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Piero BENATTI

Ricercatore Universitario
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.

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 - The non-invasive mechanical ventilation: the experience of the department of Internal Medicine and Critical Area of the Polyclinic Hospital of Modena [Articolo su rivista]
Brugioni, Lucio; Benatti, Piero; Mazzali, Eleonora; DE NIEDERHAUSERN, Francesca
abstract

Acute respiratory failure (ARF) is a deficiency of the respiratory system that causes an alteration of normal levels of oxygen and/or carbon dioxide in the blood. ARF may be due to alterations in gaseous diffusion in alveolar-capillary level (type “1” acute respiratory failure), or to alterations in the functioning of the respiratory pump (type “2” acute respiratory failure) or to an association of the above causes. ARF specific etiological treatment must be associated to oxygen administration, through ventilation, which may be spontaneous or mechanical (non-invasive or invasive). The actual study describes experience about non-invasive mechanical ventilation in the department of Internal Medicine and Critical Area of the Polyclinic Hospital of Modena, from 2010 to 2014, examining clinical parameters and outcomes. Respiratory failure is a condition in which the respiratory system is not able to adequately carry out its gas exchange functions, such as oxygenation of the arterial blood and/or elimination of carbon dioxide from the venous blood. Conventionally, (1),(2),(3) respiratory failure is defined in case of: Partial pressure of arterial oxygen (PaO2) <60 mmHg; Partial pressure of carbon dioxide in the arterial blood (PCO2)> 45 mmHg; Association of both previous. You can distinguish two types of acute respiratory failure(4)(ARF): ARF type “1”, with gas exchange impairment and hypoxemia (associated with hypo/normocapnia). The pathophysiological mechanism behind is an important intrapulmonary shunt with changes in ventilation/perfusion ratio. Generally diseases responsible for this condition are acute pulmonary edema, ARDS, severe pneumonia and pulmonary embolism. ARF type “2”, with hypoventilation and hypercapnia. It is caused by a reduction of the ventilation volume/minute or by an increase of physiologic dead space. Among the most common diseases there are neuromuscular diseases, myopathies, chronic obstructive pulmonary disease (COPD), bronchial asthma and restrictive lung disease. The two types of respiratory failure are closely connected and can evolve into one another. The ARF therapy can be divided into: Etiological therapy: it is directed to the treatment of the specific cause that induced ARF, it can be delivered with inotropic agents, antibiotics, bronchodilators, steroids etc. Supportive therapy (or symptomatic): aimed at correcting hypoxemia and respiratory acidosis, is indicated in all respiratory insufficiencies and it is based on the administration of O2 and postural therapy. Ventilation can be spontaneous (delivered by low or high flow systems) or mechanical. Mechanical ventilation is classifiable under invasive ventilation (IMV) or non-invasive (NIV). The IMV provides the invasion of the patient’s airways to put them in communication with the respiratory system. It can be through tracheal intubation or tracheotomy and it’s a relevant method adopted by resuscitation intensive departments and partly by respiratory diseases departments. The NIV despite is a method that requires training and experience to be used optimally, it has the advantage to be used in emergency medicine departments and in other departments from specialists who are not resuscitators or pulmonologists. Moreover, compared to the IMV, the NIV offers the following advantages: reduction in the respiratory work, absence of complications related to prosthesis, possibility of avoiding sedation required for the IMV, conservation of laryngeal functions and cost reduction.(5) The NIV techniques most used in emergency medicine departments are CPAP (Continuous positive airway pressure) and BiPAP (or BiLevel - BiLevel positive airway pressure) CPAP provides a predetermined positive pressure, greater than atmospheric, which is maintained constant throughout the respiratory cycle, and it improves oxygenation by increasing the functional residual capacity, favouring the recruitment an

2016 - Clinical features of colorectal cancer patients in advanced age: a population-based approach [Articolo su rivista]
Maffei, Stefania; Colantoni, Alessandra; Kaleci, Shaniko; Benatti, Piero; Tesini, Ester; de Leon, Maurizio Ponz
abstract

In the immediate future, the number of geriatric patients will continue to rise; consequently we should expect an increase of colorectal cancer, a disease of the elderly population. Through the data of a Cancer Registry, we examined (a) the effect of ageing on the main features of colorectal cancer; (b) changes in management, especially for individuals older than 80Â&nbsp;years; and (c) changes in prognosis and survival in subgroups of patients with different age. The Registry provided information on colorectal cancer up to 2010 (27Â&nbsp;years). A total of 5293 patients were registered; these were divided into three groups: A (0–64Â&nbsp;years), B (65–79) and C (80 or more). Three periods of observation were chosen: 1 (1984–1992), 2 (1993–2001) and 3 (2001–2010). Group A included 1571 patients (29Â&nbsp;%), Group B 2539 (48Â&nbsp;%) and Group C 1183 (22.3Â&nbsp;%). The fraction of old individuals increased during the 27Â&nbsp;years of the investigation. In these patients, tumours were predominantly localized to the right colon (42.6Â&nbsp;%). The rate of surgery and ratio between curative and palliative approaches were similar among the three groups (pÂ&nbsp;

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 - 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.

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 - 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 - 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.

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.

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.

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 - Erratum: Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients (Tumori (2009) 95:6 (731-738)) [Articolo su rivista]
Russo, A.; De Leon, M. P.; Lucci-Cordisco, E.; Genuardi, M.; Messerini, L.; Stigliano, V.; Cama, A.; Curia, M. C.; De Lellis, L.; Signoroni, S.; Pierotti, M. A.; Pedroni, M.; Benatti, P.; Sala, P.; Alberici, P.; Gazzoli, I.; Radice, P.; Montefusco, C.; Torrini, M.; Mareni, C.; Fornasarig, M.; Santarosa, M.; Viel, A.; Bertario, L.
abstract

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 - Attitude of the Italian general population towards prevention and screening of the most common tumors, with special emphasis on colorectal malignancies. [Articolo su rivista]
Domati, Federica; Travlos, E; Cirilli, C; Rossi, Giuseppina; Benatti, Piero; Marino, M; Ponti, Giovanni; Vandelli, Maria; Valmori, S; Oursana, A; Pezzi, A; PONZ DE LEON, Maurizio
abstract

Screening and early diagnosis of cancer represent relatively recent tools in the long-lasting battle against tumors. If the American public opinion manifests its enthusiasm towards screening, the attitude of European is less well known. The purpose of the present study was to assess the level of knowledge and awareness of cancer screening (with particular emphasis on colorectal neoplasms) among middle-aged individuals. The study group consisted of 945 healthy individuals (489 men, 456 women, average age 57 +/- 12.4 years) who were asked to answer a series of questions about cancer screening and surveillance through a questionnaire presented by trained residents. Each interview lasted 20-30 min. Middle-aged Italians of both sexes seem to be aware of the fact that cancer is a frequent disease; moreover, many of the interviewed subjects believe almost all neoplasms are incurable. Diet, style of life, other environmental factors and familial factors are fully appreciated as relevant risk factors. The exact meaning of prevention was clear to less than half of the subjects. When various cancer sites were analyzed, the existence of preventive measures was well known for breast, cervical and prostate tumors, but their role was less clear for colorectal cancer. Only a fraction of the interviewed individuals were willing to undergo screening; the main reasons for refusal were lack of usefulness and fear of results. Among various tests, ultrasound and endoscopy were usually carried out in the presence of symptoms. Finally, multivariate analysis showed that the two factors significantly associated with the decision to undergo screening procedures were increasing age and level of education. The results of the study suggest that middle-aged Italian individuals, predominantly from Northern regions, have a correct perception of some aspects (frequency, risk factors) of cancer biology, whereas the knowledge of other aspects (outcome, prevention) remains poor or approximate. It follows that one of the main objectives of the Political Class should be to obtain a better education of overage individuals about cancer and the many problems related to this common disease.

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 - Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients. [Articolo su rivista]
Russo, A; Sala, P; Alberici, P; Gazzoli, I; Radice, P; Montefusco, C; Torrini, M; Mareni, C; Fornasarig, M; Santarosa, M; Viel, A; Benatti, Piero; Pedroni, Monica; PONZ DE LEON, Maurizio; Lucci Cordisco, E; Genuardi, M; Messerini, L; Stigliano, V; Cama, A; Curia, Mc; de Lellis, L; Signoroni, S; Pierotti, Ma; Bertario, L.
abstract

AIMS AND BACKGROUND: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. METHODS: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. RESULTS: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). CONCLUSIONS: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

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 from salivary glands adenoid cystic carcinoma in European populations. [Articolo su rivista]
Ciccolallo, L; Licitra, L; Cantú, G; Gatta, G; Benatti, Piero; EUROCARE Working, Group
abstract

Adenoid cystic carcinoma (ACC) of salivary gland origin is rare. The EUROCARE data provide a good opportunity to study the survival of this uncommon cancer in a large population. A total of 2611 cases, aged 15 to 99 years, diagnosed between 1983 and 1994 with primary salivary gland ACC were analyzed. Thirty-two population based cancer registries from seventeen countries participating in EUROCARE contributed the data. Relative survival by sex, age, period of diagnosis, region, site and stage, and the adjusted relative excess risk (RER) of death were estimated. Survival since diagnosis was 94%, 78% and 65% at 1, 5 and ten years, respectively. Ten-year survival was best (69%) in patients of the youngest age group (15-54 years) and from Northern Europe (69%). In the UK was higher (65%) than in Western (62%) and Eastern (56%) Europe. ACCs in nasal cavity (RER 2.6), pharynx (RER 3.5) and larynx and bronchus (RER 3.9) had a worse prognosis compared to those of oral cavity. A strong effect of stage at diagnosis on RERs and some worsening of survival at five years over time (80% in 1983-1985, 76% in 1992-1994) were also evident. The findings of the present study, as those from clinical studies, confirm the important impact of primary site and stage at diagnosis on survival. Furthermore, we could demonstrate that survival for ACC did not improve over time and that cases from Eastern countries had a significant worse prognosis. Improvements in the disease detection in its early stage and international collaborative research should be encouraged

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 - Influence of morphology on survival for non-Hodgkin lymphoma in Europe and the United States [Articolo su rivista]
Sant, M; Allemani, C; DE ANGELIS, R; Carbone, A; DE SANJOSÈ, S; Gianni, Am; Giraldo, P; Marchesi, F; MARCOS GRAGERA, R; MARTOS JIMÉNEZ, C; Maynadié, M; Raphael, M; Berrino, F; Benatti, Piero
abstract

We explored the influence of morphology on geographic differences in 5-year survival for non-Hodgkin lymphoma (NHL) diagnosed in 1990-1994 and followed for 5years: 16,955 cases from 27 EUROCARE-3 cancer registries, and 22,713 cases from 9 US SEER registries. Overall 5-year relative survival was 56.1% in EUROCARE west, 47.1% in EUROCARE east and 56.3% in SEER. Relative excess risk (RER) of death was 1.05 (95% confidence interval (CI) 1.01-1.10) in EUROCARE west, 1.52 (95% CI 1.44-1.60) in EUROCARE east (SEER reference). Excess risk of death was significantly above reference (diffuse B lymphoma) for Burkitt's and NOS lymphoma; not different for lymphoblastic and other T-cell; significantly below reference (in the order of decreasing relative excess risk) for NHL NOS, mantle cell/centrocytic, lymphoplasmacytic, follicular, small lymphocytic/chronic lymphocytic leukaemia, other specified NHL and cutaneous morphologies. Interpretation of marked variation in survival with morphology is complicated by classification inconsistencies. The completeness and standardisation of cancer registry morphology data needs to be improved.

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 - Hepatocellular carcinoma: Trends of incidence and survival in Europe and the United States at the end of the 20th century [Articolo su rivista]
Capocaccia, R.; Sant, M.; Berrino, F.; Simonetti, A.; Santi, V.; Trevisani, F.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hedelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Mace-Lesech, J.; Faivre, J.; Chaplain, G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Esteve, J.; Kaatsch, P.; Ziegler, H.; Holzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Taussig, E.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Contiero, P.; Ramazzotti, V.; Vercelli, M.; Quaglia, A.; Pannelli, F.; Vitarelli, S.; Mosciatti, P.; Federico, M.; Artioli, M. E.; Ponz De Leon, M.; Benatti, P.; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafa, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmark, F.; Andersen, A.; Rachtan, J.; Bielska-Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleko, I.; Obsitnikova, A.; Pompe-Kirn, V.; Izarzugaza, I.; Martinez-Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris-Bonet, R.; Barlow, L.; Moller, T.; Jundt, G.; Lutz, J. -M.; Usel, M.; Coebergh, J. W. W.; Van Der Does-Van Den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, S.; Verne, J.; Moller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

OBJECTIVES: There is large geographic variation in incidence levels and time trends of hepatocellular carcinoma. We compared population-based liver cancer incidence and survival in European and U.S. populations in order to elucidate geographic differences and time trends for these variables. METHODS: Since comparisons based on cancer registry data are problematic because of variations in liver cancer definition and coding, we considered a subset of cases likely to be mainly hepatocellular carcinoma, suitable for international comparison. Incidence and 5-yr relative survival were calculated from cases diagnosed in five European regions (30,423 cases) and the United States (6,976 cases) in 1982-1994. RESULTS: Age-standardized incidence was highest in southern Europe (12/100,000 in men and 3/100,000 in women in 1992-94) and lowest in northern Europe, where incidence was similar to that of the United States (3/100,000 in men, &lt;1/100,000 in women). Over the study period, incidence remained stable in the United States and most of Europe, except for a notable increase in southern Europe. Five-year relative survival was &lt;10% in Europe, ranging from 8% (southern Europe) to 5% (eastern Europe), and 6% in the United States. Survival increased slightly with time, mainly in southern Europe and was unaffected by sex, but was better in younger patients. CONCLUSIONS: Increasing incidence in southern Europe is probably related to hepatitis B and C infection and increasing alcohol intake, while improving survival may be due to greater surveillance for cirrhosis. The survival gap between clinical and population-based series suggests management is better in centers of excellence. © 2007 by Am. Coll. of Gastroenterology.

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 - Trends in cervical cancer survival in Europe, 1983-1994: A population-based study [Articolo su rivista]
Bielska-Lasota, M.; Inghelmann, R.; van de Poll-Franse, L.; Capocaccia, R.; Storm, H. H.; Aareleid, T.; Jechova, M.; Rousarova, M.; Hakulinen, T.; Hedelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Mace-Lesec'h, J.; Faivre, J.; Chaplain, G.; Carli, P. -M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, B.; Grosclaude, P.; Esteve, J.; Kaatsch, P.; Ziegler, H.; Holzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Crosignani, P.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Sowe, S.; Ferretti, S.; Conti, E.; Vercelli, M.; Quaglia, A.; Pannelli, F.; Federico, M.; Artioli, M. E.; Ponz De Leon, M.; Benatti, P.; De Lisi, V.; Servente, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafa, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Dalmas, M.; Langmark, F.; Andersen, A.; Pinheiro, P.; Rachtan, J.; Bielska-Lasota, M.; Wronkowski, Z.; Zwierko, M.; Plesko, I.; Obsitnikova, A.; Pompe-Kirn, V.; Primic-Zakelj, M.; Izarzugaza, I.; Martinez-Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris-Bonet, R.; Barlow, L.; Moller, T.; Jundt, G.; Lutz, J. M.; Bouchardy, C.; Coebergh, J. W. W.; van der Does-van den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Moller, H.; Bell, J.; Botha, H.; Lawrence, G.; Black, R.; Steward, J. A.
abstract

Objective.: To evaluate trends in survival from cervical cancer in Europe and in European countries participating in the EUROCARE study as a function of age, morphology and stage at diagnosis. Methods.: Relative survival and relative excess risk of death within 5&nbsp;years of diagnosis, as a function of age, morphology and stage, among 73,022 women aged 15-99&nbsp;years diagnosed during 1983-1994 and followed up to 1999 in each of 18 European countries participating in the EUROCARE study, using data from 34 population-based cancer registries. Results.: Overall five-year relative survival was 62%, rising by 2% during the period 1983-1994. The highest survival occurred in Northern and Western Europe and the lowest in Central Europe. Survival falls with age at diagnosis, but mainly for localised disease. Survival is higher for adenocarcinoma in younger women, but higher for squamous cell carcinoma in older women. The proportions of younger women, localised cancer and adenocarcinoma all increased. The main improvements in survival were for women under 65, and for metastatic disease. Conclusions.: Survival in Europe has improved slowly but steadily, but the trend is not geographically uniform. Central European countries and the UK saw little or no improvement, and survival in those countries remains the lowest among participating countries in Europe. Further reduction of cervical cancer mortality in Europe may be expected from expansion of screening, and improvement in the treatment of older women, and of metastatic disease. © 2007 Elsevier Inc. All rights reserved.

2006 - A genetic model for determining MSH2 and MLH1 carrier probabilities based on family history and tumor microsatellite instability. [Articolo su rivista]
Marroni, F; Pastrello, C; Benatti, Piero; Torrini, M; Barana, D; Cordisco, El; Viel, A; Mareni, C; Oliani, C; Genuardi, M; Bailey Wilson, Je; PONZ DE LEON, Maurizio; Presciuttini, S.
abstract

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.

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 - In response. Adjuvant chemotherapy in colorectal cancer patients with microsatellite instability. [Articolo su rivista]
Benatti, Piero; PONZ DE LEON, Maurizio; Gafa, R; Lanza, G; Barana, D; Oliani, C.
abstract

To the Editor: In a recent issue of Clinical Cancer Research (1), we read Benatti et al.'s article with interest, therein they showed significantly better survival in microsatellite instability high (MSI-H) patients than microsatellite stable patients, and concluded that the type of genomic instability could influence the prognosis of colorectal cancer, in particular, in stages II and III. Furthermore, in relation to adjuvant treatment, they concluded that fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. Although Benatti et al. introduced our results, our research on the similar topic came to a different conclusion (2). There are major issues to be discussed as to how Benatti et al. drew their conclusions. The first point is the total number of MSI-H patients who received chemotherapy. In Benatti et al.'s study, only 65 MSI-H patients received fluorouracil-based chemotherapy; among these 65 patients, 31 patients had stage IV disease. Considering that most of the patients who had stage IV disease would have received postoperative chemotherapy, the total number of MSI-H patients, in stages II and III, who received chemotherapy seems to be much fewer than 65. The second point is how they examined the survival rate. Benatti et al. examined the survival in stage II and stage III patients separately. Therefore, the number of MSI-H patients who received chemotherapy in either stage II or III should be 20 at most. This number of patients seems to be too small to find any difference in survival. In fact, MSI-H patients who underwent chemotherapy showed higher survival rates than those who did not, although it did not reach statistical significance. Furthermore, according to the survival curve of stage II cancers, there seems to be no cancer-related death in MSI-H patients who had undergone chemotherapy. Considering all these points, the small number of MSI-H patients who underwent chemotherapy seems to be the main reason why they could not find significant differences in survival between MSI-H patients who did or did not undergo chemotherapy. All of these points are also true in an analysis of MSI-H patients in stage III. In Benatti et al.'s study, the number of MSI-H patients with chemotherapy in stage II or III seems to be too small to draw any conclusion. In our previous study, we examined 73 MSI-H patients who received chemotherapy and showed a significant difference in survival between MSI-H patients and microsatellite stable patients (2). Taken together, Benatti et al.'s study may potentially bias the significance of MSI-H as a predictor of survival in patients with adjuvant-treated colon cancer.

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 - Survival from rare cancer in adults: A population-based study [Articolo su rivista]
Gatta, G.; Ciccolallo, L.; Kunkler, I.; Capocaccia, R.; Berrino, F.; Coleman, M. P.; De Angelis, R.; Faivre, J.; Lutz, J. M.; Martinez, C.; Möller, T.; Sankila, R.; Oberaigner, W.; Storm, H. H.; Aareleid, T.; Jechova, M.; Rousarova, M.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesec'h, J.; Chaplain, G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, B.; Grosclaude, P.; Estève, J.; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Allemani, C.; Baili, P.; Crosignani, P.; Micheli, A.; Sant, M.; Taussig, E.; Sowe, S.; Ferretti, S.; Conti, E.; Vercelli, M.; Quaglia, A.; Pannelli, F.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Servente, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafa, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Carrani, E.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Dalmas, M.; Langmark, F.; Andersen, A.; Pinheiro, P.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pleško, I.; Obsitníkováa, A.; Pompe Kirn, V.; Primic Zakelj, M.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Jundt, G.; Bouchardy, C.; Coebergh, J. W. W.; van der Does van den Berg, A.; Visser, O.; Godward, S.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, H.; Lawrence, G.; Black, R.; Steward, J. A.
abstract

Backround: Rare cancers are a challenge to clinical practice, and treatment experience, even in major cancer centres to which rare cancers are usually referred, is often limited. We aimed to study the epidemiology of rare cancers in a large population of several countries. Methods: We analysed survival by age, sex, subsite, and morphology in 57 144 adults with 14 selected rare cancers diagnosed 1983-94. Variations in survival over time and between European regions were also assessed for variations in quality of care. We also estimated the adjusted relative excess risk of death for every rare cancer. Findings: Overall 5 -year relative survival was good (ie, >65%) for placental choriocarcinoma (85.4% [95% CI 81.4-89.5]), thyroid medullary carcinoma (72.4% [69.2-75.5]), ovarian germ-cell cancer (73.0% [70.0-76.0]), lung carcinoid (70.1% [67.3-72.9]), and cervical adenocarcinoma (65.5% [64.3-66.6]); intermediate (ie, 35-65%) for testicular cancer at age 65 years or older (64.0% [59.3-68.7]), sarcoma of extremities (60.0% [58.9-61.2]), digestive-system endocrine cancers (55.6% [54.9-56.3]), anal squamous-cell carcinoma (53.1% [51.5-54.8]), and uterine sarcoma (43.5% [42.0-44.9]); low for carcinoma of adrenal-gland cortex (32.7% [28.3-37.2]) and bladder squamous-cell carcinoma (20.4% [18.8-22.0]); and poor for angiosarcoma of liver (6.4% [1.8-11.0]) and mesothelioma (4.7% [4.3-5.2]). Survival was usually better for women than men and poor in those aged 75 years or older. Survival significantly improved over time for ovarian germ-cell cancer, sarcomas of extremities, digestive-system endocrine tumours, anal squamous-cell carcinoma, and angiosarcoma of liver. Survival in northern Europe was higher than in the other geographic groupings for most cancers. Interpretation: Because effective treatments are available for several of the rare cancers we assessed, further research is needed to ascertain why survival is lower in some European countries than in others, particularly in older patients. Audit of best practice for rare cancers with treatment protocols would be useful.

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 - Investigation of APC mutations in a Turkish familial adenomatous polyposis family by heterodublex analysis [Articolo su rivista]
B., Tunca; M., Menigatti; Benatti, Piero; U., Egeli; G., Cecener; Pedroni, Monica; A., Scarselli; F., Borghi; E., Sala; T., Yilmazlar; A., Zorluoglu; O., Yerci; PONZ DE LEON, Maurizio
abstract

PURPOSE: Familial adenomatous polyposis is an autosomal dominant disease characterized by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis coli gene are primarily responsible for the development of this disease. This study was designed to investigation of adenomatous polyposis coli (APC) gene mutations in members of familial adenomatous polyposis family to identify individuals at risk of the disease. METHODS: We examined one patient with familial adenomatous polyposis and 21 family members including one affected person from familial adenomatous polyposis and 20 nonsymptomatic persons. We studied E, D, F, and G segments of exon 15 of the adenomatous polyposis coli gene by heteroduplex analysis. RESULTS: We used silver staining method for staining. We found a mutation for five persons at segment F of exon 15 of the adenomatous polyposis coli gene. Two of them were affected by colorectal cancer, one of whom was the proband, and the other three were non-symptomatic family members. The pathogenetic mutation was a T deletion at codon 1172, causing a frameshift in the adenomatous polyposis coli gene, as a result of the sequencing analysis of these cases. CONCLUSIONS: Investigation of adenomatous polyposis coli gene mutations is very important for the identification of genetic susceptibility to colorectal cancer and for the definition of tumor developing at an early stage. Furthermore, the identification of this mutation for the first time in a Turkish family will be useful to foster further studies on familial adenomatous polyposis in Turkey.

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 - A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability. [Articolo su rivista]
Caluseriu, O; Lucci Cordisco, E; Santarosa, M; Trojan, J; Brieger, A; Benatti, Piero; Pedroni, Monica; Colibazzi, T; Bellacosa, A; Neri, G; PONZ DE LEON, Maurizio; Viel, A; Genuardi, M.; DI GREGORIO, Carmela
abstract

no abstract

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 - 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 - EUROCARE-3 summary: Cancer survival in Europe at the end of the 20th century [Articolo su rivista]
Coleman, M. P.; Gatta, G.; Verdecchia, A.; Estève, J.; Sant, M.; Storm, H.; Allemani, C.; Ciccolallo, L.; Santaquilani, M.; Berrino, F.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesec'h, J.; Faivre, J.; Chaplain, G.; Carl, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estèv, Z; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Contiero, P.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P. Guzzinati S.; Dalmas, M.; Langmark, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kirn, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Möller, T.; Jundt, G. Lutz J. M.; Usel, M.; Coebergh, J. W. W.; Van Der Does Van Den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

No abstract available

2003 - EUROCARE-3: survival of cancer patients diagnosed 1990–94—results and commentary [Articolo su rivista]
Sant, M.; Aareleid, T.; Berrino, F.; Bielska Lasota, M.; Carli, P. M.; Faivre, J.; Grosclaude, P.; Hédelin, G.; Matsuda, T.; Møller, H.; Möller, T.; Verdecchia, A.; Capocaccia, R.; Gatta, G.; Micheli, A.; Santaquilani, M.; Roazzi, P.; Lisi, D.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesech, J.; Faivre, J.; Chaplain, G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estève, J.; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Contiero, P.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, ; L., Aw; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmak, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kirn, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Möller, T.; Jundt, G.; Lutz, J. M.; Usel, M.; Coebergr, J. W. W.; Van Der Does Van Den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

EUROCARE-3 analysed the survival of 1 815584 adult cancer patients diagnosed from 1990 to 1994 in 22 European countries. The results are reported in tables, one per cancer site, coded according to the International Classification of Diseases (ICD)-9 classification. The main findings of the tables are summarised and commented on in this article. For most solid cancers, wide differences in survival between different European populations were found, as also reported by EUROCARE-1 and EUROCARE-2, despite a remarkable (10%) overall increase in cancer survival from 1985 to 1994. Survival was highest in northern Europe (Sweden, Norway, Finland and Iceland), and fairly good in central-southern Europe (France, Switzerland, Austria and Spain). Survival was particularly low in eastern Europe, low in Denmark and the UK, and fairly low in Portugal and Malta. The mix of tumour stage at diagnosis explains much of the survival differences for cancers of the digestive tract, female reproductive system, breast, thyroid, and also skin melanoma. For tumours of the urinary tract and prostate, the differences were explained mainly by differences in diagnostic criteria and procedures. The case mix by anatomic subsite largely explains differences in survival for head and neck cancers. For oesophagus, pancreas, liver and brain cancer, with poor prognoses, survival differences were limited. Tumours, for which highly effective treatments are available, such as testicular cancer, Hodgkin's lymphoma and some haematological malignancies, had fairly uniform survival across Europe. Survival for all tumours combined (an indicator of the overall cancer care performance of a nation's health system) was better in young than old patients, and better in women than men. The affluence of countries influenced overall cancer survival through the availability of adequate diagnostic and treatment procedures, and screening programmes. © 2003 European Society for Medical Oncology.

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

2003 - The EUROCARE-3 database: Methodology of data collection, standardisation, quality control and statistical analysis [Articolo su rivista]
Capocaccia, R.; Gatta, G.; Roazzi, P.; Carrani, E.; Santaquilani, M.; De Angelis, R.; Tavilla, A.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesech, J.; Faivre, J. n. Chaplain G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estève, J.; Kaatch, P.; Ziegler, H.; Hölzel, D.; Fritschle, G. S.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Tagliabue, G.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmark, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kim, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Perisbonet, R.; Barlow, L.; Möller, T.; Jundt, G.; Lutz, J. M.; Usel, M.; Coebergh, J. W. W.; Van Der Does Van Den, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

The EUROCARE database contains data on 6.5 million cancer patients diagnosed from 1978 to 1994 in populations covered by 67 cancer registries in 22 European countries. The quality-checked entries specify age, sex, diagnosis date, cancer site, morphology, microscopic confirmation and vital status, as well as containing broad indicators of stage. For EUROCARE-3, which refers to diagnoses from 1990 to 1994, 3389 cases with major data problems and 142 525 second or subsequent cancers were removed, leaving more than 2 million cases for analysis. From these data, observed and relative survival for each cancer site and country were calculated at 1, 3 and 5 years from diagnosis. Overall European survival for each cancer site and for all cancers combined were calculated combining country-specific survival figures. Overall, 1.1% of cases were lost to follow-up, 4.2% were known from death certificates only and 1.2% were known at autopsy only. The percentage of microscopically confirmed cases varied with cancer site and country, and was always higher in northern European countries. Comparison of quality indicators for the EUROCARE-3 database with earlier EUROCARE databases indicates that data quality and standardisation have improved.

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 - Investigation of APC mutations of a patient with FAP and her family members by heterodublex analyses [Abstract in Atti di Convegno]
Tunca, B; Menigatti, M; Benatti, Piero; Cecener, G; Pedroni, Monica; Scarselli, A; Borghi, F; Sala, E; Yylmazlar, T; Zorluoglu, A; Egeli, U; Yerci, O; PONZ DE LEON, Maurizio
abstract

Familial adenomatous polyposis coli (FAP) is an autosomal dominant disease characterised by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis gene(APC) gene primarily responsible for the development of this disease. In this study, we examined one patient with FAP and 21 family members including one effected person from FAP and 20 nonsemptomatic persons. Our proband case who have a retinal lesions (congenital hypertrophy of the retinal pigment epithelium,called CHRPE) and hundreds adenomatous polyps on all colon and rectum is a 36 years old woman. We isolated DNA from pheripheral blood samples of proband and her family members by proteinaz K incubation and phenol-chloroform extraction. We studied E,D, F,and G segments of exon 15 of APC gene by heterodublex analyses (HDA). For staining, we used non-radioactive silver staining method. We determined mutation in 5 person from this family in segmentF of exon 15 of APC. Two of them were patients with FAP (one is ourproband case) and another three persons were non semptomatic family members. Result of sequencing analysis of these cases, wedetermined T deletion at position 3554 causing a frameshift mutation in APC gene.

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 - 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 - The role of hPMS1 and hPMS2 in predisposing to colorectal cancer [Articolo su rivista]
Liu, T; Yan, H; Kuismanen, S; Percesepe, Antonio; Bisgaard, Ml; Pedroni, Monica; Benatti, Piero; Kinzler, Kw; Vogelstein, B; PONZ DE LEON, Maurizio; Peltomaki, P; Lindblom, A.
abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hRWS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.

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 - 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.

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 - 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 - 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 - 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 - 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 - Collection of Italian hereditary non-polyposis colorectal cancer (HNPCC) pedigrees [Articolo su rivista]
A., Arrigoni; S., Bargiacchi; Benatti, Piero; A., Heouaine; C., Mareni; L., Messerini; Mp, Montera; S., Mori; Percesepe, Antonio; S., Presciuttini; Mp, Rocci; P., Sala
abstract

In this multicenter study we report clinical and familial characteristics of italian families affected by hereditary Non-Polyposis Colorectal Cancer

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 - 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 - 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 - 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

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.

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 - CANCER OCCURRENCE IN THE FOLLOW-UP OF 25 FAMILIES WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER (HNPCC) [Abstract in Atti di Convegno]
PONZ DE LEON, Maurizio; Benatti, Piero; Sassatelli, R.
abstract

not available