequent in patients with Peutz-Jeghers


2006 - Prognostic significance of histological features and biological parameters in stage I (pT1 and pT2) colorectal adenocarcinoma [Articolo su rivista]
Losi, Lorena; Ponti, Giovanni; Di Gregorio, Carmela; Marino, M; Rossi, Giuseppina; Pedroni, Monica; Benatti, Piero; Roncucci, Luca; Ponz De Leon, Maurizio
abstract

Patients with stage I colorectal cancer have a good prognosis, however, a small fraction of them die of local or distant recurrence after curative resection. The aggressive behavior reflects some biological properties of these tumors. In this study, we evaluated the prognostic role of some histopathological and biological parameters in stage I colorectal carcinomas. From the Colorectal Cancer Registry of Modena, we selected two series of patients; the first included all patients who had died of disease progression, the second included patients with a favorable outcome. The histopathological parameters assessed were grade of differentiation, growth pattern at the invasive tumor front, peritumoral lymphocytic infiltration, tumor budding and vascular invasion. The biological variables were proliferative activity (using Ki-67 nuclear antigen), overexpression of p53 protein and altered expression of the mismatch repair proteins (MLH1 and MSH2). The results showed that an infiltrating growth pattern, absent or sparse peritumoral lymphocytic infiltration, the presence of tumor budding and vascular invasion are significantly related to the risk of recurrence. Among the biological parameters, p53 overexpression was significantly correlated with a poor clinical outcome. Our study showed that the histopathologial features are relevant prognostic indicators and might be used as markers for an appropriate treatment strategy in patients with stage I carcinomas.


2006 - Subcellular localization of beta-catenin and APC proteins in colorectal preneoplastic and neoplastic lesions RID B-2583-2012 [Articolo su rivista]
Sena, Paola; Saviano, Massimo; Monni, Sebastiano Graziano; Losi, Lorena; Roncucci, Luca; Marzona, Laura; DE POL, Anto
abstract

Adenomatous polyposis coli (APC) is a tumor suppressor gene whose main function is the destabilization of beta-catenin, a key effector of the Wnt signaling pathway. This gene is defective in familial adenomatous polyposis (FAP), a dominantly inherited disease, but inactivation of APC has been reported also in most sporadic colorectal tumors and it is considered an early event in colorectal tumorigenesis. The aim of the present study was to evaluate the intracellular ultrastructural distribution of beta-catenin and APC proteins in epithelial cells of normal colorectal mucosa, aberrant crypt foci (ACF, an early premalignant lesion) and cancer. We used the immunogold electron microscopic method to identify both proteins. Normal colonic epithelial cells showed a strong membranous expression of beta-catenin and lacked cytoplasmic and nuclear expression. Normal cells showed APC localization pattern characterized by diffuse nuclear expression and along the plasma membrane. In ACF and in carcinoma an absent or reduced membranous expression of beta-catenin was associated with an increased nuclear and cytoplasmatic expression. In aberrant crypt foci and carcinoma, APC was evident inside the nucleus and at the level of cell-cell junctions, but it was decreased in the cytoplasm. This method allowed the accurate localization of proteins of the Writ signaling pathway in the early steps of colorectal carcinogenesis. The similar pattern of subcellular distribution of APC and beta-catenin in dysplastic ACF and colorectal cancer suggests that ACF are precursor lesions of sporadic and FAP-associated colorectal carcinoma. (c) 2005 Elsevier Ireland Ltd. All rights reserved.


2006 - Whipple's disease in a father-son pair [Articolo su rivista]
PONZ DE LEON, Maurizio; A., Borghi; F., Ferrara; Contri, Miranda; Roncucci, Luca
abstract

Non c'è


2005 - Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations. [Articolo su rivista]
Ponti, Giovanni; PONZ DE LEON, Maurizio; Maffei, S; Pedroni, Monica; Losi, L; Di Gregorio, C; Gismondi, V; Scarselli, A; Benatti, Piero; Roncari, B; Seidenari, S; Pellacani, Giovanni; Varotti, C; Prete, E; Varesco, L; Roncucci, Luca
abstract

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.


2005 - Different phenotypes in Muir-Torre Syndrome: clinical and biomolecular characterization in two italian families [Articolo su rivista]
Ponti, Giovanni; PONZ DE LEON, Maurizio; Losi, Lorena; C., Di Gregorio; Benatti, Piero; Pedroni, Monica; A., Scarselli; G., Riegler; L., Lembo; Pellacani, Giovanni; Seidenari, Stefania; Rossi, Giorgio; Roncucci, Luca
abstract

The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C -> T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.


2005 - Identification of Muir-Torre Syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability and immunohistochemistry [Articolo su rivista]
Ponti, Giovanni; Losi, Lorena; Di Gregorio, C; Roncucci, Luca; Pedroni, Monica; Scarselli, A; Benatti, Piero; Seidenari, S; Pellacani, Giovanni; Lembo, L; Rossi, G; Marino, M; Lucci Cordisco, E; PONZ DE LEON, Maurizio
abstract

BACKGROUND: The Muir-Torre syndrome (MTS) is an autosomal-dominant genodermatosis characterized by the presence of sebaceous gland tumors, with or without keratoacanthomas, associated with visceral malignancies. A subset of patients with MTS is considered a variant of the hereditary nonpolyposis colorectal carcinoma, which is caused by mutations in mismatch-repair genes. The objective of the current study was to evaluate whether a combined clinical, immunohistochemical, and biomolecular approach could be useful for the identification of Muir-Torre syndrome among patients with a diagnosis of sebaceous tumors and keratoacanthomas. METHODS: The authors collected sebaceous skin lesions and keratoacanthomas recorded in the files of the Pathology Department of the University of Modena during the period 1986-2000. Through interviews and examination of clinical charts, family trees were drawn for 120 patients who were affected by these skin lesions. RESULTS: Seven patients also were affected by gastrointestinal tumors, thus meeting the clinical criteria for the diagnosis of MTS. In the MTS families, a wide phenotypic variability was evident, both in the spectrum of visceral tumors and in the type of skin lesions. Microsatellite instability was found in five MTS patients: These patients showed concordance with immunohistochemical analysis; moreover, a constitutional mutation in the MSH2 gene was found in 1 patient. Lack of expression of MSH2/MSH6 or MLH1 proteins was evident in the skin lesions and in the associated internal malignancies of 3 patients and 2 patients with MTS, respectively. CONCLUSIONS: The clinical, biomolecular, and immunohistochemical characterization of sebaceous skin lesions and keratoacanthomas may be used as screening for the identification of families at risk of MTS, a disease that is difficult to recognize and diagnose.


2005 - Incidence and survival of patients with Dukes' A (stages T1 and T2) colorectal carcinoma: a 15-year population-based study. [Articolo su rivista]
Benatti, Piero; Roncucci, Luca; Rossi, G; Ponti, Giovanni; Marino, M; Pedroni, Monica; Scarselli, A; Roncari, Barbara; PONZ DE LEON, Maurizio; Di Gregorio, C; Losi, Lorena
abstract

BACKGROUND AND AIMS: Patients with stage I (Dukes' A) colorectal carcinoma tend to show a good prognosis; however, recurrences can be observed in some patients. Through a specialized colorectal cancer Registry, we attempted to investigate the epidemiological and clinical features of individuals with Dukes' A neoplasms.PATIENTS AND METHODS: From 1984 to 1998, 295 individuals were diagnosed with Stage I /Dukes' A tumors; 150 of these had lesions infiltrating the muscular wall (T2), while 145 had neoplasms limited to the submucosa (T1).RESULTS: Dukes' A tumors represented 13.8% of all registered neoplasms; the percentage doubled over the study period (8.1% in the first year vs. 16.8% in the final year). In each year of observation, the preferential locations were the rectum and sigmoid colon (75% of all lesions). Most patients required surgery, but only 21.3% could be managed by endoscopic polypectomy. Overall 5-year survival was 81.0% (82.1% in T1, 80.0% in T2). Recurrences were seen in 6.8% (2.8% in T1, 10.7% in T2), while 36 patients (12.2%) died of causes unrelated to colorectal cancer. In 17 out of 20 patients who died of cancer, the lesions were localized in the rectosigmoid region. Survival analysis showed a significantly better prognosis (P<0.007) for patients with T1 tumors.CONCLUSIONS: The proportion of stage I colorectal tumors tended to increase over time. Although the overall prognosis is good in four-fifths of the cases, approximately one-fifth of these patients die of recurrent disease or of other causes. As expected, the prognosis was significantly more favorable for patients with T1 lesions. For patients with T2 tumors, radical surgery is the most appropriate approach.


2005 - Local recurrences of rectal cancer. [Articolo su rivista]
Roncucci, Luca
abstract

WITHOUT ABSTRACT


2005 - Microsatellite instability and colorectal cancer prognosis. [Articolo su rivista]
Benatti, Piero; Gafà, R; Barana, D; Marino, M; Scarselli, A; Pedroni, Monica; Maestri, I; Guerzoni, L; Roncucci, Luca; Menigatti, M; Roncari, B; Maffei, S; Rossi, G; Ponti, Giovanni; Santini, A; Losi, Lorena; Di Gregorio, C; Oliani, C; PONZ DE LEON, Maurizio; Lanza, G.
abstract

PURPOSE: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy.EXPERIMENTAL DESIGN: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables.RESULTS: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year-specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non-polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared.CONCLUSIONS: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non-polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.


2005 - Microsatellite instability and prognosis of colorectal cancer [Relazione in Atti di Convegno]
Benatti, Piero; Marino, M; Gafa, R; Barana, D; Pedroni, Monica; Scarselli, A; Di Gregorio, C; Roncucci, Luca; Oliani, C; Lanza, G; PONZ DE LEON, Maurizio
abstract

Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) asa prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC);however, the results are not conclusive.The aim of this study was to analyze the prognostic significanceof high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy.ExperimentalDesign: In three different institutions,1,263 patientswithCRCwere tested for thepresence of MSI, and CRC-specific survival was then analyzed in relation toMSI status, chemotherapy,and other clinical and pathologic variables.Results:Two hundred and fifty-six tumorswereMSI-H(20.3%): theseweremore frequently at aless advanced stage, right-sided, poorly differentiated, withmucinous phenotype, and expansivegrowth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of5-year ^ specific survival revealed stage, tumor location, grade of differentiation, MSI, gender,and age as significant prognostic factors.The prognostic advantage of MSI tumors was particularlyevident in stages II and III in which chemotherapy did not significantly affect the survival ofMSI-H patients. Finally, we analyzed survival inMSI-H patients in relation to the presence ofmismatchrepair gene mutations. MSI-H patients with hereditary non ^ polyposis colorectal cancershowed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis,this difference disappeared.Conclusions:The type of genomic instability could influence the prognosis of CRC, in particularin stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival amongMSI-Hpatients.The survival benefit for patientswithhereditary non ^ polyposis colorectal canceris mainly determined by younger age and less advanced stage as comparedwith sporadicMSI-Hcounterpart.


2005 - Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes. [Articolo su rivista]
Losi, Lorena; Di Gregorio, C; Pedroni, Monica; Ponti, Giovanni; Roncucci, Luca; Scarselli, A; Genuardi, M; Baglioni, S; Marino, M; Rossi, G; Benatti, Piero; Maffei, S; Menigatti, M; Roncari, Barbara; PONZ DE LEON, Maurizio
abstract

OBJECTIVES: Colorectal cancer (CRC) occurs rarely in young individuals (<45 yr) and represents one of the criteria for suspecting hereditary cancer families. In this study we evaluated clinical features and molecular pathways (chromosomal instability [CIN] and microsatellite instability [MSI]) in early-onset CRC of 71 patients.METHODS: Detailed family and personal history were obtained for each patient. Expression of APC, beta-catenin, p53, MLH1, MSH2, and MSH6 genes was evaluated by immunohistochemistry. MSI analysis was performed and constitutional main mutations of the mismatch repair (MMR) genes were searched by gene sequencing.RESULTS: Fourteen (19.7%) out of the 71 cases showed both MSI and altered expression of MMR proteins. In the 57 MSI-negative (MSI-) lesions altered expression of APC, beta-catenin, and p53 genes were found more frequently than in MSI-positive(MSI+) tumors. Seven (50%) out of the 14 patients with MSI+ tumors presented clinical features of Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) and in all but one, constitutional mutations in MLH1 or MSH2 genes could be detected. The same mutations were also found in other family members.CONCLUSIONS: Our study demonstrates the involvement of CIN in a majority of early-onset colorectal tumors. Furthermore, we identified Lynch syndromes in seven cases (50%) of early-onset colorectal carcinomas with impairment of the MMR system. These results suggest that patients with early-onset CRC should be screened for hereditary cancer syndrome through clinical and molecular characterizations.


2004 - Aetiology of colorectal cancer and relevance of monogenic inheritance. [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Borghi, Francesca; Pedroni, Monica; Scarselli, Alessandra; DI GREGORIO, C; Losi, Lorena; Viel, A; Genuardi, M; Abbati, G; Rossi, Giuseppina; Menigatti, Mirco; Lamberti, Igor; Ponti, Giovanni; Roncucci, Luca
abstract

BACKGROUND AND AIMS: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors.PATIENTS AND METHODS: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing.RESULTS: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected.CONCLUSIONS: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.


2004 - Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) - Reply [Articolo su rivista]
Roncucci, Luca; PONZ DE LEON, Maurizio; Benatti, Piero; Borghi, F; Pedroni, Monica; Scarselli, A; di Gregorio, C; Losi, Lorena; Viel, A; Genuardi, M; Abbati, G; Rossi, G; Menigatti, M; Ponti, Giovanni
abstract

NOTHING


2004 - Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) [2] (multiple letters) [Articolo su rivista]
Jass, J. R; Roncucci, Luca; PONZ DE LEON, Maurizio; Benatti, Piero; Borghi, F.; Pedroni, Monica; Scarselli, A.; DI GREGORIO, Carmela; Losi, Lorena; Viel, A.; Genuardi, M.; Abbati, Gian Luca; Rossi, G.; Menigatti, Mirco; Ponti, Giovanni
abstract

Letter to the Editor


2004 - Genetic testing among high-risk individuals in families with hereditary non polyposis colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, P.; Di Gregorio, C.; Pedroni, Monica; Losi, L.; Genuardi, M.; Viel, A.; Fornasarig, M.; Lucci Cordisco, E.; Anti, M.; Ponti, Giovanni; Borghi, F.; Lamberti, I.; Roncucci, Luca
abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P&lt;0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.


2004 - Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacantomas: role of clinical features, microsatellite instability and immunohistochemistry [Abstract in Rivista]
Losi, Lorena; Ponti, Giovanni; Scarselli, A.; Roncucci, Luca; Pedroni, Monica; P., Benatti; PONZ DE LEON, Maurizio; C., Di Gregorio
abstract

The clinical, biomolecular and immunohistochemical characterization of sebaceous skin lesions and keratoakantomas migh be used in population-based screening for the identification of families at risk of Muir-Torre syndrome, a rare disease difficult to recognize and diagnose.


2004 - Relationship between MUC5AC and altered expression of MLH1 protein in mucinous and non-mucinous colorectal carcinomas [Articolo su rivista]
Losi, Lorena; Scarselli, A; Benatti, Piero; PONZ DE LEON, Maurizio; Roncucci, Luca; Pedroni, Monica; Borghi, F; Lamberti, Igor; Rossi, Giorgio; Marino, M; Ponti, Giovanni; Zangardi, G; Menigatti, M; Di Gregorio, C.
abstract

The main purpose of this study was to examine the expression of mucins and mismatch repair proteins in colorectal carcinomas. The immunohistochemical distribution of apomucins MUC2, MUC5AC, and the expression of MLH1 and MSH2 proteins were examined in 76 mucinous and 60 non-mucinous colorectal carcinomas. MUC2 was noted in all mucinous carcinomas, whereas MUC5AC was present in 41 cases only (54%). In non-mucinous carcinomas, MUC2 was expressed in 61.7% of the tumors; by contrast, MUC5AC was present in 20% of the cases. The expression level of apomucins was significantly different in mucinous and non-mucinous lesions (p < 0.001). Twenty-seven (35.5%) of the mucinous carcinomas showed no MLH1 expression, whereas I I (18.3%) of the non-mucinous tumors did. This difference was statistically significant (p < 0.005). Altered expression of MSH2 protein was never observed. The lack of MLH1 expression was considerably more frequent in carcinomas with secretion of MUC5AC (p<0.005). Our study has demonstrated this close relationship by immunohistochemical methods. In summary, our data show: (1) differences in the expression of mucins between mucinous and non-mucinous tumors; (2) a high frequency of altered MLH1 protein expression (35.5%) in mucinous carcinomas; (3) a significant relationship between the presence of MUC5AC and the altered expression of MLH1 protein in colorectal carcinomas.


2004 - Trend of incidence, subsite distribution and staging of colorectal neoplasms in the 15-year experience of a specialised cancer registry. [Articolo su rivista]
PONZ DE LEON, Maurizio; Marino, M; Benatti, P; Rossi, G; Menigatti, M; Pedroni, Monica; Di Gregorio, C; Losi, Lorena; Borghi, F; Scarselli, A; Ponti, Giovanni; Roncari, B; Zangardi, G; Abbati, G; Ascari, E; Roncucci, Luca
abstract

BACKGROUND: Two-thirds of colorectal malignancies are localised in the left colon and rectum. Recent studies suggest a trend towards an increase of right-sided tumours which might have important implications for screening and surveillance. A colorectal cancer registry was set up in Modena, northern Italy, with the purpose of examining incidence, subsite distribution and staging of colorectal malignancies over a 15-year period.PATIENTS AND METHODS: From 1984 to 1998, 2517 tumours in 2462 patients were detected and staged with the tumour node metastasis (TNM) system. The 'right colon' was considered from caecum to splenic flexure; the 'left colon' included descending and sigmoid colon; and the 'rectum' included rectosigmoid junction, ampulla and anus.RESULTS: Cancer incidence showed an overall increase. Considering the various subsites, an increase of 33.7% in all colonic segments was shown whereas rectal tumours tended to decline. TNM staging showed a gradual increase of localised lesions (41.2% in 1984 versus 53.3% in 1998), with a proportional reduction of advanced tumours.CONCLUSIONS: Our study indicates an increase of tumour incidence in all colonic segments more than a shift to the right colon. TNM staging tended to improve with an appreciable increase of localised lesions. These findings could be consequent to a more extensive use of colonoscopy.


2003 - Caratterizzazione immunoistochimica e biomolecolare del carcinoma colorettale giovanile [Abstract in Rivista]
Losi, Lorena; Di Gregorio, C; Pedroni, Monica; Lamberti, I; Roncucci, Luca; Ponti, Giovanni; Rossi, G; PONZ DE LEON, Maurizio; Benatti, Piero
abstract

Rivista della Società Italiana di Anatomia Patologica e Citopatologia Diagnostica


2003 - Comparison of two marker panels for microsatellite instability analysis in the detection of constitutional MLH1 and MSH2 mutations.. [Abstract in Atti di Convegno]
Roncucci, Luca; Pedroni, Monica; Borghi, F; Scarselli, A; Lamberti, I; Menigatti, M; Rossi, G; Ponti, Giovanni
abstract

Abstract


2003 - Different involvement of target genes mutations in hereditary and sporadic colorectal cancer with Microsatellite Instability. [Poster]
Borghi, F; Pedroni, Monica; Lamberti, I; Menigatti, M; Ponti, Giovanni; Rossi, G; Di Gregorio, C; Losi, Lorena; Scarselli, A; Benatti, P; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Functional inactivation of Mismatch Repair (MMR) genes by mutations or epigenetic mechanisms favors the acquisition of mutations in 'target genes'. We analysed 94 colorectal cancer (CRC) with microsatellite instability-high (MSI-H) for the presence of mutations in microsatellites located in the coding regiobns (CDRs) of 6 geens: TGF; RII, BAX, hMLH3, hMSH6, MBD4 and BLM.


2003 - Identification and biomolecular characterization of Muir-Torre Syndrome [Abstract in Rivista]
Ponti, Giovanni; Roncucci, Luca; Di Gregorio, C; Pedroni, Monica; Borghi, F; Lamberti, I; Rossi, G; Abbati, G; Scarselli, A; Riegler, G; Seidenari, S; Pellacani, Giovanni; Lembo, L; Benatti, P; PONZ DE LEON, Maurizio
abstract

Abstract


2003 - L'immunoistochimica delle proteine del mismatch repair può essere un utile test per identificare i pazienti HNPCC? [Abstract in Atti di Convegno]
Di Gregorio, C; Scarselli, A; Pedroni, Monica; Borghi, F; Lamberti, I; Ponti, Giovanni; Roncucci, Luca; Losi, Lorena; PONZ DE LEON, Maurizio; Benatti, P.
abstract

abstract


2003 - Mutations of the hMSH6 geen as a possibel cause of Hereditary Nonpolyposis colorectal cancer [Abstract in Rivista]
PONZ DE LEON, Maurizio; Scarselli, A; Benatti, Piero; Roncucci, Luca; Ponti, Giovanni; Losi, L; Pedroni, Monica; Borghi, F; Menigatti, M; Di Gregorio, C.
abstract

Abstract


2003 - Mutations of the hMSH6 gene as a possible cause of hereditary nonpolyposis colorectal cancer [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; Scarselli, A; Benatti, Piero; Roncucci, Luca; Ponti, Giovanni; Losi, Lorena; Pedroni, Monica; Borghi, F; Menigatti, M; Di Gregorio, C.
abstract

Not avaivable


2002 - Alternative marker panel for Microsatellite Instability analysis in deection of contitutional MLH1 and MSH2 mutations. [Abstract in Atti di Convegno]
Pedroni, Monica; Borghi, F; Lamberti, I; Scarselli, A; Menigatti, M; Ponti, Giovanni; Benatti, P; Losi, Lorena; Di Gregorio, C; Abbati, G; Rossi, G; Viel, A; Genuardi, M; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Atti del convegno


2002 - Alternative marker panel for microsatellite instability analysis in detection of constitutional MLH1 and MSH2 mutations. [Monografia/Trattato scientifico]
Pedroni, Monica; Borghi, F.; Lamberti, I.; Scarselli, A.; Menigatti, M.; Ponti, Giovanni; Benatti, Piero; Losi, Lorena; Di Gregorio, C.; Abbati, G.; Rossi, Giorgio; Viel, A.; Genuardi, M.; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Hereditary Nonpolyposis Colorectal Cancer (I-INPCC) is an autosomal dominant syndrome characterized by predisposition to develop a number of neoplasms including colorectal, endometrium, urinary, extracolonic gastrointestinal, brain and ovarian cancers. HNPCC is caused by inherited mutations in DNA Mismatch Repair (MMR) genes. Defective DNA Mismatch Repair results in genetic instability, which can easily be owerved inshort repetitive sequences as microsatellites (Microsatellite Instability, MSI). An international workshop on MSIheld in Bethesda in 1997 proposed a panel of live microsatellite markers to be used in MSI analysis. This panelincludes two mononucleotide repeats (BAT25, BAT26) and three dinucleotide repeats (D2SI23, D5S346 andDI7S250). In our laboratory we are currently using a di&`erent microsatellite panel composed by threemononucleotide repeats (BAT25, BAT26, BAT40) and two dimmleotide repeats (D2SI23 and Dl8S57). 'I`heaim of this study was to evaluate the specificity ofthe Bethesda markers, as compared with our panel, to idmtifyMLHI and MSIE mutation—positive IINPCC. We compared the results of MSI-analysis in cancer from 27HNPCC Iizmilies (according to the Amsterdam criteria II) and ii•om 75 families in which not all the Amsterdamcriteria were met (Suspected IINPCC), using both the Bethesda and the alternative panel. In addition,immunohistochemistry of MLIII and MSH2 proteins was pertbrmed in all tumors in order to study thecorrelation between the two MSI-panels and the expression of MLIII and MSIE proteins.Using the Bethesda markers, 49 (48%) of tumors showed MSI. On the other hand, using the alternative panel, 33(32,3%) of tumors and displayed MSI. Loss of MLHI or MSIE was evident in 25 of 49 (5I%) MSI tumorsaccording to the Bethesda panel, whereas with the alternative panel 25 of 33 (75,7%) MSI tumors showed noprotein expression. In this group, eleven patients were tested for germline mutations of MMR genes, and all ofthem showed constitutional alterations.Our data suggest that the Bethesda panel is more sensitive to define MSI tumors, but the proposed marker panelis more specific than the Bethesda one to identity MSI tumors with no expression of MLHI and MSIE proteins.'I`he proposed marker panel seems to have a higher predictive value in the identification of


2002 - Biological characterization of mucinous carcinoma of the colon and rectum [Abstract in Rivista]
Losi, Lorena; Scarselli, A; Benatti, P; PONZ DE LEON, Maurizio; Roncucci, Luca; Pedroni, Monica; Borghi, F; Rossi, G; Ponti, Giovanni; Zangardi, G; Menigatti, M; Di Gregorio, C.
abstract

Atti del convegno


2002 - Contributo di un registro tumori sede specifico per il cancro colorettale nell'individuazione di Sindromi rare. [Relazione in Atti di Convegno]
Ponti, Giovanni; Di Gregorio, C; Scarselli, A; Rossi, G; Zangardi, G; Losi, Lorena; Roncucci, Luca; Pedroni, Monica; Borghi, F; Lamberti, I; Benatti, P; PONZ DE LEON, Maurizio
abstract

nd


2002 - HMSH6 immunohistochemistry in patients with clinical suspicion of Hereditary Non-Polyposis Colorectal Cancer. [Monografia/Trattato scientifico]
Scarselli, A.; Benatti, Piero; Chichierchia, G.; Ponti, Giovanni; Lucci Cordisco, E.; Losi, Lorena; Menigatti, M.; Pedroni, Monica; Borghi, F.; Roncucci, Luca; Viel, A.; Genuardi, M.; PONZ DE LEON, Maurizio; Di Gregorio, C.
abstract

Colorectal Cancer (HNPCC) occurs in hMLHl or hMSH2. Recent observations have shown that mutations at hMSl·I6 also involved. Aim of our study is to investigate the role of hMSH6 gene in HNPCC by imnohistochernisny.Materials and methods. 28 colorectal cancer patients with clinical diagnosis of HNPCC or suspected HNPCC were inelected. Immunoliistochemical studies of hMSH6, hMLl—Il and hMSH2 were carried out on paraflin-embedded tumoursamples. lmrm1noperoxidase—staining using diarninobenzidinc as chromogen was carried out with the NEX-ES,Automatic Staining System (Ventana). Mouse monoclonal antibodies to 11MLI-I1 and hMSI-12 proteins (6163-15 andGI29-1129, Pharmingen) were used at 1:40 dilution, mouse monoclonal antibody to hMSH6 protein (clone 44,Transduction Laboratories) was used at 1:2000 dilution. All tumour samples were tested for MSI. Results. Lack of bMSH6 expression was detected in 7 out of 28 tumors. 4 of them also showed absence of hMSH2expression All 7 patients (mean age 56.6 yrs) were affected by right-sided colon cancer, most trequently mucinous and MSI+. 3 patients were from HNPCC families fulfilling Amsterdam Criteria I or I1, 2 were diagnosed as having Muir- Torre syndrome (MTS), and 2 had a diagnosis of suspected HNPCC. An excess of extracolonic tumours was observed in ali the pedigrees but one. interestingly, in both MTS patients, colorectal cancers and sebaceous dermatologic lesionsif thowed the same immunohistochemical pattern. At the moment, the complete MMR gene sequencing has been performed for 3 out of the 7 patients. 2 IJMSH6 and l hMSH2 ramcshifl mutations were detected- Conclusions. l1MSH6 mutations could be characteristic of a subset of HNPCC families. Altered hMSH6 immunohistochemical expression (although often associated with lack of hMSH2 protein), MSI positivity, proximal ` lllcalization, later age at diagnosis and association with extracolonic tumours, all seem to be prognostic features for the presence of this genetic alteration.


2002 - Il registro dei tumori colorettali [Monografia/Trattato scientifico]
PONZ DE LEON, Maurizio; Benatti, Piero; Di Gregorio, C.; Rossi, Giorgio; Losi, Lorena; Foroni, M.; Pedroni, Monica; Menigatti, M.; Zangardi, G.; Roncucci, Luca; Borghi, F.; Scarselli, A.; Percesepe, Antonio; Pasquale, C.
abstract

Not available


2002 - Management clinico-endoscopico di soggetti appartenti a famiglie con caratteristiche di sospetta HNPCC:la Sindrome di Muir-Torre. [Abstract in Atti di Convegno]
Ponti, Giovanni; Benatti, Piero; Scarselli, A; Rossi, G; Zangardi, G; Abbati, G; Roncucci, Luca; Pedroni, Monica; Borghi, F; Lamberti, I; Riegler, G; Losi, Lorena; PONZ DE LEON, Maurizio
abstract

Atti del convegno


2002 - Two different marker panels for microsatellie instability analysis in detection of constitutional MLH1 and MSH2 mutations. [Monografia/Trattato scientifico]
Pedroni, Monica; Borghi, F.; Lamberti, I.; Scarselli, A.; Menigatti, M.; Ponti, Giovanni; Benatti, Piero; Losi, Lorena; Di Gregorio, C.; Abbati, G.; Rossi, Giorgio; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), an autosomal dominant susceptibility syndroriie, for approximately 5% of all colorectal tumours. Members of HNPCC families have a predisposition to the of colorectal cancer at an early age and an increased incidence of extracolonic cancer, e.g-, endometrium, ovaries, small bowel, biliary tract, renal pelvis and ureter. Gerrnline mutations in DNA mismatch repair genes, in particular MLI-Il and MSH2, are present in individuals with I-INPCC. Defective DNA mismatch results in genetic instability, which can easily be observed in short repetitive sequences such as microsatellites instability, MSI). MSI has been detected in most MMR-deficient tumours and it is considered the of I-INPCC. An international workshop on MSI held in Bethesda in 1997 proposed a panel of live markers to be used in MSI analysis. This panel, lmown as "Bethesda markers", includes two reats (BAT25, BAT26) and three dinucleotide repeats (D2Sl23, D5S346 and Dl7S250). ln our we are currently using a different microsatellite panel composed by three rnononucleotide repeats (BAT25, BAT40) and two dinucleoide repeats (D2Sl23 and Dl8S57). Aim of our study is to evaluate the speciticity ofr Q Btllhcsda markers, as compared with our panel, to identify MLHI and MSI-I2 mutation-positive HNPCC.We compared the results of MSI~analysis in tumours from 17 HNPCC families (according to and from 75 families in which not all the Amsterdam criteria were met (Suspected HNPCC),both the Bethesda panel and our alternative panel. MSI-H tumours were defined as having instability at two or markers (out of 5), while MSI-L tumours had instability at only one marker and MSS tumours were stable at all In addition, imrrninohistochemistry of MLH1 and MSH2 proteins was performed in all MSI-H and MSI-L to study the correlation between thc two MSI—panels and the expression of MLHI and MSH2 proteins. Results. Using the Bethesda markers, 27 (36%) out of the 75 Suspected HNPCC tumours and I2 (70,6%) out of the HNPCC tumours showed MSI. On the other hand, using our alternative panel, 16 (21.3%) Suspected HNPCC and 7 (41,2%) HNPCC tumours displayed MSI. In Suspected HNPCC tumours we found I5 (20%) md 5 (6.7%) MSI.,using the Bethesda panel and our alternative panel respectively, while in I-INPCC tumours no MSI-L was detected us either panel. Loss of MLHI or MSH2 was evident in 15 out of 39 (38,5%) MSI tumours according to the Beth panel, whereas with our alternative panel 15 out of 23 (65.2%) MSI tumours showed no protein expression.Conclusions. Our data suggest that the Bethesda panel is more sensitive to defne MSI tumours, but the propose marker panel is more sensitive to identify MSI tumours lacking expression of MLHI and MSI-I2 proteins. The marker panel seems to have higher predictive value in the identification of patients with ML!-Il and MSH2 mutations.


2002 - Two different marker panels for microsatellite instability analysis in detection of constitutional MLH1 and MSH2 mutations. [Abstract in Rivista]
Pedroni, Monica; Borghi, F; Lamberti, I; Scarselli, A; Menigatti, M; Ponti, Giovanni; Benatti, P; Losi, L; Di Gregorio, C; Abbati, G; Rossi, G; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), an autosomal dominant susceptibility syndroriie, for approximately 5% of all colorectal tumours. Members of HNPCC families have a predisposition to the of colorectal cancer at an early age and an increased incidence of extracolonic cancer, e.g-, endometrium, ovaries, small bowel, biliary tract, renal pelvis and ureter. Gerrnline mutations in DNA mismatch repair genes, in particular MLI-Il and MSH2, are present in individuals with I-INPCC. Defective DNA mismatch results in genetic instability, which can easily be observed in short repetitive sequences such as microsatellites instability, MSI). MSI has been detected in most MMR-deficient tumours and it is considered the of I-INPCC. An international workshop on MSI held in Bethesda in 1997 proposed a panel of live markers to be used in MSI analysis. This panel, lmown as "Bethesda markers", includes two reats (BAT25, BAT26) and three dinucleotide repeats (D2Sl23, D5S346 and Dl7S250). ln our we are currently using a different microsatellite panel composed by three rnononucleotide repeats (BAT25, BAT40) and two dinucleoide repeats (D2Sl23 and Dl8S57). Aim of our study is to evaluate the speciticity of r Q Btllhcsda markers, as compared with our panel, to identify MLHI and MSI-I2 mutation-positive HNPCC.We compared the results of MSI~analysis in tumours from 17 HNPCC families (according to and from 75 families in which not all the Amsterdam criteria were met (Suspected HNPCC), both the Bethesda panel and our alternative panel. MSI-H tumours were defined as having instability at two or markers (out of 5), while MSI-L tumours had instability at only one marker and MSS tumours were stable at all In addition, imrrninohistochemistry of MLH1 and MSH2 proteins was performed in all MSI-H and MSI-L to study the correlation between thc two MSI—panels and the expression of MLHI and MSH2 proteins. Results. Using the Bethesda markers, 27 (36%) out of the 75 Suspected HNPCC tumours and I2 (70,6%) out of the HNPCC tumours showed MSI. On the other hand, using our alternative panel, 16 (21.3%) Suspected HNPCC and 7 (41,2%) HNPCC tumours displayed MSI. In Suspected HNPCC tumours we found I5 (20%) md 5 (6.7%) MSI., using the Bethesda panel and our alternative panel respectively, while in I-INPCC tumours no MSI-L was detected us either panel. Loss of MLHI or MSH2 was evident in 15 out of 39 (38,5%) MSI tumours according to the Beth panel, whereas with our alternative panel 15 out of 23 (65.2%) MSI tumours showed no protein expression.Conclusions. Our data suggest that the Bethesda panel is more sensitive to defne MSI tumours, but the propose marker panel is more sensitive to identify MSI tumours lacking expression of MLHI and MSI-I2 proteins. The marker panel seems to have higher predictive value in the identification of patients with ML!-Il and MSH2 mutations.


2002 - hMSH6 immunohistochemistry in patients with clinical suspicion of Hereditary Non-Polyposis Colorectal Cancer. [Abstract in Atti di Convegno]
Scarselli, A; Benatti, Piero; Chichierchia, G; Ponti, Giovanni; Lucci Cordisco, E; Losi, Lorena; Menigatti, M; Pedroni, Monica; Borghi, F; Roncucci, Luca; Viel, A; Genuardi, M; PONZ DE LEON, Maurizio; Di Gregorio, C.
abstract

Congresso Italiano Patologia e Diagnostica Molecolare


2001 - Clinical and biologic heterogeneity of Hereditary NonPolyposis Colorectal Cancer. [Articolo su rivista]
Benatti, Piero; Roncucci, Luca; Ganazzi, Dorval; Percesepe, Antonio; Di Gregorio, C.; Pedroni, Monica; Borghi, F.; Sala, E.; Scarselli, A.; Menigatti, M.; Rossi, Giuseppina; Genuardi, M.; Viel, A.; PONZ DE LEON, Maurizio
abstract

MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clinical HNPCC families were divided into 3 groups: A, families with hMLH1 or hMSH2 gene mutations; B, MMR gene mutations not present but MSI present in at least 50% of tumors tested; C, mutational and MSI analyses negative. We evaluated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (colon and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and ureter) were more frequent in the first 2 groups than in the latter. Colon cancer was more frequently located in the proximal colon and showed an earlier age at onset in families with MMR gene mutation or with MSI than in families with stable tumors. Comparing the occurrence of tumors in the follow-up, in the first 2 groups patients younger than 50 years had a higher RR, which was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a better clinical prognosis. The results of molecular analysis could distinguish, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed. Copyright 2001 Wiley-Liss, Inc.


2001 - Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology Study Section of the Italian Society of Gastroenterology (SIGE). [Articolo su rivista]
Corleto, Vd; Panzuto, F; Falconi, M; Cannizzaro, R; Angeletti, S; Moretti, A; Delle Fave, G; Farinati, F; Roncucci, Luca
abstract

BACKGROUND:New insights in the diagnosis and treatment of digestive neuroendocrine tumours have prompted a renewed interest in these rare and complex diseases.AIM:To establish how many new cases of digestive neuroendocrine tumours were diagnosed, and how they were treated, at gastroenterological centres across Italy during a two-year period (1997-1998).METHODS:The 12 centres taking part filled in a data collection form reporting type of tumour, methods of diagnosis and therapeutic strategies adopted in each case. Data were collected and analysed by the authors of the present report.RESULTS:Data refer to 98 patients, 22 with functioning and 76 with non-functioning digestive neuroendocrine tumours [50 carcinoids, 48 pancreatic endocrine tumour syndromes]. Primary tumours were localised in 96% (38% with metastases) of non-functioning and 81% (50% with metastases) of functioning tumours. These were surgically removed in >80% of patients in both groups. Somatostatin analogue treatment, with or without interferon, was administered in 35% of patients, while chemotherapy was used in 9% and 23% of functioning and non-functioning tumours, respectively. The imaging study always included a computed tomography scan (20% helical computed tomography). Magnetic resonance and somatostatin receptor scintigraphy were also performed, the former in 41% and 21% of the two (functioning and non-functioning tumour) groups, the latter in 45% and 30%.CONCLUSIONS:The number of functioning digestive neuroendocrine tumours reported was lower than expected. Surgery plays a major role in the treatment of these tumours in all centres. Overall, in only a small number of patients was a multidisciplinary approach applied.


2001 - Epidemiologia dei tumori del colon-retto. Incidenza, mortalità, familiarità e sopravvivenza nella ex USL di Modena, 1984-1998. [Monografia/Trattato scientifico]
PONZ DE LEON, Maurizio; Benatti, Piero; Rossi, Giorgio; Di Gregorio, C.; Roncucci, Luca; Losi, Lorena; Foroni, M.; Pedroni, Monica; Menigatti, M.; Zangardi, G.; Scarselli, A.; Percesepe, Antonio; Borghi, F.; Pasquale, C.
abstract

not available


2001 - Genotype-phenotype association in Italian HNPCC families:preliminary results and proposal of a National collaborative study. [Monografia/Trattato scientifico]
Benatti, Piero; Lucci Cordisco, E.; Caluseriu, O.; Pedroni, Monica; Scarselli, A.; Losi, Lorena; Menigatti, M.; Borghi, F.; Roncucci, Luca; Viel, A.; Genuardi, M.; PONZ DE LEON, Maurizio
abstract

not available


2001 - Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer. [Articolo su rivista]
Di Gregorio, C; Borghi, F; Sala, E; Scarselli, A; Pedroni, Monica; Foroni, M; Benatti, Piero; Roncucci, Luca; PONZ DE LEON, Maurizio; Percesepe, Antonio; Menigatti, M
abstract

Nonrandom, widespread promoter methylation of tumor suppressor genes is a common mechanism of gene inactivation during tumorigenesis. We examined the methylation status of two distinct regions of the MLH1 promoter (proximal and distal to the transcription start site) and the MLH1 gene expression by methylation-specific PCR and immunohistochemistry. A total of 72 colorectal tumors, both with (n = 51, 22 affected by hereditary nonpolyposis colorectal cancer, HNPCC, defined according to the international clinical criteria and 29 sporadic cases) and without microsatellite instability (MSI) (n = 21) were studied. Methylation was present in at least one of the two promoter regions in 86% of the sporadic MSI cases, in 33% of the cases lacking MSI, and in 23% of the HNPCC tumors. In the HNPCC cases with a known MLH1 mutation (n = 10) none of the two promoter regions was methylated. Hypermethylation in both MLH1 promoter regions was seen in 45% of the MSI sporadic cases vs. 5% of the MSI-negative cases and 0% of the HNPCC cases. The overall concordance between the two promoter regions regarding methylation status was good (P = 0.009), but no significant correlation between methylation and suppression of the MLH1 immunohistochemical expression was found. Our data confirm that mutation and hypermethylation are mutually exclusive mechanisms in inducing mismatch repair deficiency and support the hypothesis of methylation as a process evenly distributed along the different regions of the promoter.


2001 - Microsatellite instability and mismatch-repair protein expression in hereditary and sporadic colorectal carcinogenesis [Articolo su rivista]
Pedroni, Monica; Sala, E; Scarselli, A; Borghi, F; Menigatti, M; Benatti, Piero; Percesepe, Antonio; Rossi, Giorgio; Foroni, M; Losi, Lorena; Di Gregorio, C; DE POL, Anto; Nascimbeni, R; Di Betta, E; Salerni, B; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Aberrant crypt foci (ACF) are microscopic clusters of altered colonic crypts considered premalignant lesions in the large bowel. Genomic instability at short tandem repeats in the DNA, referred to as microsatellite instability (MSI) is the hallmark of hereditary nonpolyposis colorectal carcinoma (HNPCC) caused by mutations in DNA mismatch-repair genes, mostly hMLH1 and LMSH2. In this study, we evaluated for MSI ACF (n = 16), adenomas (n = 18), carcinomas (n = 22), and lymph node metastases (n = 3) from 17 patients with colorectal cancer positive for MSI, Ten patients were members of HNPCC families; 7 patients had no family history of cancer. MSI was found in 7 of 7 (100%) ACF and 11 of 12 (91%) adenomas from patients with HNPCC, MSI was not related to histology and size of ACF. A progressive increase in instability as estimated by the number of shifted bands was observed along the ACF-adenoma-carcinoma sequence, In contrast, two of nine (228) ACF and none of six adenomas from patients with MSI sporadic carcinoma were unstable at microsatellite loci. hMLH1 or hMSH2 protein expression was altered only in MSI-positive premalignant lesions (ACF and/or adenomas), but not in all MSI-positive lesions in patients with HNPCC. These observations provide evidence of the premalignant nature of ACF in HNPCC and suggest that MSI is a very early event both in HNPCC and in sporadic colorectal carcinogenesis, although in the latter it seems infrequent.


2001 - Molecular screening for Hereditary Non Polyposis Colorectal Cancer (HNPCC): a prospective, population-based study [Articolo su rivista]
Percesepe, Antonio; F., Borghi; M., Menigatti; Losi, Lorena; M., Foroni; C., Di Gregorio; Rossi, Giuseppina; Pedroni, Monica; E., Sala; F., Vaccina; Roncucci, Luca; Benatti, Piero; A., Viel; M., Genuardi; G., Marra; P., Kristo; P., Peltomäki; PONZ DE LEON, Maurizio
abstract

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer.PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1.RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations.CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.


2001 - Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation [Articolo su rivista]
PONZ DE LEON, Maurizio; L., Varesco; Benatti, Piero; R., Sassatelli; P., Izzo; M. I., Scarano; G. B., Rossi; C., DI GREGORIO; V., Gismondi; Percesepe, Antonio; M., DE ROSA; Roncucci, Luca
abstract

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In the present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of desmoid neoplasms) associated with an unusual mutation of the adenomatosis polyposis coli gene. If confirmed by other investigations, these findings might help to understand the biologic mechanisms by which specific adenomatosis polyposis coli mutations predispose to desmoid tumors. METHODS: The family with familial adenomatous polyposis, living in southern Italy, was studied from 1985 to the end of 1999; at this date, 15 individuals have been affected by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors, A total of 19 family members were studied for adenomatosis polyposis coli gene mutations; 13 of them tested positive and 6 negative. The analytical procedure-previously described-consisted of the extraction of peripheral blood cell DNA, amplification of exon 15 by polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing of the DNA fragment containing the mutation. RESULTS: The main clinical features of the family were 1) a high frequency of desmoid tumors and, consequently, a high penetrance of the desmoid trait in all branches of the family and in 11 (73.3 percent) of 15 affected individuals and 2) severity of desmoids in at least 4 family members, 2 of whom died for causes related to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting of a large deletion of 310 base pairs at codon 1,464, with duplication of the breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the adenomatosis polyposis coli gene at the beginning of the region frequently associated with desmoids induced a familial adenomatous polyposis phenotype featured by a high penetrance of the desmoid trait, with severe disease in several affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli.


2001 - hMSH6 immunohistochemistry in families with clinical suspicion of Hereditary Non Polyposis Colorectal Cancer [Monografia/Trattato scientifico]
Scarselli, A.; Lucci Cordisco, E.; Benatti, Piero; Losi, Lorena; Menigatti, M.; Pedroni, Monica; Borghi, F.; Roncucci, Luca; Viel, A.; Genuardi, M.; PONZ DE LEON, Maurizio; Di Gregorio, C.
abstract

Not available


2000 - Aberrant crypt foci in colorectal carcinogenesis. Cell and crypt dynamics [Articolo su rivista]
Roncucci, Luca; Pedroni, Monica; F., Vaccina; Benatti, Piero; Marzona, Laura; DE POL, Anto
abstract

Aberrant crypt foci (ACF) have been identified on the colonic mucosal surface of rodents treated with colon carcinogens and of humans after methylene-blue staining and observation under a light microscope. Several lines of evidence strongly suggest that ACF with certain morphological, histological, cell kinetics, and genetic features are precursor lesions of colon cancer both in rodents and in humans. Thus, ACF represent the earliest step in colorectal carcinogenesis. This paper has the main purpose of reviewing the evidence supporting this view, with particular emphasis on cell and crypt dynamics in ACF. ACF have been used as intermediate biomarkers of cancer development in animal studies aimed at the identification of colon carcinogens and chemopreventive agents. Recently, evidence has also shown that ACF can be effectively employed in chemopreventive studies also in humans.


2000 - Genomic instability and target gene mutations in colon cancers with different degrees of allelic shifts [Articolo su rivista]
Percesepe, Antonio; Pedroni, Monica; Sala, E; Menigatti, M; Borghi, F; Losi, Lorena; Viel, A; Genuardi, M; Benatti, Piero; Roncucci, Luca; Peltomaki, P; PONZ DE LEON, Maurizio
abstract

Two grades (high and low) of microsatellite instability (MSI) are known, depending on the number of mutated markers and the amount of allelic shifts. Forty-two colorectal tumors, previously found to have high-degree MSI at dinucleotidic repeat loci, were revisited with BAT26, a mononucleotide marker, and the number of shifted bases were counted. Seven tumors, all with local stages at diagnosis, had less than or equal to 6-bp deletions and consistently displayed shorter shifts also with other intronic mononucleotide markers. Analysis of mononucleotide tracts in the coding regions of MSH3, MSH6, BAX, and TGF beta R11 in the groups with large (>6 bp) and short (less than or equal to 6 bp) allelic shifts showed specific patterns of involvement for the individual genes: TGF beta R11 displayed a uniformly high rate of mutations, while MSH3, MSH6, and BAX were less frequently altered in tumors with short shifts. Our findings suggest that microsatellite instability arises gradually, evenly involving loci with similar features of length and repetition. However, target genes have a specific timing of mutation in this process: TGF beta R11 is involved in the early phases, while BAX and MSH6 are frequently associated with big size shifts and tumors with more advanced stages.


2000 - Microsatellite instability in colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

non c'è


2000 - Problems in the identification of hereditary nonpolyposis colorectal cancer in two families with late development of full-blown clinical spectrum [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Pedroni, Monica; A., Viel; M., Genuardi; Percesepe, Antonio; Roncucci, Luca
abstract

The recognition of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) remains difficult despite the most recent advancements of molecular biology and technology. We describe two families with early onset of cancer but no suspicion of hereditary tumors; during follow-up, both families developed a tumor spectrum highly suggestive of HNPCC, thus emphasizing the importance of family history For a proper identification of hereditary tumors or cancer aggregation. Microsatellite instability was negative in tumors from both families and, as expected, no germline mutations of the major DNA mismatch repair genes (MSH2 and MLH1) could be detected. Suspicion of the disease at the time of proband´s lesion might have led to prevention, or early diagnosis, of at least three malignant turners. We conclude that a possible genetic origin should always be suspected in individuals with early-onset neoplasms of the large bowel and probably of other organs such as the endometrium, small bowel, and urothelium, even when the initial pedigree does not show marked aggregation of cancers or vertical transmission.


2000 - Staging and survival of colorectal cancer: are we making progress? The 14-year experience of a Specialized cancer Registry [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Di Gregorio, C; Fante, R; Rossi, Giorgio; Losi, Lorena; Pedroni, Monica; Percesepe, Antonio; Roncucci, Luca
abstract

Background and Aims. It is still unclear whether recent advancements in colorectal cancer research have led to an improvement in management and prognosis of the disease. Through the data of a specialized colorectal cancer Registry we aimed at analysing pathological staging and 5-year survival of ail patients with malignancies of large bowel diagnosed between 1984 and 1997. Main objective was to ascertain whether or not we are making progress in the control of this common neoplasm. Patients and Methods. During the 14-year period 1984-97, a total of 2,240 colorectal cancer patients were registered, for a crude incidence rate of 64.5 and 55.2/100,000/year in males and females, respectively Tumours were staged with Tumour Node, Metastasis system, corresponding to Dukes' classification, into four main groups. Survival was assessed with Life Table analysis, and statistical significance - between various subgroups - evaluated with Log-Rank Test. Results. Crude incidence rates of colorectal neoplasms showed minor fluctuations during initial period of registration, increasing sharply after 1990 mainly due to localized (stage I and II) lesions and, to a lesser degree, to stage ill tumours. Number of advanced (stage IV and unstaged) malignancies remained virtually stable. When results were expressed as percent of total cases, the fraction of localized lesions increased from 39% in the biennium 1984-5 to 51.6% in 1986-97, and the proportion of advanced tumours fail from 39% to 21.6% (p for trend <0.001). As expected, 5-year survival was significantly (p<0.002) more favourable for individuals diagnosed in 1990-91 than for patients registered in 1984-89. Conclusions. In Northern Italy, incidence rates of colorectal carcinoma are rising. This trend is associated with a sharp increase of newly detected localized lesions and with a significant improvement of overall 5-year survival The result may be attributed to several concomitant factors, such as: A) wider use of colonoscopy, B) increased education of patients, C) more attention given to symptoms.


2000 - The cause of colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Colorectal cancer continues to represent one of the major causes of cancer-related morbidity in all western countries. A review has been made of the main aetiological factors which have been related to colorectal cancer development with particular attention being focused on: a) new advancements in molecular biology, and b) the interaction between genetic predisposition and environmental factors. Worldwide, approximately 900,000 cases of colorectal malignancies have been diagnosed in 1996 and this accounts for 8.5% of all new Gases of cancer. Crude incidence rates range from 0.6-5.0 cases/100,000/year in Senegal and India to 50-70 cases in developed countries. Environmental factors, such as meat, saturated fat, low physical activity, obesity, smoking, alcoholic beverages, and inflammatory bowel diseases seem to increase the risk of colorectal cancer. in contrast, fruit, vegetables, fibre, antioxidant vitamins, calcium, folate, physical exercise and non-steroidal anti-inflammatory drugs seem to show a protective effect. For some of these factors, the molecular basis of their mechanism of action begins to be elucidated. Colorectal cancer develops from benign precursors, the adenomatous polyps; there is extensive evidence that polyps transform into cancer in a stepwise manner, and that several molecular abnormalities (mutations of oncogenes, inactivation of tumour suppressor genes and microsatellite instability) accompany and, somehow, determine colorectal tumourigenesis. Two major Hereditary Colorectal Cancer syndromes - Familial Adenomatous Polyposis and Hereditary Non-polyposis Colorectal Cancer - have been described and characterized st molecular levels; it is estimated that these inherited conditions might account for up to 5% of all large bowel malignancies. Familial colorectal cancer remains undefined and is presumably due to multifactorial inheritance. Recently, identified germline mutations (such as /1307K in the APC gene) might account for a fraction of these familial cases, at least in some populations. At variance with many other tumours, the aetiology and pathogenesis of colorectal cancer have been partially clarified, so that we are now in the position to take preventive measures and to design surveillance programmes which might lead to a certain reduction in incidence and mortality. However, since many of the aetiological factors are strictly related to modern customs and lifestyle, they will be difficult to eradicate; this awareness should stimulate further investigations in this exciting field of research.


1999 - Cancer prevalence in Italian cancer registry areas: The ITAPREVAL study [Articolo su rivista]
Micheli, A.; Francisci, S.; Krogh, V.; Giorgi Rossi, A.; Crosignani, P.; Micheli, A.; Gatta, G.; Sant, M.; Giorgi Rossi, A.; Francisci, S.; Saltarelli, S.; Dell'Era, L.; Gasparre, N.; Verdecchia, A.; Capocaccia, R.; Mariotto, A.; Dally, L.; Corazziari, I.; Conti, E.; Ramazzotti, V.; Caperle, M.; Vercelli, M.; Caselli, C.; Parodi, S.; Crosignani, P.; Tagliabue, G.; Berrino, F.; Federico, Massimo; Mangone, L.; Santacroce, M.; PONZ DE LEON, Maurizio; Roncucci, Luca; Benatti, Piero; Zanetti, R.; Rosso, S.; Patriarca, S.; Falchi, F.; Milandri, C.; Vattiato, R.; De Lisi, V.; Serventi, L.; Barili, A.; Gafà, L.; Tumino, R.; La Rosa, E.; Barchielli, A.; Balzi, D.; Crocetti, E.; Paci, E.; Guzzinati, S.; Simonato, L.; Bovo, E.
abstract

Aim: To present data on cancer prevalence for the areas covered by Italian cancer registries, by using a standardized set of data collection and elaboration criteria, and a single method of data analysis. Subjects and Methods: Data on over 250,000 patients with cancer, diagnosed between 1978 and 1992, from 11 Italian cancer registries covering about 12% of the Italian population were collected, validated and analyzed according to the unified protocol of the ITAPREVAL project. The method implemented in the PREVAL computer program was used to provide prevalence estimates for the period covered by cancer registration. The total prevalence for each registry and for the pool of all registries was then estimated by correcting for incomplete observations due to the period in which the registration was not yet activated. All prevalence estimates were for 1992. Results: Prevalence figures are presented by cancer site, age, sex, years from diagnosis and registry area. For all malignancies combined, total prevalence ranged from 1,350 per 100,000 inhabitants in Ragusa to 3,650 per 100,000 inhabitants in Romagna, the ratio between these two extremes being 2.7. For the pool of the areas covered by registration cancer prevalence was 3,100 per 100,000 females and 2,250 per 100,000 males. About a third of the total female cases and about half the male cases were diagnosed in the previous five years. Among those aged over 75 years, total prevalence was higher for males than for females: 11,300 versus 8,900 per 100,000 respectively. Conclusions: This is the first large-scale estimate of the burden of cancer in Italy. It is also one of the first studies in the world which was aimed to study cancer prevalence in detail. These data are necessary for predicting health service needs and help in the evaluation of differences in health service demand by sex, age and Italian regions.


1999 - Clinical and molecular diagnosis of hereditary non-polyposis colorectal cancer: problems and pitfalls in an extended pedigree [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Percesepe, Antonio; Rossi, Giorgio; A., Viel; M., Santarosa; Pedroni, Monica; Roncucci, Luca
abstract

Hereditary non-polyposis colorectal cancer (or Lynch syndrome) is an autosomal dominant disease in which early onset colorectal carcinomas aggregate in families together with tumours of other organs. The genetic basis of the syndrome has been clarified with the identification of mutations in several DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We describe the clinical features and molecular characterization of a large hereditary nonpolyposis colorectal cancer family which has been followed for almost 10 years. The kindred showed a striking aggregation of colorectal tumours in 3 successive generations; most of these neoplasms developed before the age of 50 years and were localized in the proximal colon. Molecular tests (carried out in ten individuals) showed specific alterations at the MLH1 gene, consisting in the insertion of a T nucleotide between bases 2,269 and 2,270; the mutation caused frameshift of the open reading frame and synthesis of a polypeptide longer than normal. The only tumour that could be analysed was positive for microsatellite instability. Physicians should become more confident with hereditary tumours and their implications, which are not limited to a single individual but concern all family members at risk of cancer This family approach is different, and requires more expertise than the traditional individual approach. Common problems encountered in Hereditary Non-polyposis Colorectal Cancer families include: A) poor collaboration of subjects at risk (a situation which may cause some conflict between the doctor's duty to inform patients about their risk of disease and the rights of patients to choose and decide about their health); B) definition of the most appropriate surveillance programme for a given family (how many investigations to propose to the patients, and how often); C) possible interaction between genes and environmental factors (for instance, a gene carrier - in this family - developed an endometrial carcinoma after standard tamoxifen adjuvant therapy for breast cancer).


1999 - Clinical features and genotype-phenotype correlations in 41 Italian families with Adenomatosis Coli [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Percesepe, Antonio; A., Cacciatore; R., Sassatelli; G., Bertoni; G., Sabadini; L., Varesco; V., Gismondi; C., Mareni; M., Montera; C., DI GREGORIO; P., Landi; Roncucci, Luca
abstract

Background: Familial Adenomatous Polyposis in an autosomal dominant disease in which the large bowel is carpeted by polyps of various dimensions appearing during the second or third decade of life. Several extracolonic manifestations complete the clinical spectrum of Familial Adenomatous Polyposis. If untreated, the disease lends invariably to colorectal cancel: The gene responsible for the disease, adenomatous Polyposis Coli, has been localized at chromosome 5q21. Aims: To describe the clinical features of 156 Familial Adenomatous Polyposis patients (from 41 families) and to analyze possible correlations between genotype and phenotype. Patients and Methods: Familial Adenomatous Polyposis was defined as the presence of 100 or more polyps in the large bowel. In 17 families (41 %), the proband was the only affected individual (single cases). Adenomatous Polyposis Coli gene mutations were studied on DNA extracted from peripheral white blood cells and evaluated by polymerase chain reaction single strand conformation polymorphism, followed by direct sequencing of samples showing abnormal banding at single strand conformation polymorphism. Results: The large majority of Familial Adenomatous Polyposis patients underwent surgery; colectomy with ileorectal anastomosis was the most frequent approach, however cancer of the rectal stump developed in 11.6% of patients submitted to colectomy and ileorectal anastomosis. Adenomas were rare in the stomach (8.8%), but their frequency increased in the duodenum (33.8%) and jejunum (55.0%, chi(2) for trend 23.7, p<0.001). Desmoid rumours were diagnosed in 17 patients (10.9% of the total) and in 6 families. Mutations of the Adenomatous Polyposis Coli gene were studied in 20 out of 25 families (80%) and on a total of 75 individuals. The most frequent alterations were Ito 5 bp deletions lending to stop codons and truncated proteins. Desmoid tumors, presence of duodenal or jejunal adenomas were associated with an ample range of mutations, from codon 215 to codon 1464, In contrast, particularly severe polyposis (mean age at appearance of polyps 11-16 years, and of cancer development 27-32 years) was associated with a hot-spot mutation site at codons 1303-1309. Conclusions: In patients with Familial Adenomatous Polyposis, subtotal colectomy with ileorectal anastomosis is still the treatment of choice. Adenomatous lesions seem to show a gradient distribution from the stomach to the large bowel. Desmoid tumours are relatively common, though their incidence is limited to some of the families. Constitutional mutations can be detected in 80% of the investigated families. Genotype-phenotype correlations showed a hat-spot at codons 1303-1309, frequently associated with severe polyposis.


1999 - Epidemiologic and genetic factor in colorectal cancer: development of cancer in dizygotic twins in a family with Lynch syndrome [Articolo su rivista]
PONZ DE LEON, Maurizio; Pedroni, Monica; Benatti, Piero; Percesepe, Antonio; Rossi, Giorgio; M., Genuardi; Roncucci, Luca
abstract

Human tumours usually develop due to a close inter action between environmental and genetic factors. This concept applies also to well defined genetic diseases such as Hereditary Nonpolyposis Colorectal Cancer (HNPCC or Lynch syndrome), which is featured by early onset tumours of the large bowel(and other target organs), striking aggregation of neoplasms in families, and vertical transmission consistent with an autosomal dominant pattern of inheritance. As a further example of gene/environment interaction, we report on a Hereditary Nonpolyposis Colorectal Cancer family in which two dizygotic twins were affected by cancer of the large bowel. One of the twins was slightly overweight and showed many common risk factors for colorectal carcinoma he developed a Dukes' C lesion at the age of 52 The other twin was not overweight and was much less exposed to exogenous risk factors; a Dukes' B carcinoma was diagnosed nt age 60 during a control endoscopy. This anedoctal report suggests that diet and lifestyle are of relevance also in patients with genetically determined tumours of the large bowel. It follows that the control of these environmental factors might be associated with a delay of tumour occurrence and possibly with a less aggressive tumour behaviour.


1999 - Epidemiology of cancer of the large bowel - The 12-year experience of a specialized registry in Northern Italy [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Percesepe, Antonio; C., Di Gregorio; R., Fante; Losi, Lorena; Rossi, Giorgio; Pedroni, Monica; Roncucci, Luca
abstract

Background. In 1984 a specialized colorectal cancer registry was instituted in Modena; aims of the Registry were: the evaluation of incidence and mortality, the study of morphological aspects, staging, staging and familiarity of the registered patients. Aims. Purpose of the research was to provide an updated description of the main findings (in particular incidence, staging, morphology and survival) observed in the 12-year registration period. Patients and methods. Between January 1984 and December 1995, 1,899 malignancies of the large bowel in 1,831 patients were registered. Tumours were classified according to the International Classification of the Diseases for Oncology (ICD-O) and staged with the TNM system Cancer specific srm il nl was assessed with life table analysis and Log-Rank tests. Results. Crude incidence rare showed minor fluctuations between 1984 and 1989, but tended to rise in the following pears. Tumours were mostly located distal to the splenic flexure (73.3% of the total), with a slight tendency over time to a gradual shift to the right colon. Staging became progressively more favourable throughout the registration; in 1984 both stages I, II and stage IV + unstaged lesions represented 40% of the total, but in 1995 the former rose to 50% whereas the latter fell to 21.6% (p<0.001). This more to earlier stages resulted in an improved survival of patients registered in 1990-91 versus 1983-85 (Log-Rank 14.3 p<0.002). Factors associated with a poor survival were the advanced age of patients at diagnosis (>74) and clinical stage. Conclusions. Main aspects of the investigation were the increasing crude incidence rates of colorectal turnovers and the gradual increase of neoplasms diagnosed irt a more favourable staging. It is like likely that the improvement of staging and survival observed in the 12 fears of registration can be attributed to the improved attitude to health care of the population, and possibly to the improvement of surgical techniques.


1999 - Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis [Articolo su rivista]
PONZ DE LEON, Maurizio; Pedroni, Monica; Benatti, Piero; Percesepe, Antonio; Di Gregorio, C; Foroni, M; Rossi, Giorgio; Genuardi, M; Neri, G; Leonardi, F; Viel, A; Capozzi, E; Boiocchi, M; Roncucci, Luca
abstract

Background-Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited disorders predisposing to cancer. The genes responsible for the disease have recently been cloned and characterised; their mutations induce a generalised genomic instability which is particularly evident at microsatellite loci (replication error (RER)+ phenotype). Aims-To investigate how to select individuals and families in the general population who should be screened for constitutional mutations predisposing to colorectal cancer. Patients/Methods-Between 1984 and 1995, 1899 colorectal malignancies in 1831 patients were registered, and in 1721 of these (9-1%), family trees could be obtained. Patients and families were classified into five categories according to a more or less likely genetic basis: HNPCC; suspected HNPCC;; juvenile cases; aspecific cancer aggregation; sporadic cases. In 18 families with HNPCC as well as in 18 with suspected HNPCC, microsatellite instability in tumour tissues and constitutional mutations of two DNA mismatch repair genes (MSH2 and MLH1) could be evaluated. RER status was studied with five markers (BAT40, D2S123, D18S57, D17S787, and BAT26) in paraffin embedded tissues. Germline mutations of MSH2 or MLH1 genes were assessed on DNA and RNA extracted from lymphomonocytic cells, using reverse transcription polymerase chain reaction, single strand conformation polymorphism analysis, and direct DNA sequencing. Results-HNPCC represented 2.6% and suspected HNPCC 4.6% of all registered colorectal neoplasms. Eleven out of 18 HNPCC families (61%) showed microsatellite instability as opposed to four (of 18) suspected HNPCC (22%; p<0.02). Three germline mutations (two in MSH2 and one in MLH1 gene) were found in three different large HNPCC families, whereas no mutations were detected in suspected HNPCC. Conclusions-In this study of cancer genetic epidemiology, data from a tumour registry were analysed and this ultimately led to the identification and selection of families that should be tested for mutator gene mutations. With the use of a population based approach, the incidence of mutations was appreciably lower than previously reported and limited to families with full blown HNPCC. It is possible that in most families with a clinical spectrum Of HNPCC (or suspected HNPCC) other DNA mismatch repair genes are involved in the pathogenesis of the disease.


1999 - Microsatellite instability in multiple colorectal tumors [Articolo su rivista]
Pedroni, Monica; Mg, Tamassia; Percesepe, Antonio; Roncucci, Luca; Benatti, Piero; G., Lanza; R., Gafa; C., Di Gregorio; R., Fante; Losi, Lorena; L., Gallinari; PONZ DE LEON, Maurizio; F., Scorcioni; F., Vaccina; Rossi, Giuseppina; A. M., Cesinaro
abstract

Tumor multiplicity is a hallmark of hereditary cancers: in the colon-rectum multiple tumors represent 5-10% of all colorectal cancer cases. A portion of these cases belongs to hereditary non-polyposis colorectal cancer (HNPCC), a genetic cancer syndrome due to mismatch repair (MMR) gene mutations, phenotypically expressed as microsatellite instability (MSI); the majority of multiple tumors, however, is apparently without any family history. We analyzed 78 (38 synchronous and 40 metachronous) neoplasms from 37 patients with multiple tumors of the large bowel, both HNPCC and sporadic, with the aim of identifying a common genetic basis in multiple tumors. DNA was extracted from normal and cancerous formalin-fixed tissue and was analyzed for MSI using 6 markers. Tumors showing MSI in at least 2 of 6 microsatellite loci were defined as MSI(+). The overall number of MSI(+) tumors was 22 (28.2% of the total). A significant difference in the rate of MSI(+) between HNPCC and sporadic tumors was observed (85% vs. 17%). In the same patients, the MSI phenotype of synchronous tumors (both HNPCC and sporadic) tended to be more concordant than that of the metachronous ones. The higher frequency of MSI in HNPCC than in sporadic tumors, even when multiple, suggests that the involvement of MMR genes in the pathogenesis of the sporadic cases may be uncommon, thus confirming that screening for MSI in multiple colorectal tumors could be a useful tool in the identification of HNPCC in the general population.


1998 - Aberrant crypt foci in patients with colorectal cancer [Articolo su rivista]
Roncucci, Luca; S., Modica; Pedroni, Monica; Mg, Tamassia; M., Ghidoni; Losi, Lorena; R., Fante; C., Di Gregorio; Manenti, Antonio; L., Gafa; PONZ DE LEON, Maurizio
abstract

Aberrant crypt foci (ACF) are clusters of abnormally large colonic crypts identified on the mucosal surface of the human colon. They are thought to be preneoplastic lesions. The aim of the present study was to compare density (number of ACF per square cm of mucosal surface), crypt multiplicity (number of crypts per ACF) and histology of ACF in colonic resections of colorectal cancer patients resident in two Italian provinces with a twofold difference in colorectal cancer incidence rates. Thirty-two and 26 colonic resections were collected after operation in Ragusa (Southern Italy) and Modena (Northern Italy), respectively, and fixed in 10% formalin. Mucosal layers were observed under a light microscope at 25x after staining with methylene blue. Density of ACF was significantly higher in Modena (median 0.101 ACF cm(-2)) than in Ragusa (0.049, P= 0.001), whereas there was no difference in crypt multiplicity. ACF were classified into three groups according to histological features. ACF with mild alterations (hypertrophic ACF, 73%), ACF with hyperplasia (hyperplastic ACF, 17%) and ACF with dysplasia (microadenomas, 10%). The proportions of ACF in the three groups were similar in the two provinces, Density of ACF was higher and crypt multiplicity lower proceeding from proximal to distal large bower. Microadenomas were observed only in the colon, whereas hyperplastic ACF were more frequent in the rectum, In conclusion, density of ACF correlates with colorectal cancer rates in two Italian provinces, and shows a positive gradient from proximal to distal large bowel. Histology of ACF suggests that they may be precursors of both hyperplastic and adenomatous polyps. These data provide further evidence of the role of ACF in human colorectal carcinogenesis.


1998 - Frequency and type of colorectal tumors in asymptomatic high-risk individuals in families with hereditary nonpolyposis colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; Della Casa, G; Benatti, Piero; Percesepe, Antonio; Di Gregorio, C; Fante, R; Roncucci, Luca
abstract

In hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome) a close surveillance is usually proposed to high-risk family members with the ultimate goal of reducing cancer incidence and mortality. Through a specialized registry, between 1984 and 1996, we identified 31 families with clinical features of HNPCC, A total of 390 first-degree relatives of affected patients were considered at high risk for colorectal cancer. The main purposes of this study were: (a) to assess overall compliance; and (b) to evaluate the frequency and morphological features of tumors detected at endoscopy, Two hundred twenty-three subjects could be directly interviewed and colonoscopy strongly recommended. Each of the 86 individuals who underwent colonoscopy was matched to a control of the same age (+/-3 years) and sex (control subjects were seeking endoscopy for constipation, rectal bleeding or abdominal discomfort). Of the 390 individuals traced as at risk, 223 (57.2%) could be contacted, and, of these, 86 (38,6%, or 22.0% of the total) underwent colonoscopy, One or more colorectal lesions were found in 35 of 86 (40.7%) HNPCC asymptomatic family members and in 15 (17.4%; P < 0.001) controls. In the former group, 29 adenomas were detected in 20 individuals as opposed to 11 adenomas in 9 subjects among controls (P < 0,03), Moreover, adenomas in family members were significantly larger [9.1 +/- 5.9 mm (mean +/- SD) versus 5.8 +/- 3.7 mm; P < 0.02] and more frequently showed a tubulovillous histological type and a high degree of dysplasia, Five colorectal carcinomas (in four patients) were detected among cases (four of which were located between the cecum and the hepatic flexure); only one was detected among controls, Surveillance of high-risk subjects in HNPCC families can be carried out only in a fraction of them, because the majority cannot be reached or refuse to collaborate. On the other hand, the frequency of newly detected lesions among family members and the possible aggressive behavior of the lesions render pancolonoscopy necessary at regular intervals of time.


1998 - MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer. [Articolo su rivista]
M., Genuardi; M., Anti; E., Capozzi; F., Leonardi; M., Fornasarig; E., Novella; A., Bellacosa; A., Valenti; G. B., Gasbarrini; Roncucci, Luca; Benatti, Piero; Percesepe, Antonio; PONZ DE LEON, Maurizio; C., Coco; A., De Paoli; M., Valentini; M., Boiocchi; G., Neri; A., Viel
abstract

Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (<40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.


1998 - Scanning electron microscopy of aberrant crypt foci in human colorectal mucosa [Articolo su rivista]
F., Vaccina; F., Scorcioni; Pedroni, Monica; Mg, Tamassia; PONZ DE LEON, Maurizio; DE POL, Anto; Marzona, Laura; Roncucci, Luca
abstract

Background: Aberrant crypt foci (ACF) are clusters of morphologically altered crypts which can be observed by light or stereomicroscopy on the mucosal surface of the colon after staining with methylene-blue. They probably represent one of the earliest events in human colorectal carcinogenesis. The main purpose of the present study was to observe the surface features of aberrant and normal colonic crypts in humans using scanning electron microscopy (SEM) in order to find and measure differences between aberrant and normal. Materials and Methods: Fifteen mucosal specimens containing ACF and 8 with normal mucosa taken from patients operated on for colon cancer were observed under a scanning electron microscope. Results: By SEM ACF were easily observed on the mucosal surface because they showed a well defined border and were elevated on the mucosal surface. Under higher magnification luminal openings of aberrant crypts had a larger overall average diameter than normal (37.6 mu m +/- 13.5, mean a SD, vs 15.9 mu m +/- 4.9, P=0.001), though when crypt multiplicity of ACF (number of crypts per ACF) was higher, the diameter of luminal openings tended to be smaller and similar to those of normal crypts, with weak negative correlation between crypt multiplicity of ACF and mean diameter of aberrant luminal openings (r=-0.27). Finally, the mucosal surface among aberrant crypts was flattened because of a loss of microvilli. In conclusion, scanning electron microscopy allows a better definition of the topological features of aberrant crypt foci than light or stereomicroscopy.


1998 - Small bowel carcinoma in hereditary nonpolyposis colorectal cancer [Articolo su rivista]
Benatti, Piero; Roncucci, Luca; Percesepe, Antonio; A., Viel; Pedroni, Monica; Mg, Tamassia; F., Vaccina; R., Fante; S., De Pietri; PONZ DE LEON, Maurizio
abstract

A 53-yr-old man, a member of a hereditary nonpolyposis colorectal cancer (HNPCC) family, with previous colonoscopic polypectomies, presented for persisting vomiting and marked signs of dehydration. Previous radiological and endoscopic examinations of the upper digestive tract were negative, with the exception of the presence of a duodenal adenomatous polyp. Enteroclysis led to a diagnosis of obstruction at the Treitz angle due to a moderately differentiated adenocarcinoma, Microsatellite instability was demonstrated in the DNA extracted from the tumor. The patient was the carrier of a mutation in the intron 13 of the hMLH1 gene, one of the four mismatch repair genes known to be responsible for HNPCC.


1997 - A two-locus model for hereditary non-polyposis colorectal cancer in Modena, Italy [Articolo su rivista]
C., Scapoli; A., Collins; Benatti, Piero; Percesepe, Antonio; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Complex segregation analysis was conducted in a series of patients with hereditary non-polyposis colorectal cancer (HNPCC) ascertained through probands registered in the Cancer Registry of the Health Care District of Modena, Northern Italy. Altogether there were 125 nuclear families segregating for HNPCC, for a total of 672 individuals. The analysis favoured a two-locus model, with both susceptibility genes rare and dominant. The gene frequency of the deleterious allele at the major locus is estimated to be low qm = 0.004 and for the second locus the estimate is even lower q = 0.00003. Both genes defining the two-locus model seem to be highly penetrant. The lifetime penetrance of the abnormal gene at the major locus is estimated to be 0.73 for female, while the estimation for male is higher, 0.85.


1997 - Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer. [Articolo su rivista]
A., Viel; M., Genuardi; E., Capozzi; A., Bellacosa; M., PARAVATOU PETSOTAS; M. G., Pomponi; M., Fornasarig; Percesepe, Antonio; Roncucci, Luca; Tamassia, M. G.; Benatti, Piero; PONZ DE LEON, Maurizio; A., Valenti; M., Covino; M., Anti; M., Foletto; M., Boiocchi; G., Neri
abstract

Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the ´´Amsterdam criteria´´ A combination of different techniques, including reverse transcription-polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations.


1997 - Chemoprevention of colorectal tumors: Role of lactulose and of other agents [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Chemoprevention can be defined as an attempt at cancer control in which the occurrence of the disease is prevented by the administration of one (or more) chemical compounds. Main problems in chemoprevention studies are the choice of a suitable drug; the choice of an appropriate intermediate or definitive end point, and the definition of the population which should be investigated. Main classes of chemopreventive agents include vitamins, non-steroid antinflammatory drugs, minerals such as calcium or selenium, and other antioxidants such as N-acetylcysteine. Chemoprevention is particularly appealing in colorectal cancer, either because these lesions develop through a multistep process, or owing to the concept of 'field carcinogenesis'. Between 1985 and 1990 we carried out a controlled study in which antioxidant vitamins or lactulose were used in an attempt to prevent the recurrence of colorectal polyps after their endoscopic removal. Among the 209 patients who could be evaluated, polyps recurred in 5.7% of the individuals who were given vitamins (A, C and E), 14.7% of patients given lactulose and 35.9% of untreated controls (chi(2) = 17.1, P < 0.001). The study suggested that either antioxidant vitamins or lactulose could be effective in reducing the recurrence rate of adenomatous polyps. In a subsequent on-going study, lower doses of the same vitamins were tested versus N-acetylcysteine (600 mg/day) or no treatment. Preliminary results showed a 40% reduction of the recurrence of polyps (versus controls) in individuals given N-acetylcysteine, while the effect of lower doses of vitamins was less appreciable. Definitive results of the study should be available by the end of 1998.


1997 - Colorectal carcinoma in different age groups: A population based investigation [Articolo su rivista]
R., Fante; Benatti, Piero; S., Depietri; Pedroni, Monica; Mg, Tamassia; Percesepe, Antonio; Losi, Lorena; Roncucci, Luca; PONZ DE LEON, Maurizio; DI GREGORIO, Carmela; Rossi, Giuseppina
abstract

Although colorectal cancer is a disease of the older population, these tumors are not infrequent before the age of 55. Through the data of a population-based registry, we proposed giving a description of the clinical features of three groups of patients in whom the disease occurred at a relatively early age of onset (group I: < 40 yr; group II: 41-50 yr; group III: 51-55 yr). There were only 14 patients under the age of 40 yr (1.1% of total registered patients, n = 1298 in the period 1984-1992). Group II and III represented 5.9% and 6.0%, respectively (n = 76 and 78), with minor fluctuations throughout the 9-yr period of registration. Inherited colorectal tumors [hereditary nonpolyposis colorectal cancer (HNPCC), adenomatosis coli, and suspected HNPCC] accounted for 38.4% of group I patients (5 of 14), 17.1% of group II, 10.2% of group III, and only 3.5% of individuals older than 55 (p, for trend, < 0.001). Thus, hereditary colorectal tumors were detected significantly more often in younger individuals. The majority of colorectal malignancies were localized in the left colon or rectum in all three groups,,vith a tendency (not significant) to a preferential localization in the right colon for tumors developed in group I (37% vs 18% and 14% in groups II and III, respectively). Pathological stage and main histological types did not differ among the three groups. Finally, life-table analysis did not show significant differences in 5-yr survival among the three groups; however, when considered together, early onset cases showed a more favorable prognosis than older individuals (log-rank 11.6; p < 0.001). In conclusion, colorectal cancer is diagnosed very rarely before the age of 40 yr, whereas about 12% of all cases belong to the age group 41 to 55 yr of age. Hereditary tumors were found more frequently in younger patients, with a well-defined inverse relationship between age of onset and frequency of genetically determined tumors. Finally, the clinical outcome was more favorable in the whole series of early onset cases than in older registered patients.


1997 - Estimation and projections of colorectal cancer trends in Italy. [Articolo su rivista]
Capocaccia, R; De Angelis, R; Frova, L; Gatta, G; Sant, M; Micheli, A; Berrino, F; Conti, E; Gafà, L; Roncucci, Luca; Verdecchia, A.
abstract

n/a


1997 - Factors associated with gallstone disease in the MICOL experience [Articolo su rivista]
Attili, Af; Capocaccia, R; Carulli, Nicola; Festi, D; Roda, E; Barbara, L; Capocaccia, L; Menotti, A; Okolicsanyi, L; Ricci, G; Lalloni, L; Mariotti, S; Sama, C; Scafato, E; the MICOL, Group; Roncucci, Luca
abstract

The epidemiological associations of gallstone disease were evaluated in a general population sample of 29,584 individuals (15,910 men and 13,674 women; age range, 30-39 years) belonging to 14 cohorts examined between December 1984 and April 1987. Subjects were screened for the presence of gallstones by gallbladder ultrasonography, completed a questionnaire, and underwent a physical examination and blood chemistry tests. Participants were considered to have gallstone disease if they had already had cholecystectomy or gallstones. Statistical associations were established by univariate analysis of the age-standardized data and by stepwise multiple logistic regression. Increasing age and body mass index and a maternal family history of gallstone disease were the most consistent associations (both at univariate and multivariate analysis and in both sexes) found in this study. Personal history of dieting was associated with gallstone disease in men, and at univariate analysis, in women. Decreasing serum total cholesterol levels and increasing serum triglycerides were associated with gallstone disease in both sexes in the multivariate analysis. In women, associations were also found with a number of pregnancies and paternal family history of gallstone disease. A slight but negative association with contraceptive pill use was identified only at multivariate analysis. Associations (investigated at univariate analysis) were also found with diabetes, cirrhosis, angina or myocardial infarction, and peptic ulcer. There was no association with smoking habits and use of aspirin or antirheumatic drugs.


1997 - Histology of aberrant crypt foci in the human colon [Articolo su rivista]
Di Gregorio, C; Losi, Lorena; Fante, R; Modica, S; Ghidoni, M; Pedroni, Monica; Tamassia, Mg; Gafà, R; PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

Aberrant crypt foci (ACF) have been identified in the methylene-blue stained mucosa of the human colon, Some lines of evidence suggest that ACF may be precursors of colon cancer, The objective of the present study was to establish morphological criteria able to define and classify ACF in histological sections, Twenty four colectomy specimens were collected after operation for colorectal cancer and fixed in 10% formalin, Strips of grossly normal mucosa were stained in a 0.2% solution of methylene blue in saline for 5-10min. The strips were measured, put on a glass slide and observed under a light microscope at x25, One hundred and fourteen ACF identified by topology were sectioned parallel to the muscularis mucosae. Eighty-four ACF were evident at histological examination and could be classed into three main groups: group A (61 ACF 72.6%) including foci whose epithelial cells had regular nuclei, with only mild or focal crowding but no stratification, no mucin depletion and no dysplasia; group B (16 ACF 19.1%), in which features of hyperplasia were evident; and group C (seven ACF 8.3%) including foci with enlarged, crowded and stratified nuclei, mucin depletion, frequent mitoses, and evident dysplasia, diffuse or focal (mild in five cases, moderate in two) representing microadenomas, Finally, hyperplastic foci were significantly larger than foci of group A and C, Group B ACF were also more frequent in the rectum than in the colon. In conclusion, selected histological features allow the definition of groups of ACF, which may represent sequential steps in the development of human colorectal tumours.


1997 - K-ras and p53 mutations in hereditary non-polyposis colorectal cancers [Articolo su rivista]
Losi, Lorena; PONZ DE LEON, Maurizio; Jiricny, J; Di Gregorio, C; Benatti, Piero; Percesepe, Antonio; Fante, R; Roncucci, Luca; Pedroni, Monica; Benhattar, J.
abstract

Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). To test that the targets of genetic instability could include critical transforming genes involved in colon tumor progression, we examined 23 colorectal carcinomas in patients with HNPCC in order to detect somatic mutations in K-ros and p53 genes. Using single strand conformation polymorphism followed by direct DNA sequencing, we detected 4 mutations in K-ros gene (17%) and 3 in p53 gene (13%) which change the aminoacid sequence of the protein p53. This is significantly lower than in sporadic cancer. Our data suggest that colon cancer in HNPCC might partly involve a distinct pathogenetic mechanism that involves other genes than those altered in sporadic tumors.


1997 - Survival analysis in families affected by hereditary non-polyposis colorectal cancer [Articolo su rivista]
Percesepe, Antonio; Benatti, Piero; Roncucci, Luca; R., Sassatelli; R., Fante; D., Ganazzi; A., Bellacosa; M., Genuardi; G., Neri; A., Viel; PONZ DE LEON, Maurizio
abstract

Previous survival studies suggested a better prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with the sporadic counterpart. In the present study we evaluated the clinical outcome of HNPCC patients with respect to that of patients with colorectal cancer re corded in a population-based cancer registry. We assessed survival of 85 colorectal cancer patients from 24 unrelated families defined as having HNPCC according to the criteria of the international Collaborative Group, for whom adequate information on subject- and tumor-related parameters and a 5-year follow-up (cancer diagnosis from 1980-1989) were available. Three hundred and seventy-seven colorectal cancer patients, registered from 1984-1986, with a 5-year followup, were used for comparison. Colorectal cancer-specific 5-year survival rates were 55.2% and 42.5% for HNPCC and non HNPCC, respectively. Using Cox regression analysis, tumor staging and location were independently associated with survival, whereas HNPCC diagnosis was not. Stage II HNPCC cases exhibited a better prognosis than non-HNPCC patients. By Cox regression analysis, none of the variables were significantly related to survival. Both overall and stage II HNPCC cases showed a survival advantage in comparison with non-HNPCC patients. However, the difference disappeared when clinical and pathological variables were controlled for with a Cox regression analysis.


1996 - Clinical features, frequency and prognosis of Dukes' a colorectal carcinoma: A population-based investigation [Articolo su rivista]
C., Digregorio; R., Fante; Roncucci, Luca; Mg, Tamassia; Losi, Lorena; Benatti, Piero; Pedroni, Monica; Percesepe, Antonio; S., Depietri; PONZ DE LEON, Maurizio
abstract

The main aim of this study was, through the data of a population-based Registry, to establish the incidence of Dukes´ A lesions by year of registration and the main clinical features, and to assess cancer-specific survival. One hundred and eighteen Dukes´ A colorectal tumours were diagnosed (in 117 patients) out of 1337 registered between 1984 and 1992 in the Health Care District of Modena, Northern Italy; 94 patients were treated with surgery and 23 with endoscopic polypectomy. The frequency of Dukes´ A tumours ranged between 4.8% and 18% by year of registration. Dukes´ A carcinomas were significantly more frequent in the distal colon. Only 5 patients (4%) died of their cancer, and in all patients the tumour was localised in the rectum. Carcinomas associated with a poor prognosis did not show any of the biological variables usually associated with an unfavourable outcome, but, our data suggest the possibility of incomplete removal of tumours at surgery. Copyright


1996 - Clinico-pathological correlation and prognostic significance of nuclear p53 protein in colorectal cancer [Articolo su rivista]
R., Fante; C., Digregorio; Losi, Lorena; Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Overexpression of p53 protein was studied in neoplastic specimens of 150 patients registered for colorectal adenocarcinoma in the Health Care District 16 of Modena, Italy, from 1984 to 1986, We selected Dukes' stage B (92) and C (58) patients whose survival and recurrence rates are not easily predictable, with the purpose of defining subgroups of patients at high risk of recurrence, Monoclonal antibody PAb 1801 was used on formalin-fixed, paraffin embedded specimens, Nuclear staining was assessed to divide tumours into three groups: a) negative, b) low expressors, c) high expressors, Histomorphological variables of tumours, major clinical features of the patients and 5-year specific survival, were evaluated and related to p53 status. p53 was found in 71 out of 150 cases (47.3%); 50 tumours were high and 21 low expressors, No correlation was found between p53 overexpression and clinico-pathological variables. No difference in survival was found between patients with p53 positive and negative tunours in the entire series or within Dukes' stage B and C patients, However, the subgroup of patients with stage C rectal cancer seemed to have a better prognosis if the tumour was p53 negative (of borderline significance, p=0.15), The same results were obtained by grouping low expressor tunours alternatively with negative or high expressors. We conclude that p53 nuclear overexpression does not seem to influence the prognosis of Dukes' stage B or C colorectal cancer patients.


1996 - Frequency and clinical features of multiple tumors of the large bowel in the general population and in patients with hereditary colorectal carcinoma [Articolo su rivista]
Fante, R; Roncucci, Luca; Di Gregorio, C; Tamassia, Mg; Losi, Lorena; Benatti, Piero; Pedroni, Monica; Percesepe, Antonio; De Pietri, A; PONZ DE LEON, Maurizio
abstract

BACKGROUND. Reports on the frequency of multiple carcinomas of the colon and rectum have varied from 3-4% to more than 10% of all tumors of the large bowel. METHODS. We reviewed the files of a specialized colorectal cancer registry with chronous or metachronous) in the general population; b) to compare these values with those observed in patients with hereditary nonpolyposis colorectal carcinoma the following objectives: a) to determine the frequency of multiple tumors (synchronous or metachronous) in the general population; b) to compare these values with those observed in patients with hereditary nonpolyposis colorectal carcinoma (HNPCC); and c) to evaluate the clinical outcome of patients with multiple tumors and the role of other clinical parameters in the development of these neoplasms. RESULTS. From 1984 to 1992, 53 patients with multiple tumors (of 1298 registered patients, 4%) had large bowel carcinoma; 33 (2.5%) were synchronous and 20 (1.5%) metachronous. The total number of multiple colorectal carcinomas was 95, which was 7% of all registered colorectal carcinomas (1337 carcinomas in 1298 patients). Multiple tumors occurred significantly more often in patients with HNPCC than in those with sporadic carcinomas (P < 0.001); this increased prevalence was more marked for metachronous lesions, which occurred almost 4 times more often in patients with HNPCC (5.8% vs. 1.3%; P < 0.001). The average interval of time between the first and the second malignancy was 8.7 years; there was no significant difference between hereditary and sporadic tumors. Patients with synchronous tumors did not show appreciable differences in survival when compared with individuals who had single neoplasms. In contrast, a poor clinical outcome was observed in patients with metachronous tumors after the development of the second carcinoma. Finally, polypoid adenomas of the large bowel were found significantly more often in patients with multiple primary tumors than in those with a single tumor. CONCLUSIONS. These results emphasize the importance of preoperative pancolonoscopy for the identification of possible synchronous tumors (both benign and malignant) and long-lasting endoscopic follow-up for the detection of recurrent or metachronous lesions. The conclusions are even more pertinent for patients with HNPCC, whose risk of metachronous tumors is significantly higher than that of patients with sporadic carcinoma.


1996 - Inheritance and susceptibility to tumours of the large bowel: A new classification of colorectal malignancies [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Roncucci, Luca
abstract

non c'è


1996 - K-ras and p53 mutations in human colorectal aberrant crypt foci [Articolo su rivista]
Losi, Lorena; Roncucci, Luca; Di Gregorio, C; PONZ DE LEON, Maurizio; Benhattar, J.
abstract

Aberrant crypt foci (ACF) are putative precursor lesions of colon cancer, recently identified on the methylene blue-stained mucosal surface of human colon. No mutations in K-ras or p53 genes were found by non-radioactive single-strand conformation polymorphism analysis in 14 ACF collected from five patients. Using the more sensitive method of allele-specific polymerase chain reaction (PCR) for K-ras, 8 of 14 ACF were found to contain K-ras mutations, suggesting that mutated cells are present in minute clones in ACF, No dysplasia was observed in any of the ACF containing a mutated clone. The presence of K-ras mutations in ACF suggests that these lesions occur at a very early stage in human colorectal carcinogenesis.


1996 - Survival for colon and rectal cancer in a population-based cancer registry [Articolo su rivista]
Roncucci, Luca; R., Fante; Losi, Lorena; C., Digregorio; A., Micheli; Benatti, Piero; N., Madenis; D., Ganazzi; Mt, Cassinadri; P., Lauriola; PONZ DE LEON, Maurizio
abstract

Dukes' stage is the most powerful indicator of patient outcome for colorectal cancer. Several cancer survival studies have considered other prognostic variables, but results are often conflicting. We sought to assess the independent value of several clinical and morphological variables in defining colorectal cancer specific survival. 397 colorectal cancer patients diagnosed from 1984 to 1986, and registered in a large bowel cancer registry instituted in a local health district of Northern Italy, were actively followed-up until 31 December 1991. Univariate and multivariate survival analyses were carried out in colon and rectal cancer cases, separately, using the actuarial life-table method and Cox proportional hazard regressions. Crude and specific 5-year survival rates were 37.5 and 41.4%. In univariate analysis, TNM (tumour, nodes and metastases) stage was the strongest predictor of prognosis in both sites. Other variables significantly related to survival were age of patient at diagnosis and pattern of tumour growth in colon cancer, type of differentiation and pattern of tumour growth in rectal cancer. In multivariate analyses, after adjusting for stage, age had a weak but significant negative effect on colon cancer survival, whereas rectal tumours with the infiltrating type of growth had a significantly worse prognosis than those with the expanding type. Colorectal cancer survival should be analysed in the main large bowel subsites in order to define high-risk groups within each TNM stage category.


1995 - Argyrophilic nucleolar organizer regions and bromodeoxyuridine and h3-thymidine labelling indices in colorectal cancer [Articolo su rivista]
Losi, Lorena; C., Di Gregorio; R., Fante; Migaldi, Mario; Roncucci, Luca; Pedroni, Monica; PONZ DE LEON, Maurizio; G. P., Trentini
abstract

The count of argyrophilic nucleolar organizer regions (AgNORs) has been proposed as a useful method for evaluating cell replication in human tumours. The current study was undertaken to compare AgNOR values in colorectal cancers with two better established methods for investigating cell proliferation such as bromodeoxyuridine (BrdUrd) and (3)[H]-thymidine ((3)[H]dT) labelling indices (LIs). Because some concern still exists regarding accuracy and reproducibility of AgNOR quantifying methods, we carried out a control study by independently repeating the same measurements (number, area and area per silver-stained NOR particle) in two centres with different operators and computer-assisted image analysers on 40 colorectal carcinomas. AgNOR values recorded in the two centres were strictly correlated (r = 0.75; P &lt; 0.001 for number; r = 0.62, P &lt; 0.01 for area; r = 0.63, P &lt; 0.001 for area per silver-stained NOR particle) and the range of values were almost identical, Then, AgNOR values were compared with BrdUrd and (3)[H]dT LIs, respectively obtained by in vivo incorporation and in vitro incubation in the same series of colorectal carcinomas. No correlation was found between AgNOR values and BrdUrd or (3)[H]dT LIs. BrdUrd and (3)[H]dT LIs were instead reciprocally significantly correlated, No evident correlation was seen between LIs or AgNOR values and clinico-pathological parameters of the tumour. In conclusion, in colorectal neoplasms, AgNOR values did not appear to relate with more direct parameters of cell proliferation. It follows that AgNOR reliability as a biomarker of cell proliferation remains questionable.


1995 - Biologic characterization of Hereditary Non-Polyposis Colorectal Cancer. Nuclear ploidy, AgNOR count, microvessel distribution, oncogene expression, and grade-related parameters. [Articolo su rivista]
Losi, Lorena; R., Fante; C., DI GREGORIO; M. L., Aisoni; G., Lanza; I., Maestri; Roncucci, Luca; Pedroni, Monica; PONZ DE LEON, Maurizio
abstract

The identification of hereditary non-polyposis colorectal cancer (HNPCC) is important not only for the patient, but also for family members who are at increased risk of developing cancer. To determine if measuring various pathobiologic features of the colon carcinomas is useful in separating sporadic from HNPCC tumors, the authors studied tumor tissues from 46 patients with HNPCC and compared them to 70 with sporadic colorectal carcinoma. Parameters investigated included DNA ploidy (flow cytometry), AgNOR count (by silver staining), microvessel density (immunohistochemistry), p53 and K-vas expression, and grade-related parameters. Diploid tumors were more frequent in patients with HNPCC (65% vs 40%, P <.02), thus confirming previous observations concerning such an association. Higher AgNOR counts and greater AgNOR areas were observed in sporadic tumors than in HNPCC (5.2 +/- 1.5 vs 4.5 +/- 1.8, P <.01). Hereditary tumors tended to be less vascularized, whereas oncogene expression and grade-related parameters did not show appreciable differences between the two types of tumors. In conclusion, some of the investigated parameters may contribute to defining the biologic profile of HNPCC. In addition, these findings support the clinical impression of a more favorable outcome that is frequently seen in HNPCC patients.


1995 - Clinical and biologic features of adenomatosis coli in Northern Italy [Articolo su rivista]
S., DE PIETRI; R., Sassatelli; Roncucci, Luca; G., Bertoni; P., Landi; G., Sabadini; P., Tansini; Cavallini, Gian Maria; E., Cantoni; C., Mareni; M., Montera; PONZ DE LEON, Maurizio; L., Varesco; V., Gismondi; C., Davighi
abstract

Background: Familial adenomatous polyposis (FAP) is a hereditary disease characterized by more than 100 adenomas scattered in the large bowel and by various extracolonic manifestations. We proposed a) to establish the frequency of the disorder in Northern Italy, b) to describe the most relevant clinical findings, and c) in a subgroup of 21 patients (from 8 families), to evaluate the spectrum of mutations of the APC gene. Methods and Results: Patients with FAP diagnosed between 1961 and 1991 were referred to our Study Group from surgery and gastroenterology units of the region Emilia-Romagna. The incidence of FAP was in the order of 1 in 16,500, with about a third of patients being 'single' cases. Colorectal malignancies were present in 75.6% of symptomatic patients but absent in most (93.75%) of the asymptomatic family members ('call-up' individuals). Gastric, duodenal, and jejunal adenomas were found in 8.2%, 30.6% and 53.3% of the investigated patients, respectively. Congenital hypertrophy of the retinal pigment epithelium and occult jaw lesions were seen in 64.7% and 39.5% of FAP patients but only in 0.5% and 2.5% of a matched, by age and sex, control population. These two clinical markers had a specificity of 99% and 97%, although their sensitivity was 64% and 39%. Finally, mutations of the APC gene were detected in 6 families (16 affected individuals) of the 8 families (21 affected individuals) tested; no correlation could be found between genotype and phenotype. Conclusions: This study confirms that early diagnosis is essential for an appropriate management of FAP patients, although this aim remains elusive in single cases. High-risk individuals are ideal candidates for APC gene mutation analysis, which should be offered to all first-degree relatives of affected patients.


1995 - Familial aggregation of tumors and detection of hereditary non-polyposis colorectal cancer in 3-year experience of 2 population-based colorectal-cancer registries [Articolo su rivista]
S., Modica; Roncucci, Luca; Benatti, Piero; L., Gafa'; Mg, Tamassia; L., Dardaioni; PONZ DE LEON, Maurizio
abstract

The clinical data of 2 population-based registries, located in areas with different incidence rates of colorectal cancer, were used in order to assess the role of familial factors in the pathogenesis of these tumors. The occurrence of tumors in family members was investigated in 389 subjects with colorectal cancer registered in Modena (Northern Italy, an area characterized by a high incidence of colorectal malignancies) between 1984 and 1986; similar information was obtained in 213 patients with tumors of the large bowel registered in Ragusa (Sicily, Southern Italy, an area of similar magnitude acid with low incidence rates for these tumors) in the 3-year period 1988 to 1990. In both series, colorectal cancer occurred significantly more often among relatives of patients. Controls were patients of the same sex and age (+/- 5 years) hospitalized during the study periods, but not for gastrointestinal or neoplastic diseases. There were 89 cancer cases (3.1%) among 2,851 relatives of patients in Modena, vs. 17 cases among 1,744 relatives (1.0%) in Ragusa (p < 0.01). Apart from colorectal cancer, there was no excess of other types of tumors in patients´ families (in both series). During the 3 years of registration, 17 cases of hereditary non-polyposis colorectal cancer (HNPCC, or Lynch syndrome) were diagnosed in Modena; in contrast, this syndrome was more rare in Ragusa (one case only during 3 years of observation). Similarly, many more families with clinical suspicion of HNPCC were recorded in Northern regions (44 vs. 10). Although incidence rates of colorectal cancer are appreciably higher in Northern than in Southern Italian regions, the excess of this cancer type among close relatives is similar. However, full-blown HNPCC or suspected Lynch syndrome were significantly more frequent in Northern Italy.


1995 - First observation of microadenomas in the ileal mucosa of patients with familial adenomatous polyposis and colectomies [Articolo su rivista]
G., Bertoni; R., Sassatelli; E., Nigrisoli; P., Tansini; Roncucci, Luca; PONZ DE LEON, Maurizio; G., Bedogni
abstract

Background and Aims: Little data are available on the type and prevalence of mucosal changes involved in the development of ileal adenomas in patients with familial adenomatous polyposis who have undergone colectomy. However, colonic metaplasia of the ileal epithelium is thought to be an important step in the development of such adenomas. Methods: Retrograde endoscopy and biopsy of the distal ileum were performed in 17 affected patients who underwent total colectomy or proctocolectomy 3-184.1. months (mean, 80.3 +/- 13.9 months) before the study. Results: Macroscopic ileal polyps were identified in 14 (82.4%) patients. All polyps were sessile and 1-5 mm in size. Histological analysis showed adenomas in 9 (52.9%) patients and lymphoid hyperplasia or inflammation in the others. In 1 patient, an area of colonic-type metaplasia of the ileal mucosa was found close to an adenoma. However, in 5 (29.4%) patients, random biopsy specimens of the normal-appearing mucosa showed foci of abnormal crypts in the absence of metaplasia, with histological appearence similar to the findings described in dysplastic aberrant crypt foci of the colon. Such lesions, previously observed only in colorectal mucosa and referred to as microadenomas or oligocryptal adenomas, are considered putative preneoplastic abnormalities. Conclusions: Although the hypothesized sequence normal ileal mucosa leading to colonic-type metaplasia leading to adenoma cannot be excluded, our findings support the sequence normal ileal mucosa leading to microadenoma leading to gross adenoma and possibly cancer as the main histogenetic pathway, as already suggested for the large bowel.


1995 - GENETIC EPIDEMIOLOGY OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER [Articolo su rivista]
PONZ DE LEON, Maurizio; Percesepe, Antonio; Benatti, Piero; Roncucci, Luca
abstract

Lynch syndrome or Hereditary non-polyposis colorectal cancer (HNPCC) has recently received considerable attention either for its clinical implication or for the characterization of the molecular basis. HNPCC is an autosomal dominant disorder featured by the development of early onset colorectal malignancies frequently localized in the proximal colon, synchronous and metachronous lesions of the large bowel, and association with tumors of other organs, especially endometrium, stomach and urinary tract. In typical cases the clinical diagnosis may be relatively easy, but in many other instancies small size of families, possible low penetrance, variable expressivity, and frequency of phenocopies may render the identification of Lynch syndrome extremely complex. Molecular biology will be of considerable help in diagnosis HNPCC, since at least four genes have recently been identified whose mutations are closely associated with the development of this phenotype. Various studies in different races and continents seem to indicate that the frequency of Lynch syndrome is in the order of 1 to 5% of all colorectal malignancies. In most of these investigations the clinical guideline for the definition of HNPCC were the so-called ''Amsterdam Criteria'', proposed by the International Collaborative group on HNPCC. In some of these series, gene mutation were found in 50-70% of the families. However, the problem is much more complex owing to the existence - in a given population - of ''suspected'' HNPCC families and juvenile cases that might represent possible first mutations of a HNPCC kindred. Molecular studies should make clear how many of these families are true HNPCC and how many represent spurious aggregates of cancer. Finally, segregation analysis repetedly showed that the autosomal dominant model was the most plausible type of transmission in HNPCC families, though more complex models (i.e., codominant) cannot be excluded and deserve further investigations.


1995 - RISK OF CANCER REVEALED BY FOLLOW-UP OF FAMILIES WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER - REPLY [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Pedroni, Monica; R., Sassatelli; Roncucci, Luca
abstract

N/A


1995 - THE EFFECT OF FAMILY-SIZE ON ESTIMATES OF THE FREQUENCY OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER [Articolo su rivista]
Percesepe, Antonio; Anti, M; Roncucci, Luca; Armelao, F; Marra, G; Pahor, M; Coco, C; PONZ DE LEON, Maurizio; Gasbarrini, G.
abstract

Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely. to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features.


1994 - Antioxidant vitamins and colorectal adenoma [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca
abstract

non c'è


1994 - Genetic epidemiology of Hereditary Non-Polyposis Colorectal Cancer syndromes in Modena, Italy: results of a complex segregation analysis. [Articolo su rivista]
C., Scapoli; PONZ DE LEON, Maurizio; R., Sassatelli; Benatti, Piero; Roncucci, Luca; A., Collins; N. E., Morton; I., Barrai
abstract

Complex segregation analysis was conducted in a series of patients with hereditary nonpolyposis colorectal cancer (HNPCC) ascertained through probands registered in the Cancer Registry of the Health Care District of Modena in Northern Italy. Altogether there were 71 nuclear families segregating for HNPCC in 28 pedigrees. The analysis favoured the two-loci model, in which the segregation at the major locus is compatible with codominant transmission with a frequency of 0.0044 for the high-risk allele for HNPCC and a lifetime penetrance of 0.728 for heterozygotes.


1994 - Role of clinical criteria in the diagnosis of HNPCC: results of a multivariate analysis [Articolo su rivista]
Percesepe, Antonio; M., Anti; G., Marra; Roncucci, Luca; M., Pahor; C., Coco; F., Armelao; G., Gasbarrini; PONZ DE LEON, Maurizio
abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by early-onset colorectal tumors, primarily in the right colon, that are frequently associated with other cancers. In the absence of a reliable biomarker, clinical criteria for diagnosing HNPCC have been proposed by the international collaborative group on HNPCC (ICG-HNPCC). However, these criteria are often too restrictive for application in small families. We analyzed 6 clinical/pathological features suggestive of genetic colon-cancer risk in 970 colorectal-cancer patients defined according to the ICG criteria as HNPCC (96) or non-HNPCC (874). Logistic regression analysis was used to determine their relative potentials for predicting the diagnosis of HNPCC. The most predictive were then used to estimate HNPCC risk levels within the non-HNPCC group. Multivariate analysis showed the following associations with HNPCC diagnosis: vertically transmitted cancer (´´highly predictive´´), early-onset (<50 years) colorectal cancer, aggregation of tumors in the nuclear pedigree and proximal-colon tumors (the last 3 considered ´´predictive´´). Re-evaluation of all families revealed that 76 non-HNPCC families (8.9% of the whole series) satisfied our highly predictive vertical-transmission criterion plus at least one of the other ´´predictive´´ criteria. The presence of 2 consecutive generations affected by colorectal cancer or early primaries seems to be a major risk indicator of hereditary colorectal cancer. Using this approach we identified a large group of families that require further evaluation, although they do not currently meet the ICG-HNPCC criteria for HNPCC.


1993 - ANTIOXIDANT VITAMINS OR LACTULOSE AS CHEMOPREVENTIVE AGENTS FOR COLORECTAL CANCER [Capitolo/Saggio]
Roncucci, Luca; PONZ DE LEON, Maurizio
abstract

Not applicable


1993 - Antioxidant vitamins and lactulose for the prevention of the recurrence of colorectal adenomas [Articolo su rivista]
Roncucci, Luca; P., DI DONATO; L., Carati; Ferrari, Alberto; M., Perini; G., Bertoni; G., Bedogni; B., Paris; F., Svanoni; M., Girola; PONZ DE LEON, Maurizio; Pisani,
abstract

Colonic adenomas represent the natural precursor lesions of most colorectal cancers. The treatment of choice is endoscopic polypectomy. However, after endoscopic removal, polyps recur in a large fraction of cases. Thus, we evaluated the effect of antioxidant vitamins or lactulose on the recurrence rate of adenomatous polyps. After polypectomy, 255 individuals were randomized into three groups. Group 1 was given vitamin A (30,000 IU/day), vitamin C (1 g/day), and vitamin E (70 mg/day); Group 2 was given lactulose (20 g/day); Group 3 received no treatment. Forty-six subjects had to be excluded because the histologic diagnosis was not consistent with adenoma. The remaining 209 individuals were included in the analysis according to the ''intention to treat'' criterion, though 34 did not adhere to the scheduled treatment or were lost during the follow-up. Subjects were followed at regular intervals for an average of 18 months. Polyps recurring before one year from index colonoscopy were considered missed by the endoscopist. In the 209 evaluable subjects, the percentages of recurrence of adenomas were 5.7 percent, 14.7 percent, and 35.9 percent in the vitamins, lactulose, and untreated groups, respectively. The fraction of subjects remaining free of adenomas, estimated by Kaplan-Meier survival curves, was significantly different among the three groups (log-rank chi-squared = 17.138; P < 0.001). Using Cox's regression analysis, treatment was the only variable that significantly contributed to the model (regression coefficient = 0.905; P < 0.001). In conclusion, either antioxidant vitamins or, to a lesser extent, lactulose lower the recurrence rate of adenomas of the large bowel and can be proposed as chemopreventive agents, at least in high-risk individuals.


1993 - Cell kinetic evaluation of human colonic aberrant crypts [Articolo su rivista]
Roncucci, Luca; Pedroni, Monica; Fante, R; DI GREGORIO, C; PONZ DE LEON, Maurizio
abstract

Foci of aberrant crypts (ACF) have been observed on the unsectioned, methylene blue-stained mucosal surface of the human colon. Experimental evidence and the histological features of the lesions suggest that they might be early events in colon cancer development. The main objective of the present study was to evaluate cell kinetic properties of ACF in the human colon. Five samples of colon mucosa were collected immediately after operation following the administration of 500 mg of 5'-bromo-2'-deoxyuridine prior to surgery. ACF were then identified on the fixed, unsectioned, methylene blue-stained mucosal surface under a light microscope. Some specimens containing ACF were serially sectioned perpendicular to the luminal surface of the intestine, along with specimens of normal-appearing mucosa. Several sections were prepared for the immunohistochemical identification of 5'-bromo-2'-deoxyuridine-incorporating cells (in the S phase of the cell cycle). The results of this study demonstrated that aberrant crypts have more cells per crypt than normal glands. Total labeling index and labeling index values in each of the five longitudinal compartments in which each crypt was divided showed an increased total proliferative activity in all ACF examined, although limited to the lower crypt compartments in almost all aberrant crypts evaluated. These findings are in keeping with previous cell kinetic studies and observations in experimental animals and provide evidence of the involvement of human aberrant crypts in the stepwise process leading from normal mucosa to colon cancer.


1993 - Descriptive epidemiology of colorectal cancer in Italy: the 6-year experience of a specialized registry [Articolo su rivista]
PONZ DE LEON, Maurizio; R., SASSATELLI; A., SCALMATI; C., DI GREGORIO; R., FANTE; G., ZANGHIERI; RONCUCCI, Luca; M., SANT; A., MICHELI
abstract

The Colorectal Cancer Registry of Modena recorded 838 malignancies of the large bowel between 1984 and 1989. Crude Incidence rates were 59.5 new cases per 100 000 per year in men and 47.4 in women (age-standardised values 33.1 and 20.6, respectively). 35 incident cases (4.2%) had multiple colorectal tumours, whereas 42 (5.1%) had extraintestinal malignancies (mainly breast, endometrium and stomach). Although 90.5% of the patients underwent surgery, this was ''curative'' in 634 (77.6% of the total), while 105 individuals (12.8%) had palliative operations; 78 patients (9.5%) were not operated, mainly because of metastatic disease or poor clinical condition. Finally, emergency operations-due to intestinal obstruction, perforation or massive bleeding-were carried out in 46 patients (6.1%). A total of 659 tumours (79%) were accurately staged. Among first-degree relatives of the registered patients a significant excess of cases of colorectal cancer was found in each year of the study. 5-year survival was evaluated in 132 (out of 140) patients registered in 1984 and followed-up until 1989. Overall 5-year survival was 37%, but rose to 43% when only colorectal cancer related deaths were taken into consideration. As expected, survival was strongly influenced by stage (P < 0.0001 by log-rank test). In conclusion, this study confirms previously reported data about incidence and mortality rates for colorectal cancer in northern Italy. The particular approach-limited to the large bowel-allowed the evaluation of the frequency of multiple tumours and of the marked aggregation of cancer among first-degree relatives. Finally, survival figures are comparable to those of many other studies and confirm that the clinical outcome of this neoplasm remains unfavourable in more than 50% of the affected patients.


1993 - IDENTIFICATION OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER IN THE GENERAL-POPULATION - THE 6-YEAR EXPERIENCE OF A POPULATION-BASED REGISTRY [Articolo su rivista]
PONZ DE LEON, Maurizio; R., Sassatelli; Benatti, Piero; Roncucci, Luca
abstract

Background. Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) is an autosomal dominant disease characterized by early-onset intestinal neoplasms, localization of tumors in the proximal colon, and frequent association with cancers at other sites, especially the endometrium, skin, and stomach. The identification of HNPCC is often difficult, owing to the lack of biomarkers and the extreme frequency of sporadic colorectal cancer in the Western World. Methods. The authors reviewed the clinical data and the family trees of all patients (n = 817) with colorectal malignancies registered in the local health district between 1984-1989 with the following objectives: (1) to identify families with HNPCC and (2) to establish the frequency of the syndrome in northern Italy. Six clinical criteria were defined (vertical transmission, familial aggregation, early age at onset, right colon localization, multiple tumors, and mucinous carcinoma), all indicative of an increased possibility of HNPCC. Results. The registered families were divided into various subgroups according to the presence (in the nuclear pedigree) of four or more criteria (41 families, 5.0% of total), three criteria (58 families, 7%), two criteria (73, 8.9%), or less than two criteria (203 families, 24.8%). The remaining 380 case families did not show criteria suggesting a genetic component. One hundred thirty-three genealogic trees were extended further to gather information on second-degree and third-degree relatives. The expanded pedigrees were further analyzed to ascertain if they met the recently proposed requisites for HNPCC. Nineteen of 37 (51%) families with four criteria met the minimum requisites and could therefore be considered HNPCC. Similarly, HNPCC was diagnosed in six extended pedigrees of the three-criteria (16.6%) and in three families (8.5%) of the two-criteria subgroups. The difference in the detection of HNPCC among various subgroups was statistically significant (P < 0.001). From the observed findings, the frequency of HNPCC in this population can be estimated to be between 3.4-4.5% of all cases of colorectal cancer. Conclusions. HNPCC can be identified in the general population through the data of a colorectal cancer registry if the nuclear pedigrees of all incident cases are traced and a proportion of them selectively expanded. The observed frequency of HNPCC was rather consistent with previous estimates in other populations.


1993 - Risk of cancer revealed by follow-up of families with hereditary non-polyposis colorectal cancer: a population-based study [Articolo su rivista]
PONZ DE LEON, Maurizio; Benatti, Piero; Pedroni, Monica; R., Sassatelli; Roncucci, Luca
abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by susceptibility to large-bowel cancer, frequently with early onset and localized in the right colon. Several tumours of other sites may also occur with increased frequency in these families. During the period 1984-1989, 28 families with HNPCC were identified in our Health Care District through a population-based colorectal cancer registry. Moreover, 61 additional families were selected and classified as having ´´suspected´´ HNPCC. The objective of the present study is to report the occurrence of new cases of cancer in the 5- to 6-year follow-up of individuals at risk of tumour development in either HNPCC or ´´suspected´´ families. There were 374 family members at risk in HNPCC and 468 in ´´suspected´´ families, contributing, respectively, 2,377 and 2,712 persons/year at risk. Thirty-four new tumours developed among HNPCC family members vs. 29.3 expected; however, the occurrence of colorectal cancer in this group was significantly higher than expected, and this excess was particularly evident in the age-groups 41-50 and 51-60. In ´´suspected´´ HNPCC, 38 new tumours developed vs. 24.5 expected; at variance with the other group, besides colorectal neoplasms, lung, liver and brain tumours also occurred significantly in excess. Moreover, the increased risk was uniformly distributed among different age-groups. In conclusion, HNPCC family members are at increased risk of developing colorectal cancer, with an earlier onset than the general population; in contrast, high-risk individuals in ´´suspected´´ HNPCC families seem to be prone to a broader neoplastic spectrum, and risk of tumours does not seem to be limited to any particular age-group.


1993 - Tumour spectrum in hereditary non-polyposis colorectal cancer (HNPCC) and in families with "suspected HNPCC". A population-based study in Northern Italy. Colorectal Cancer Study Group. [Articolo su rivista]
Benatti, Piero; R., Sassatelli; Roncucci, Luca; Pedroni, Monica; R., Fante; C., DI GREGORIO; Losi, Lorena; Gelmini, Roberta; PONZ DE LEON, Maurizio
abstract

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is characterized by the early onset of colorectal neoplasms, frequently localized in the right colon, increased occurrence of multiple primaries, vertical transmission and aggregation of tumours in families in accordance to a Mendelian dominant type of inheritance. The syndrome accounts for approximately 5% of all colorectal cancers. The purpose of the present study was to describe the tumour spectrum and the most relevant clinical features of 28 kindreds with HNPCC, classified according to the guidelines of the international Collaborative Study Group, and of 61 ''suspected'' HNPCC. These families were observed during a 6-year registration of colorectal neoplasms in a health-care district of Northern Italy. Colorectal cancer was by far the most frequent malignancy; gastric cancer was the second. Uterine carcinoma was only slightly more frequent than expected. Lung- and breast-tumour rates were lower than expected. Cancer distribution in the large bowel showed that about two fifths of the tumours developed in the right colon. The occurrence of cancer before the age of SO to 60 was much more frequent in HNPCC. Multiple tumours developed in 25 patients with HNPCC and in 32 with ''suspected'' HNPCC. Pancolonoscopy remains the procedure of choice for surveillance; other examinations, such as gastroscopy, gynaecological investigations, urography and cholangiography, are suggested only to selected families. One of the main features of the study was the inclusion of 61 ''suspected'' HNPCC, a heterogeneous group of families which nonetheless deserves careful follow-up.


1992 - Aberrant crypt foci and microadenoma as markers for colon cancer. [Articolo su rivista]
Archer, Mc; Bruce, Wr; Chan, Cc; Corpet, De; Medline, A; Roncucci, Luca; Stamp, D.
abstract

Foci of aberrant crypts similar to those seen in experimental animals exposed to colon carcinogens have been identified and quantified on the mucosal surface of fixed resections of human colon after methylene blue staining. Many of the foci in humans showed dysplasia on histologic examination and were considered to be microadenoma (MA). These lesions may be precursors for adenomatous polyps and colorectal cancer. Rats and mice initiated with azoxymethane, then fed diets containing sucrose or casein heated at 180 degrees C to stimulate normal cooking conditions, had three to five times more large MA after 100 days than controls. Thus, cooked sugar and protein contain promoters of the growth of colonic MA. 5-Hydroxymethylfuraldehyde was identified as a promoter in cooked sugar.


1992 - Cell kinetics evaluation of colorectal tumours after in vivo administration of bromodeoxyuridine [Articolo su rivista]
Roncucci, Luca; Pedroni, Monica; A., Scalmati; Ml, Bormioli; R., Sassatelli; R., Fante; Losi, Lorena; C., DI GREGORIO; B., Petocchi; PONZ DE LEON, Maurizio
abstract

Although several biomarkers have been tested, Dukes' (or TNM) stage at diagnosis is still considered the only prognostic factor of clinical relevance in colorectal cancer. Among the various biomarkers, the fraction of cells engaged in DNA synthesis has been extensively investigated as an indicator of tumor aggressiveness. Bromodeoxyuridine (BUdR) is a non-radioactive thymidine analogue which is incorporated into DNA during the S-phase of cycling cells. In order to evaluate the relationships between cell kinetics and morphologic variables, 500 mg of BUdR were given i.v. to patients with colorectal cancer prior to surgery. After operation, a large tumor sample was taken and processed for immunohistochemical detection of BUdR-labeled cells in various regions of the neoplasm and in normal colorectal mucosa. Smaller superficial tumor specimens were also incubated with H-3-thymidine (H-3-TdR) for the autoradiographic identification of labeled cells. In the 43 evaluable tumors, the overall BUdR labeling index (BLI, percent of labeled cells) was significantly higher in carcinoma (20.30 +/- 0.86%, SEM) than in normal colonic mucosa (6.51 +/- 0.49%). BLIs in central and peripheral regions of carcinoma were closely correlated (r = 0.48, p = 0.003). In 21 neoplasms a high correlation between overall BUdR and H-3-TdR labeling index in the same tumor was observed (r = 0.57, p = 0.007). No evident association between overall BU and clinical or morphologic parameters of the tumor was seen, including number of capillaries and ras-p21 protein expression. We conclude that BUdR immunostaining after in vivo administration of BUdR is a simple method for studying cell kinetics in various regions of colorectal cancer. BUdR labeling data are comparable to those obtained with in vitro incorporation of H-3-TdR.


1992 - Chemoprevention of colorectal cancer: role of antioxidant vitamins [Articolo su rivista]
Biasco, G; Paganelli, Gm; Brandi, G; Santucci, R; Lalli, Aa; Roncucci, Luca; PONZ DE LEON, M; Miglioli, M; Barbara, L.
abstract

n/a


1992 - EARLY EVENTS IN HUMAN COLORECTAL CARCINOGENESIS - ABERRANT CRYPTS AND MICROADENOMA [Articolo su rivista]
Roncucci, Luca
abstract

Experimental studies have allowed the identification of foci of aberrant crypts on the fixed methylene-blue-stained mucosal surface of rodent colons after colon carcinogens administration. Similar lesions can also be observed and quantified on the mucosal surface of the human colon, using the same technique. Several foci showed dysplasia at histological examination, thus allowing the identification of microadenomas. Microadenoma may thus be a precursor lesion of adenomas and colorectal cancer. The identification of aberrant crypt foci and microadenomas in vivo could provide a new end-point for studies on the effect of enviromental and genetic factors in the early stages of cancer of the large intestine. Further studies are needed to define the natural history of these lesions. Moreover, a critical evaluation of current colon cancer prevention strategies should be considered.


1992 - Human colorectal microadenoma [Capitolo/Saggio]
Roncucci, Luca; Medline, A; Bruce, Wr
abstract

-


1992 - Human colorectal microadenoma [Capitolo/Saggio]
Roncucci, Luca; Medline, A; Bruce, Wr
abstract

N/A


1991 - Biological evaluation of colorectal neoplasia [Articolo su rivista]
PONZ DE LEON, Maurizio; A., Scalmati; Pedroni, Monica; Roncucci, Luca; C., Di Gregorio; R., Fante
abstract

Not applicable


1991 - Cell kinetics of normal colorectal mucosa in patients with colonic adenomatous polyps [Articolo su rivista]
A., Scalmati; Roncucci, Luca; G., Ghidoni; G., Gibertini; B., Barberini; PONZ DE LEON, Maurizio
abstract

Not applicable


1991 - Cell kinetics parameters in human tumors in vivo or determined using bromodeoxyuridine incorporation and flow cytometry [Articolo su rivista]
E., Geido; W., Giaretti; A., Di Vinci; R., Corvò; Vivitale, ; G., Margarino; Roncucci, Luca; Pedroni, Monica; PONZ DE LEON, Maurizio
abstract

Not applicable


1991 - Cell proliferation in colorectal cancer studied with in vivo administration of bromodeoxyuridine [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; Scalmati, A.; Roncucci, Luca; Calzolari, G.; Manenti, A.; Di Gregorio, C.; Giaretti, W.; Rapallo, A.
abstract

Not applicable


1991 - Classification of aberrant crypt foci and microadenomas in human colon [Articolo su rivista]
Roncucci, Luca; Medline, A; Bruce, Wr
abstract

Aberrant crypt foci (ACF) can be observed and quantified on the mucosal surface of formalin-fixed human colon resections after staining with methylene blue. To determine whether these ACF could be identified in fresh tissue, 10 colon resections were collected after surgery for colorectal cancer. Unfixed and fixed flat normal colonic mucosa from each colon were scored for ACF under a dissecting microscope after methylene blue staining. The number of ACF per cm2 and the average number of crypts per foci correlated highly in unfixed and fixed mucosa (r = 0.93 and 0.78, respectively). A significantly higher frequency of lesions was found in left-sided compared to right-sided colon resections. To determine whether the topographic features of the ACF gave an indication of the histological appearance, 68 specimens containing ACF or normal mucosa were examined histologically. The presence of slit-like lumen in the crypts of ACF on the mucosal surface correlated with the presence of dysplasia at histology, thus identifying microadenomas. These two observations suggest that the topographic classification of ACF in vivo could be used to distinguish microadenomas, a putative precursor lesion of colon cancer.


1991 - Identification and quantification of aberrant crypt foci and microadenomas in the human colon. [Articolo su rivista]
Roncucci, Luca; Stamp, D; Medline, A; Cullen, Jb; Bruce, Wr
abstract

n/a


1991 - Pattern of cell kinetics in colorectal mucosa of patients with different types of adenomatous polyps of the large bowel [Articolo su rivista]
Roncucci, Luca; Scalmati, A; PONZ DE LEON, Maurizio
abstract

It is generally accepted that adenomatous polyps represent the natural precursor of many colorectal malignancies. The sequence, however, which leads from a normally appearing mucosa to cancer is complex and involves many steps, including a hyperproliferative mucosa with an upward expansion of the replicative compartment. The current study evaluates cell replication in normal colorectal mucosa of patients with adenomatous polyps of various types and relates the observed findings to the main clinical and morphologic features of adenomas. Forty-four patients with polyps and 27 controls entered the study. Samples of colorectal mucosa were taken at endoscopy and cell replication was evaluated with a standard autoradiographic procedure. Cell replication was expressed as labeling index (LI), in the whole crypt and in each of the five longitudinal compartments in which the crypts were divided. Total LI and LI per crypt compartment were significantly higher (P < 0.02 and P < 0.01, respectively) than in controls. There was no appreciable difference of LI values between patients with single or multiple, tubular or tubulovillous, small or large adenomas, but in all of these subgroups LI was significantly higher than in controls. In conclusion, in normally appearing colorectal mucosa of patients with adenomatous polyps there was a significant increase of cell replication and a marked upward expansion of the proliferative zone; these changes were more evident in the left colon and in the rectum. Finally, cell replication did not seem to be related to the number of polyps, to the most common histotypes, or to the pattern of recurrence.


1991 - RELIABILITY OF H-3 THYMIDINE LABELING INDEX - CELL-PROLIFERATION OF COLORECTAL-CARCINOMA IN 3 DIFFERENT CENTERS [Articolo su rivista]
PONZ DE LEON, Maurizio; A., Costa; G., Lanza; A., Scalmati; Roncucci, Luca; A., Faranda; C., DI GREGORIO; R., Fante; G., Colella; R., Silvestrini
abstract

Although the H-3-thymidine labeling index (TLI) has been used extensively as a biologic marker of increased susceptibilty to neoplasms or as a prognostic indicator of the clinical outcome in cancer patients, there is still some concern regarding its accuracy and reliability as a marker of cell replication. A study on the prognostic value of TLI in colorectal cancer gave us the ability to evaluate how such a measurement may vary in different laboratories. A total of 150 malignant tumors of the large bowel were studied in the period from 1988 to 1989. Microautoradiography was carried out in tumor fragments taken at surgery. There were only slight differences among the three centers involved in the investigation, mainly as regards the culture medium, exposure time, and the addition of O2 + CO2 during the incubation. No significant difference was observed among TLI values recorded in the three centers (18.3 +/- 0.9; 17.4 +/- 0.9; 15.7 +/- 1.0 mean +/- SE), and the ranges of values were almost identical. Similarly, the numbers of total and of labeled cells counted for each patient were comparable among the three centers. The frequency distribution of TLI showed a peak value between 10 and 19.9% in all three centers. Moreover, more than 80% of the observed values were within the range of 10 to 29.9%. In addition, the neoplastic areas with the highest proliferative activity (high TLI) showed a frequency distribution once again rather similar among the three centers. In conclusion, the observed findings suggest that TLI values appear to be comparable when evaluated in different centers and with different techniques, and they further support the use of H-3-thymidine microautoradiography as a reliable method for the study of cell kinetics in human tumors.


1990 - Epithelial cell kinetics in the remaining colorectal mucosa after surgery for cancer of the large bowel [Articolo su rivista]
Scalmati, A; Roncucci, Luca; Ghidini, G; Biasco, G; PONZ DE LEON, Maurizio
abstract

We used microautoradiography in order to evaluate cell replication of the remaining colorectal mucosa in 20 patients previously operated on for cancer of the large bowel. The results were compared to those of 24 controls without neoplasms or other relevant colorectal disease. Samples of colorectal mucosa were taken during endoscopy. At histological examination each labeled intestinal hemicrypt was divided into 5 longitudinal compartments, from the base to the surface, and S-phase cells in each compartment were counted. Total labeling index (LI, ratio of labeled to total cells x 100) and labeling index per crypt compartment were similar in surgical patients and in controls. In contrast, both total LI and labeling index in the upper portions of the crypt (compartments 3, 4, and 5) were significantly higher in the 9 patients who showed recurrence of polyps than in those (n = 11) without recurrence. The LI in compartments 4 and 5 (the "high crypt region") was 4.37 +/- 0.95 (SEM) in patients with recurrence versus 0.88 +/- 0.21 (P less than 0.001) in patients with negative endoscopy finding and 1.47 +/- 0.22 in controls. Moreover, the fifth compartment was labeled in 8 of 9 individuals in whom polyps recurred but in only 2 of 11 patients without recurrence and 3 of 24 controls. In conclusion, after resection for large bowel cancer colonic epithelial cell proliferation tends to become more quiescent and similar to that of controls. However, in the subgroup of patients in whom polyps reappear, the colorectal mucosa maintains a hyperproliferative state with an expansion of the replicative zone to the most superficial portions of the crypt. These findings support the sequence adenoma-carcinoma and suggest that the evaluation of cell proliferation might be useful in the identification of subjects at increased risk for multiple tumors of the large bowel.


1990 - Evidence for the existence of different types of large bowel tumors - Suggestions from the clinical-data of a population-based registry [Articolo su rivista]
PONZ DE LEON, Maurizio; C., Sacchetti; R., Sassatelli; G., Zanghieri; Roncucci, Luca; A., Scalmati
abstract

The clinical findings of a population-based colorectal tumor registry have been analyzed to determine elements of supporting or not supporting the existence of different types of large bowel cancer. Age-specific incidence rate of the 409 registered patients rose sharply with increasing age in all segments of the large bowel; however, regarding left colon and rectum, the male: female ratio showed a marked male preponderance, more evident in the more advanced age groups. Histopathology, studied in 87% of patients, revealed adenocarcinoma as the most frequent feature; however, adenocarcinoma with concomitant adenoma (i.e., presumably arising in adenoma) was observed in 14.3% of cancers of the left colon, in 17.7% of rectal tumors, but in only 5.7% of neoplasms of the proximal colon (P less than 0.05 and P less than 0.01, respectively, vs. left colon and rectum). Some histological features (carcinoid and mucinous carcinoma) were observed in right-side tumors only. Analysis of the familial occurrence of cancer showed that a significantly larger proportion of patients with neoplasms located in proximal colonic segments had three or more first-degree relatives affected by (or deceased from) cancer of all sites. Similarly, colorectal tumors among relatives were more frequent in patients with right-side cancer. The location of the 793 polyps observed during 3 years of registration showed that more than 70% of adenomas were located beyond the splenic flexure, overlapping the distribution of cancers. In conclusion, the differences of sex ratio at different colonic subsites, the higher fraction of adenocarcinomas with adenomas in cancer of the more distal tracts of the large bowel, and the more marked familial occurrence of colorectal cancer in patients with right-side neoplasms tend to support the view that cancer of the proximal colon, cancer of the distal colon, and cancer of the rectum may actually be three different types of tumors.


1989 - Attività cinetica della mucosa colorettale dopo colectomia parziale [Articolo su rivista]
Roncucci, Luca; A., Scalmati; PONZ DE LEON, Maurizio
abstract

Not applicable


1989 - Cell proliferation kinetics and DNA ploidy in cancer of the large bowel [Articolo su rivista]
A., Scalmati; A., Costa; Roncucci, Luca; S., Veronesi; G., Colella; PONZ DE LEON, Maurizio; R., Silvestrini
abstract

Not applicable


1989 - Contenuto del DNA e assetto citoproliferativo nel carcinoma del grosso intestino [Articolo su rivista]
A., Scalmati; A., Costa; S., Veneroni; G., Cabella; Roncucci, Luca; PONZ DE LEON, Maurizio; R., Silvestrini
abstract

Not applicable


1989 - Effetto del Lattulosio e di Vitamine Ossidanti (A, C, E) sulla prevenzione della recidiva dei polipi adenomatosi del grosso intestino [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; A., Antonioli; M., Perini; B., Pani; S., Svanoni; M., Girola
abstract

Not applicable


1989 - Epithelial cell proliferation in remaining colorectal mucosa after surgery for cancer of the large bowel [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; Roncucci, Luca; A., Scalmati; G., Ghidoni
abstract

Not applicable


1989 - Familial aggregation of tumors in the 3-year experience of a population-based colorectal cancer registry [Articolo su rivista]
PONZ DE LEON, Maurizio; Sassatelli, R; Sacchetti, C; Zanghieri, G; Scalmati, A; Roncucci, Luca
abstract

The familial occurrence of tumors has been investigated in 389 subjects with colorectal cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1984-1986, in the Local Health District, for malignancies of the large bowel. Among first-degree relatives of the registered patients there were 89 cases of colorectal cancer as opposed to 19 in a hospital-based control group matched for age and sex [odds ratio (OR), 7.5, P less than 0.001]. This excess of neoplasms among relatives was particularly evident in siblings (60 versus 7, OR 14.7, P less than 0.001) but it was observed also in parents (27 versus 12, OR 4.2, P less than 0.01). Besides colorectal cancer there was no significant excess of other types of tumor in case families, whereas lung tumors tended to be more frequent in control relatives (32 versus 17). Almost half of the registered patients (182 out of 389) had one or more cases of cancer of any sites among relatives; similarly, in 68 there were one or more relatives affected by (or deceased for) colorectal cancer. Moreover, in 27 patients (7.0%) there were at least three cancers of any sites among relatives and in 15 the excess (two or more) was limited to neoplasms of the large bowel. In patients without or with only one neoplasm among relatives, cancers were mainly located in the left colon; however, cancer of the right colon became relatively more frequent in patients with two or more tumors in close relatives. In conclusion, the present study suggests that in approximately 15-20% of patients registered for colorectal cancer one or more first-degree relatives are affected by neoplasms of the large bowel. This familial occurrence of intestinal malignancies (but not of tumors of other organs) strongly suggests a genetic susceptibility to colorectal cancer in a fraction of these patients. Moreover, in a further subgroup of individuals (approximately 5% of all cases) the familial aggregation of two or more cases of colorectal cancer among relatives (besides the proband) and the frequent location of tumors in the right colon make the diagnosis of Lynch syndrome extremely probable.


1989 - Hereditary adenomatosis of the colon and rectum: clinical features of 8 families from Northern Italy [Articolo su rivista]
PONZ DE LEON, Maurizio; R. Sassatelli G., Zanghieri; C., Sacchetti; Roncucci, Luca; A., Scalmati; G., Bertoni; R., Conigliaro; M. G., Mortilla; C., Rombaldi; C., Pedrazzoli; R., Prati; P., Landi; Coppini, Maurizio; A., Ascari
abstract

Adenomatosis coli (or familial polyposis of the large bowel) and related syndromes are relatively rare diseases characterized by an autosomal dominant mode of inheritance. In these diseases, the entire colorectal mucosa is covered by hundreds (often innumerable) polyps of various dimensions. In addition, several extracolonic abnormalities have been reported. In the present study, we describe the clinical features of eight families from northern Italy fulfilling the diagnostic criteria of adenomatosis coli. Information was available on 123 unaffected and 30 affected family members. The most relevant findings of the study can be summarized as follows. 1) Gene frequency was calculated to be between 1:7,300 and 1:19,000. Segregation ratio in affected branches was 0.57, with a gene penetrance of nearly 60% and a male:female ratio of 1.73. 2) Extracolonic manifestations were present in all families and in 15 of 30 affected patients, the most frequent being cutaneous cysts and retinal lesions. No case fulfilling the classical criteria of Gardner syndrome was observed. 3) When the diagnosis of adenomatosis followed the appearance of symptoms, colorectal cancer had usually already developed, whereas no malignant changes were observed in individuals diagnosed in the asymptomatic stage. When colectomy with ileorectal anastomosis was the treatment of choice, polyps tended to recur in the rectal stump, and long-term endoscopic follow-up was necessary. In conclusion, adenomatosis coli may account for a definite proportion of colorectal neoplasms observed in the general population. Taking into consideration the genetic base of the disease, it follows that individuals at risk should be closely monitored for several years. Moreover, clinical investigations should not be limited to the large bowel, but should be extended to the skin, upper digestive tract, fundus oculi, bones, and probably other organs.


1989 - Pattern of epithelial cell proliferation after large bowel surgery [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; A., Scalmati; G., Biasco; G., Paganelli
abstract

Not applicable


1989 - Prevention of the recurrence of adenomatous polyps with antioxidant vitamins or lactulose [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; P., Di Donato; A., Ferrari; M., Perini; B., Paris; F., Svanoni; M., Girola; G., Bertoni; G., Bedogni
abstract

Not applicable


1989 - Vitamins A, C and E and lactulose in the prevention of recurrence of adenomatous polyps: preliminary results of a controlled study [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; Roncucci, Luca; P., Di Donato; M., Perini; A., Antonioli; A., Ferrari; B., Paris; S., Svanoni; M., Girola
abstract

Not applicable


1988 - Cancer of the large bowel: Dukes staging, duration of symptoms, multiple tumours and other clinical features derived from a population-based Registry [Articolo su rivista]
PONZ DE LEON, Maurizio; C., Sacchetti; R., Sassatelli; A., Scalmati; G., Zanghieri; Roncucci, Luca
abstract

Non c'è


1988 - Cell proliferation activity in the various tracts of the large bowel in normal conditions and in rectal mucosa of the patients with colorectal neoplasms [Abstract in Atti di Convegno]
R., Tassi; Roncucci, Luca; C., Sacchetti; P., Di Donato; G., Malagoli; D., De Maria; PONZ DE LEON, Maurizio
abstract

Not applicable


1988 - Epithelial cell proliferation of rectal mucosa in normal subjects of different ages [Abstract in Atti di Convegno]
Roncucci, Luca; PONZ DE LEON, Maurizio; L., Tassi; C., Sacchetti; G., Malagoli; S., Pratissoli; D., De Maria
abstract

Not applicable


1988 - Familial aggregation of tumors of the large bowel [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; R., Sassatelli; C., Sacchetti; G., Zangheri; A., Scalmati; Roncucci, Luca
abstract

Not applicable


1988 - Frequency of upper gastrointestinal lesions in patients with liver cirrhosis. [Articolo su rivista]
C., Sacchetti; M., Capello; P., Rebecchi; Roncucci, Luca; G., Zanghieri; A., Tripodi; PONZ DE LEON, Maurizio
abstract

The frequency of gastroduodenal lesions has been investigated in 142 patients with liver cirrhosis of various degrees of severity and in 63 patients with mild liver disease (controls) in whom liver biopsy excluded nodular regeneration. Cirrhotic patients were subdivided in three groups according to the Pugh modification of the Child-Turcotte criteria. Although the frequency of peptic ulcer was not different, gastroduodenal erosions were observed more frequently in cirrhotics than in controls (29.6% vs 11.1%, P less than 0.01). The occurrence of erosions was related to the severity of the disease: in Child A and B patients their frequency was 21 and 26% respectively, but rose to 48.4 (15 of 31 vs 7 of 63 in controls, P less than 0.001) in the Child C group. Both mild and severe gastroduodenitis occurred more frequently, although not significantly, in patients with liver cirrhosis. All together one or more endoscopic lesions were observed in almost 60% of cirrhotics but only in 25.4% of controls (P less than 0.001). In conclusion, our data do not show an increased prevalence of peptic ulcer in cirrhotic patients; in contrast, liver cirrhosis is significantly associated with the endoscopic finding of gastroduodenal erosions, especially in the more advanced stages of the disease. These findings would suggest a cautious use, in cirrhotic patients, of drugs which may damage the gastroduodenal mucosa; moreover, long-term administration of antacids or of other drugs with a protective effect on gastroduodenal mucosa might be taken into consideration for Child C patients.


1988 - Hepatic Encephalopathy. Management with Lactulose and Related Carbohydrates. [Capitolo/Saggio]
PONZ DE LEON, Maurizio; P., Di Donato; Roncucci, Luca; Manenti, Antonio; G. P., Rigo; M., Perini; A., Ferrari; A., Antonioli; M., Gandolfo; G., Biasco; L., Barbara
abstract

Not applicable


1988 - Lactulose and antioxidant vitamins in the prevention of the recurrence of adenomatous polyps. [Capitolo/Saggio]
PONZ DE LEON, Maurizio; Di Donato, P; Roncucci, Luca; Manenti, Antonio; Rigo, Gp; Perini, M; Ferrari, Alberto; Antonioli, A; Gandolfo, Marco; Biasco, G; Barbara, L.
abstract

There is evidence in the literature which suggests that it is theoretically possible to prevent the occurrence and recurrence of adenomatous polyps of the large bowel. Although not all polyps become malignant, it is commonly believed that adenomas represent the natural precursor of colorectal cancer. Thus, the prevention of their recurrence might represent a practical step in the control of this common neoplasm. At present, patients who have undergone endoscopic polipectomy are usually left without any specific therapy. Since the postulated ttherapies-lactulose and vitamins- are safe and well tolerated , it seems appropriate to undertake randomized controlled studies to evaluate the possibility of primary prevention of large bowel neoplasms. The preliminary results of such a controlled investigation at our institutions are encouraging, suggesting a lower recurrence rate of polyps in patients given lactulose or antioxidant vitamins than in patients without therapy. Much more data and longer follow-up are needed, however, before any conclusions can be drawn.


1988 - Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel. [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; Di Donato, P; Tassi, L; Smerieri, A; Amorico, Mg; Manenti, A; Biasco, G; Barbara, L.
abstract

Microautoradiography has been largely used to characterize the proliferative activity of colorectal mucosa. We used this technique in a large series of patients with polyps or cancer of the large bowel and in normal controls with the following objectives: (a) to define the normal pattern of cell replication in different tracts of the large bowel; (b) to compare the proliferative activity of colonic crypts in patients with colorectal cancer or polyps with that of controls; (c) to evaluate replicative activity of colorectal mucosa in the close vicinity and at distance from a neoplastic mass. Specimens of colorectal mucosa were taken during endoscopy (controls and polyps) or at surgery (cancer). During histological examination each intestinal hemicrypt was divided into five equal longitudinal compartments from the base to the surface and the labeled cells in each compartment were counted. In controls, total labeling index (ratio of labeled to total cells) and labeling index per crypt compartment showed only minor differences between the various large bowel tracts. Total labeling index tended to be higher in patients with polyps or cancer than in controls (13.5 +/- 0.4 and 12.5 +/- 0.4, respectively, versus 11.3 +/- 0.5). Labeling index per crypt compartment in the most superficial portions of the crypt (compartments 3 to 5) was significantly higher in the two groups of patients with tumors than in controls. This was particularly evident in the fifth compartment (the most superficial), in which labeled cells were observed in 15.8% (three subjects out of 19) of controls but in 71% (15 out of 21) and 87.5% (14 out of 16) of polyp and cancer patients, respectively. In patients with colorectal cancer there were not significant differences of cell proliferation between mucosal samples taken at various distances from the tumor margin; however, increased cell replication, especially in the most superficial portions of the crypt, has been observed. In conclusion, a significant upwards expansion of the proliferative zone of intestinal glands has been observed in patients with either polyps or cancer of the large bowel. In particular, labeling of the fifth compartment seems to possess the highest discriminatory power between subjects with or without intestinal neoplasms. Hyperproliferation of the entire colonic mucosa seems to be a common feature in patients with colorectal cancer.


1988 - Sterol metabolism in cirrhosis: intestinal degradation of cholesterol. [Relazione in Atti di Convegno]
Roncucci, Luca; PONZ DE LEON, Maurizio; A., Tripodi; N., Carulli
abstract

Not applicable


1988 - The influence of age on colonic epithelial cell proliferation [Articolo su rivista]
Roncucci, Luca; PONZ DE LEON, Maurizio; Scalmati, A; Pratissoli, S; Perini, M.
abstract

Cancer of the large bowel is relatively rare in persons younger than 50 years of age, but its incidence increases sharply in persons older than 60 years of age. We thought that the evaluation of colonic cell proliferation, an accurate biomarker of predisposition to colorectal cancer, might help to elucidate the susceptibility of elderly persons to this common malignancy. Accordingly, 30 persons with normal lower endoscopy results were divided into three age groups (30 to 50,51 to 65, and 66 to 90 years of age; Groups 1, 2, and 3, respectively). Samples of rectal mucosa were taken at endoscopic examination, incubated with [3H]thymidine, and processed with standard autoradiographic techniques. At histologic examination, each intestinal hemicrypt was divided into five equal longitudinal compartments from the fundus (compartment 1) to the surface (compartment 5). The number and the position of labeled cells along the crypt were recorded. The total labeling index (LI) (the ratio of labeled cells to total cells) was significantly higher in Group 3 than in the two other groups. Similarly, the LI per crypt compartment in the most superficial portions of the crypts was consistently higher in persons older than 65 years of age (P less than 0.01 at least), indicating an expansion of the proliferative zone to the most superficial portion of the colonic glands. When the proliferative profiles of the three groups of subjects investigated were compared with those of patients with polyps, an almost complete overlap of values was observed between this population at increased risk for cancer and the subjects in Group 3. We conclude that aging is characterized by an overall increase of epithelial cell proliferation in colorectal mucosa and by an upwards expansion of the proliferative compartment, similar to that observed in a population at risk for cancer of the large bowel.


1987 - Cytoproliferative pattern of colorectal mucosa in patients with tumours of the large bowel [Articolo su rivista]
Roncucci, Luca; Sacchetti, C.; Tassi, L.; Amorico, M. G.; Smerieri, O.; Malagoli, G.; Perini, M.; Manenti, A.; PONZ DE LEON, Maurizio
abstract

Not applicable


1987 - Epithelial cell prolliferation of colorectal mucosa in normal subjects and in patients with polyps or cancer of the large bowel [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; Smerieri, L. T. a. s. s. i. O.; P., Di Donato; G., Malagoli
abstract

Not applicable


1987 - Fecal neutral steroids in normal conditions and in patients with polyps or cancer of the large bowel [Articolo su rivista]
PONZ DE LEON, Maurizio; Roncucci, Luca; Di Donato, P; Sacchetti, C; Pezcoller, C; Annoni, C; Bertani, Chiara; Rebecchi, P; Balli, Fiorella; Galli, D; Carulli, Nicola
abstract

There is evidence suggesting that the excretion and conversion of neutral sterols in the human large bowel might be somewhat related to the development of colorectal cancer. Therefore, our objectives were: to characterize the excretion and the major pattern of sterol degradation in normal conditions, both in children and in adults; and to investigate if abnormalities of these parameters are frequent in patients with colorectal cancer or polyps. The study has been carried out in: 38 adult volunteers; 29 children divided into 4 age groups; 22 patients with colorectal cancer; 16 members of 6 families with adenomatosis coli; 15 members of 2 families with a high prevalence of multiple polyps or cancer of the large bowel; 12 subjects with colorectal polyps without familiality. With the subjects kept under metabolic control, fecal samples were collected for at least 3 days and analyzed by thin layer chromatography and gas-liquid chromatography. Total neutral steroid excretion was lower in children than in adult volunteers; in contrast, there was no significant difference between the latter and the other investigated group of patients with cancer or polyps, with values ranging between 230 and 680 mg/day. All the adult volunteers were "high converters" of cholesterol to its intestinal metabolites coprostanol and coprostanone [89 +/- 10% (SE) of degradation]. Children less than 1 year old degraded little or no cholesterol (10.4 +/- 6% of total neutral sterols), whereas with increasing age the fraction of conversion became more similar to that of adults. In patients with colorectal tumors 2 populations could be defined, one characterized by a large degradation of cholesterol and the other by little or no conversion. Low degradation of cholesterol was found in 3 of 6 families with adenomatosis coli. In conclusion, we did not find any significant difference in total neutral sterol excretion among controls, colorectal cancer patients, or subjects at risk. In adult volunteers the normal pattern of cholesterol degradation is characterized by a large conversion of cholesterol to its intestinal metabolites. In children this process changes with increasing age from an absolute "nonconverter" state (after birth) to the pattern typical of adults. Finally, in a minority of patients with either polyps or cancer of the large bowel and of their first-degree relatives, cholesterol is poorly degraded and represents the most abundant fecal sterol.


1987 - Incidence of cancer of the digestive tract in a Health Care District of Northern Italy [Articolo su rivista]
C., Sacchetti; G., Zanghieri; M., Capello; Roncucci, Luca; A., Antonioli; PONZ DE LEON, Maurizio
abstract

Not applicable


1987 - Intestinal degradation of cholesterol in liver cirrhosis [Articolo su rivista]
Roncucci, Luca; C., Sacchetti; PONZ DE LEON, Maurizio; N., Carulli
abstract

Not applicable


1986 - Attività citoproliferativa della mucosa colorettale in rapporto a due diverse preparazioni ad esami endoscopici [Relazione in Atti di Convegno]
R., Tassi; PONZ DE LEON, Maurizio; O., Smerieri; Roncucci, Luca; P., Di Donato; G., Amorico; G., Malagoli; D., De Maria
abstract

Not applicable


1986 - Attività citoproliferativa della mucosa rettale in pazienti con neoplasie del grosso intestino [Relazione in Atti di Convegno]
Roncucci, Luca; P., Di Donato; PONZ DE LEON, Maurizio; R., Tassi; O., Smerieri; G., Amorico; L., Malagoli; D., De Maria
abstract

Not applicable


1986 - Epithelial cell proliferation kinetics of colorectal mucosa in patients with polyps of the large bowel [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; P., Di Donato; Roncucci, Luca; M. G., Amorico; C., Sacchetti; G., Malagoli; M., Perini; L., Codeluppi; A., Ferrari
abstract

Not applicable


1986 - Excretion and degradation of faecal neutral sterols in children of different ages [Articolo su rivista]
Roncucci, Luca; P., Di Donato; F., Balli; D., Galli; C., Sacchetti; N., Carulli; PONZ DE LEON, Maurizio
abstract

Not applicable


1986 - Execution and degradation of faecal neutral sterols in children [Articolo su rivista]
C., Sacchetti; Roncucci, Luca; P., Di Donato; F., Balli; D., Galli; N., Carulli; PONZ DE LEON, Maurizio
abstract

Not applicable


1986 - Flora batterica intestinale e metabolismo degli steroli neutri: escrezione e degradazione intestinale in varie età della vita [Articolo su rivista]
Roncucci, Luca; C., Sacchetti; P., DI DONATO; F., Balli; D., Galli; N., Carulli; PONZ DE LEON, Maurizio
abstract

non c'è


1986 - Flora batterica intestinale e tumori del colon: escrezione e degradazione intestinale degli steroidi neutri in soggetti a rischio per cancro del colon [Articolo su rivista]
Roncucci, Luca; P., Di Donato; P., Rebecchi; C., Sacchetti; A., Carriero; N., Carulli; PONZ DE LEON, Maurizio
abstract

Not applicable


1986 - Frequenza di carcinomi colorettali tra i familiari di primo grado di pazienti con cancro o con polipi del grosso intestino [Relazione in Atti di Convegno]
G., Zanghieri; PONZ DE LEON, Maurizio; C., Sacchetti; A., Ascari; A., Antonioli; Roncucci, Luca
abstract

Not applicable


1986 - Incidenza di cancro e polipi colorettali in una USL dell'Italia Settentrionale [Relazione in Atti di Convegno]
C., Sacchetti; G., Zanghieri; PONZ DE LEON, Maurizio; A., Ascari; A., Antonioli; Roncucci, Luca
abstract

Not applicable


1985 - Excretion and coonversionof faecal neutral sterols in normal subjects and in patientsat increased risk for cancer of the large intestine [Capitolo/Saggio]
PONZ DE LEON, Maurizio; Di Donato, P; Roncucci, Luca; Rebecchi, P; Carulli, Nicola
abstract

N/A


1985 - Sterol excretion and colorectal cancer: excretion and degradation of faecal neutral sterols in selected groups of patients at high risk for colorectal cancer [Articolo su rivista]
Roncucci, Luca; PONZ DE LEON, Maurizio; P., Rebecchi; P., Di Donato; C., Bertani; C., Annoni; C., Pezcoller; N., Carulli
abstract

not applicable


1984 - Excretion and degradation of faecal neutral sterols in human beings under metabolic control [Articolo su rivista]
PONZ DE LEON, Maurizio; P., Di Donato; Roncucci, Luca; P., Rebecchi; N., Carulli
abstract

Not applicable


1984 - Faecal sterols and colonic tumours: extretion and degradation of faecal neutral sterols in selected groups of subjects at high risk for colorectal cancer [Articolo su rivista]
PONZ DE LEON, Maurizio; P., Rebecchi; Roncucci, Luca; P., Di Donato; C., Bertoni; C., Annoni; C., Pezcoller; N., Carulli
abstract

Not applicable