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Giovanni PONTI

Professore Associato
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa

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Pubblicazioni

2022 - Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I [Articolo su rivista]
Riva, M.; Martorana, D.; Uliana, V.; Caleffi, E.; Boschi, E.; Garavelli, L.; Ponti, G.; Sangiorgi, L.; Graziano, C.; Bigoni, S.; Rocchetti, L. M.; Madeo, S.; Soli, F.; Grosso, E.; Carli, D.; Goldoni, M.; Pisani, F.; Percesepe, A.
abstract

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000–2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2–11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5′ end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5′ end of the NF1 gene although not significant at the multivariate analysis.

2021 - Clinical application of lung ultrasound score on COVID-19 setting: A regional experience in Southern Italy [Articolo su rivista]
Lugara, M.; Oliva, G.; Pafundi, P. C.; Tamburrini, S.; Nevola, R.; Gjeloshi, K.; Ricozzi, C.; Imbriani, S.; Padula, A.; Aprea, C.; Meo, L.; Cozzolino, D.; Cuomo, G.; Marrone, A.; Romano, C.; Fiorini, V.; Coppola, M. G.; Corvino, M.; Perrella, A.; Ponti, G.; Nunnari, G.; Ranieri, R.; Ruosi, C.; Sasso, F. C.; Adinolfi, L. E.; Rinaldi, L.
abstract

Objective: We aimed to assess the correlation between LUS Soldati proposed score and clinical presentation, course of disease and the possible need of ventilation support/ intensive care. PATIENTS AND METHODS: All consecutive patients with laboratory confirmed SARS-CoV-2 infection and hospitalized in two COVID Centers were enrolled. All patients performed blood gas analysis and lung ultrasound (LUS) at admission. The LUS acquisition was based on standard sequence of 14 peculiar anatomic landmarks with a score between 0-3 based on impairment of LUS picture. Total score was computed with their sum with a total score ranging 0 to 42, according to Soldati LUS score. We evaluated the course of hospitalization until either discharge or death, the ventilatory support and the transition in intensive care if needed. Results: One hundred and fifty-six patients were included in the final analysis. Most of patients presented moderate-to-severe respiratory failure (FiO2<20%, PaO2<60 mmHg) and consequent recommendation to invasive mechanic ventilation (CPAP/NIV/OTI). The median ultrasound thoracic score was 28 (IQR 18-36) and most of patients could be ascertained either in a score 2 (40%) or score 3 pictures (24.4%). The bivariate correlation analysis displayed statistically significant and high positive correlations between the LUS score and the following parameters: ventilation (rho=0.481, p<0.001), lactates (rho=0.464, p<0.001), dyspnea (rho=0.398, p=0.001) mortality (rho=0.410, p=0.001). Conversely, P/F (rho= -0.663, p<0.001), pH (rho = -0.363, p=0.003) and pO2(rho = -0.400 p=0.001) displayed significant negative correlations. Conclusions: LUS score improve the workflow and provide an optimal management both in early diagnosis and prognosis of COVID-19 related lung pathology.

2021 - COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence [Articolo su rivista]
Ponti, G.; Pastorino, L.; Manfredini, M.; Ozben, T.; Oliva, G.; Kaleci, S.; Iannella, R.; Tomasi, A.
abstract

Background: Homocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID-19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR C677 T gene polymorphism and COVID-19 incidence and mortality worldwide. Methods: Data regarding MTHFR C677 T gene mutation were obtained from the interrogation of the Genome Aggregation Database (genomAD), which is publicly available from the web“https://gnomad.broadinstitute.org.” COVID-19 cases, including prevalence and mortality, were obtained from“https://www.worldometers.info/coronavirus” 27 August 2020. Results: There is a clear trend toward the worldwide prevalence of MTHFR 677 T and COVID-19 incidence and mortality. The prevalence of MTHFR 677 T allele in the Latino population, and the incidence and mortality for COVID-19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between C677 T and death from coronavirus. Conclusions: Genetic polymorphism of MTHFR C677 T may modulate the incidence and severity of COVID-19 pandemic infection.

2021 - Homocysteine (Hcy) assessment to predict outcomes of hospitalized Covid-19 patients: A multicenter study on 313 Covid-19 patients [Articolo su rivista]
Ponti, G.; Roli, L.; Oliva, G.; Manfredini, M.; Trenti, T.; Kaleci, S.; Iannella, R.; Balzano, B.; Coppola, A.; Fiorentino, G.; Ozben, T.; Paoli, V. D.; Debbia, D.; De Santis, E.; Pecoraro, V.; Melegari, A.; Sansone, M. R.; Lugara, M.; Tomasi, A.
abstract

2021 - Liquid biopsy with cell free DNA: new horizons for prostate cancer [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Percesepe, Antonio; Tomasi, Aldo; Ozben, Tomris.
abstract

Although prostate cancer (PCa) is one of the most common tumors in European males, the only minimally invasive diagnostic tool in PCa setup is the determination of PSA in serum. Cell-free DNA (cfDNA) has been demonstrated to be helpful for PCa diagnosis but has not yet been integrated into the clinical setting. This review aims to provide a systematic update of cfDNA and its fragmentation patterns in PCa reported in literature published over the last twenty years. Due to the high variability of the scientific methods adopted and a lack of standardized median cfDNA levels, results fluctuate across different studies. These differences may be due to the cfDNA source, the quantification method, or the fragmentation pattern. Blood plasma is the most frequently analyzed biological fluid, but seminal plasma has been reported to contain higher cfDNA concentration due to its vicinity to the tumor origin. CfDNA has been shown to be composed of single-stranded (ssDNA) and double-stranded DNA (dsDNA), so the total cfDNA concentration should be preferred as it corresponds best to the tumor mass. Fluorometry and capillary electrophoresis (CE) may be quick and cost-effective tools for cfDNA assessment in a clinical setting. The greatest future challenge is the elaboration of common guidelines and standardized procedures for diagnostic laboratories performing cfDNA analysis. A multiparametric approach combining the analysis of total cfDNA (both ssDNA and dsDNA), cfDNA fragment length, and specific genetic mutations (ctDNA assessment) is required for optimal future applications of liquid biopsy.

2020 - Biomarkers associated with COVID-19 disease progression [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Ruini, Cristel; Tomasi, Aldo; Ozben, Tomris
abstract

The SARS-COVID 19 pandemic is a scientific, medical and social challenge. The complexity of the virus is centred on the unpredictable clinical course of the disease that can rapidly develop, causing severe and deadly complications. The identification of effective laboratory biomarkers able to classify patients based on their risk is imperative in being able to guarantee prompt treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine mediated coagulation disorders as the principal actors of multi organ failure in patients with severe COVID-19 complications. The following biomarkers have been identified: haematological (lymphocyte count, neutrophil count, neutrophil-lymphocyte-ratio (NLR), and Hhemoglobin ), inflammatory (C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), procalcitonin(PCT )), immunological (IL-6 ) and biochemical (D-Dimer, Troponin, CK, AST ), especially those related to coagulation cascades in disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). New laboratory biomarkers could be identified through the accurate analysis of multicentric case series; in particular, homocysteine and angiotensin II could play a significant role.

2020 - Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients [Articolo su rivista]
Ciccarese, G.; Dalmasso, B.; Bruno, W.; Queirolo, P.; Pastorino, L.; Andreotti, V.; Spagnolo, F.; Tanda, E.; Ponti, G.; Massone, C.; Drago, F.; Parodi, A.; Ghigliotti, G.; Pizzichetta, M. A.; Ghiorzo, P.; Dalmasso, B.; Bruno, W.; Pastorino, L.; Andreotti, V.; Queirolo, P.; Spagnolo, F.; Tanda, E.; Pizzichetta, M. A.; Ghiorzo, P.
abstract

Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF-), including dermoscopic findings of melanomas and dysplastic nevi. Methods: we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available. Results: After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF-. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF-). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF- patients, whose most prevalent pattern was the multicomponent. Conclusions: MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF- patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.

2020 - Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19 [Articolo su rivista]
Ponti, G.; Ruini, C.; Tomasi, A.
abstract

2020 - Immunohistochemical mismatch repair proteins expression as a tool to predict the melanoma immunotherapy response [Articolo su rivista]
Ponti, G.; Pellacani, G.; Tomasi, A.; Depenni, R.; Maccaferri, M.; Maiorana, A.; Orsi, G.; Giusti, F.; Cascinu, S.; Manfredini, M.
abstract

In difference to other solid malignancies, the identification of biomarkers for the prediction of malignant melanoma (MM) response to immunotherapy is limited. The aim of the current study was to evaluate the immunohistochemical (IHC) expression of MMR proteins in a cohort of MM metastatic patients receiving anti PD-1 treatments. The therapeutic response of patients was also retrospectively assessed. The cohort of the current study included 14 patients with advanced MM that had received anti PD-1 from January 2014 to December 2016 (12 males, 2 females; average age, 71 years; age range, 47-88 years). IHC analysis of MLH1, PMS2, MSH2 and MSH6 proteins was performed on paraffin-embedded primary tumor samples from each patient and on the 23 available metastasis specimens obtained from the Division of Pathology (University of Modena and Reggio Emilia). The results revealed that 7% of the primary melanoma tissue obtained from the patient cohort exhibited the loss of expression of at least one MMR protein. Three samples from one patient, including one primary melanoma and two metastases, exhibited no MSH6 expression and had the most successful response to anti PD-1 treatment, with a progression-free survival and overall survival of 956 and 2,546 days, respectively. In conclusion, the assessment of MMR protein expression represents a potential predictive marker that may have critical importance for patients with primary and metastatic MM, primarily as criterion for the adoption of immunotherapy treatments.

2020 - Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1 [Articolo su rivista]
Pastorino, Lorenza; Andreotti, Virginia; Dalmasso, Bruna; Vanni, Irene; Ciccarese, Giulia; Mandalà, Mario; Spadola, Giuseppe; Pizzichetta, Maria Antonietta; Ponti, Giovanni; Tibiletti, Maria Grazia; Sala, Elena; Genuardi, Maurizio; Chiurazzi, Pietro; Maccanti, Gabriele; Manoukian, Siranoush; Sestini, Serena; Danesi, Rita; Zampiga, Valentina; Starza, Roberta La; Stanganelli, Ignazio; Ballestrero, Alberto; Mastracci, Luca; Grillo, Federica; Sciallero, Stefania; Cecchi, Federica; Tanda, Enrica Teresa; Spagnolo, Francesco; Queirolo, Paola; Imi, Italian Melanoma Intergroup; Goldstein, Alisa M; Bruno, William; Ghiorzo, Paola
abstract

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

2019 - Non-blood sources of cell-free DNA for cancer molecular profiling in clinical pathology and oncology [Articolo su rivista]
Ponti, G.; Manfredini, M.; Tomasi, A.
abstract

Liquid biopsy can quantify and qualify cell-free (cfDNA) and tumour-derived (ctDNA) DNA fragments in the bloodstream. CfDNA quantification and mutation analysis can be applied to diagnosis, follow-up and therapeutic management as novel oncologic biomarkers. However, some tumor-types release a low amount of DNA into the bloodstream, hampering diagnosis through standard liquid biopsy procedures. Several tumors, as such as brain, kidney, prostate, and thyroid cancer, are in direct contact with other body fluids and may be alternative sources for cfDNA and ctDNA. Non-blood sources of cfDNA/ctDNA useful as novel oncologic biomarkers include cerebrospinal fluids, urine, sputum, saliva, pleural effusion, stool and seminal fluid. Seminal plasma cfDNA, which can be analyzed with cost-effective procedures, may provide powerful information capable to revolutionize prostate cancer (PCa) patient diagnosis and management. In the near future, cfDNA analysis from non-blood biological liquids will become routine clinical practice for cancer patient diagnosis and management.

2019 - Quick assessment of cell-free DNA in seminal fluid and fragment size for early non-invasive prostate cancer diagnosis [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Manfredini, Marco; Micali, Salvatore; Torricelli, Federica; Milandri, Riccardo; Del Prete, Chiara; Ciarrocchi, Alessia; Ruini, Cristel; Benassi, Luisa; Bettelli, Stefania; Kaleci, Shaniko; Ozben, Tomris; Tomasi, Aldo
abstract

Liquid biopsy consists in the quantification and qualification of circulating cell-free DNA (cfDNA) and tumor-derived DNA (ctDNA) for cancer recognition. Recently, the characterization of seminal cfDNA (scfDNA) has been reported as a possible biomarker for prostate cancer (PCa) diagnosis.

2018 - Dabrafenib-trametinib combination in 'field-practice': An Italian experience [Articolo su rivista]
Depenni, R.; De Rosa, F.; Greco, S.; Ridolfi, L.; Pellacani, G.; Ponti, G.; Cascinu, S.; Guidoboni, M.
abstract

Aim: This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma. Patients & methods: Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included. Results: Median progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported. Conclusion: Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.

2018 - Innovative use of magnesium oxide in the treatment of "neuralgia of the celiac plexus of rheumatic origin" by G. Moscati in 1923 [Articolo su rivista]
Colaci, Michele; Ponti, Giovanni
abstract

We presented and discussed one interesting medical prescription by doctor Giuseppe Moscati (1880-1927), who prescribed magnesium oxide (magnesia usta) to a patient with the diagnosis of "neuralgia of the celiac plexus of rheumatic origin". Besides the traditional use of magnesium as antacid remedy at the time, we raised the hypothesis that magnesium could be administered by Moscati in order to treat the neuralgia itself. Considering the scientific background of Moscati at the school of Filippo Bottazzi (1867-1941), a father of Italian biochemistry, we suggested that the doctor tried to apply the preliminary concepts acquired from electrophysiological studies on magnesium to his clinical practice. Only after decades, magnesium was recognized a fundamental ion in the energy metabolism and in contributing to maintain the ionic intracellular homeostasis, including for neurons.

2018 - PTCH1 germline mutations and the basaloid follicular hamartoma values in the tumor spectrum of basal cell carcinoma syndrome (NBCCS) [Articolo su rivista]
Ponti, Giovanni; Manfredini, Marco; Pastorino, Lorenza; Maccaferri, Monia; Tomasi, Aldo; Pellacani, Giovanni
abstract

Background/Aim: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. Materials and Methods: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. Results: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. Conclusion: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.

2018 - Seminal cell free DNA concentration levels discriminate between prostate cancer and benign prostatic hyperplasia [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Micali, Salvatore; Manfredini, Marco; Milandri, Riccardo; Bianchi, Giampaolo; Pellacani, Giovanni; Kaleci, Shaniko; Chester, Johanna; Conti, Andrea; Prete, Chiara Del; Tomasi, Aldo
abstract

Background/Aim: Seminal plasma cfDNA (scfDNA) was recently proposed as a novel PCa biomarker. Our aim was to evaluate whether scfDNA could discriminate PCa from benign prostate hyperplasia (BPH) patients. Patients and Methods: A cohort of 43 patients (18 and 25 pathology proven PCa and BPH patients), and 13 healthy age-matched control subjects were enrolled. scfDNA quantification was performed. Data were analyzed through ANOVA testing. Results: Average scfDNA concentrations were 1,407.83 ng/μl, 128.13 ng/μl and 78.09 ng/μl for PCa patients, BPH patients and healthy subjects, respectively. Statistical analysis showed a significant difference among the groups, allowing for distinction of patients with optimal accuracy. A cut-off level of 450 ng/μl scfDNA was identified for the differentiation of PCa and BPH patients. Conclusion: scfDNA concentrations are significantly different between PCa patients and BPH patients. scfDNA is a promising biomarker with several applications in PCa diagnosis, screening programs and therapeutic monitoring.

2018 - Seminal Cell-Free DNA Assessment as a Novel Prostate Cancer Biomarker [Articolo su rivista]
Mandrioli, M.; Manfredini, M.; Micali, S.; Cotugno, M.; Ozben, T.; Pellacani, G.; Tomasi, A.; Ponti, G.; Maccaferri, M.; Bianchi, G.; Del Prete, C.
abstract

Background: Cell-free DNA (cfDNA) includes circulating DNA fragments which can be obtained from different human biological samples. It originates from apoptotic and/or necrotic cells or it is actively secreted by cancer cells. To our knowledge the quantification and size distribution assessment of seminal plasma cfDNA from prostate cancer patients was never assessed. Objective: The aim of our study was to the identify identifation of a novel sensitive non-invasive biomarker of prostate cancer, through the fluorimetric quantification and the electrophoretic analysis of seminal cfDNA in healthy individuals and prostate cancer patients. Results: The concentration of seminal plasma cfDNA in prostate cancer patient was 2243.67 ± 1758 ng/µl. In healthy individuals was 57.7 ± 6.79 ng/µl. Electrophoresis showed broad difference between healthy individuals and patients who showed presented a distinct characteristic DNA ladder fragmentationsmear ranging from 100bp to 2000 10.000 bp. Conclusion: Human seminal fluid can be a valuable source of cfDNA in the setting of liquid biopsy procedures for the identification of novel oncological biomarkers. Seminal plasma cfDNA from prostate cancer patients is significantly more concentrated than from age-matched healthy controls. Fluorimetric measurement and electrophoretic assessment allow a reliable quantification and characterization of seminal plasma cfDNA, which can be used routinely in prostate cancer screening programs.

2018 - Seminal cell-free DNA assessment as a novel prostate cancer biomarker [Relazione in Atti di Convegno]
Ponti, Giovanni; Maccaferri, Monia; Mandrioli, Mauro; Ozbenc, Tomris; Manfredini, Marco; Micali, Salvatore; Cotugno, Michele; Bianchi, Giampaolo; Pellacani, Giovanni; Tomasi, Aldo
abstract

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2018 - Seminal cell-free DNA molecular profile as a novel diagnostic and prognostic prostate cancer biomarkers [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Manfredini, Marco; Cotugno, Michele; Pellacani, Giovanni; Conti, Andrea; Micali, Salvatore; Mandrioli, Mauro; Tomasi, Aldo
abstract

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2018 - The value of fluorimetry (Qubit) and spectrophotometry (NanoDrop) in the quantification of cell-free DNA (cfDNA) in malignant melanoma and prostate cancer patients [Articolo su rivista]
Ponti, Giovanni; Maccaferri, Monia; Manfredini, Marco; Kaleci, Shaniko; Mandrioli, Mauro; Pellacani, Giovanni; Ozben, Tomris; Depenni, Roberta; Bianchi, Giampaolo; Pirola, Giacomo Maria; Tomasi, Aldo
abstract

Background Circulating cell-free tumor DNA (cfDNA) is of crucial interest in oncology. cfDNA constitutes a potential prognostic and therapeutic marker for different solid tumors and can be used in the diagnostic and therapeutic management of cancer patients for which nowadays there are no valid laboratory markers. In the present study, the quality and quantity of the cfDNA were assessed by different quantification procedures, in order to identify the potential applications of these techniques in the preliminary cfDNA quantification. Methods Qubit with single (ss) and double strand (ds) DNA assay kits, NanoDrop and quantitative Real Time PCR (qPCR), were adopted to assess the cfDNA in the blood samples of 18 melanoma patients, 67 prostate cancer patients and 15 healthy controls. Results The quantification by NanoDrop (average value 8.48 ng/μl, 95% confidence limit (CL) = 7.23–9.73), Qubit ssDNA (average value 23.08 ng/μl, CL = 19.88–26.28), dsDNA (average value 4.32 ng/μl, CL = 3.52–5.12) assay kits and qPCR (average value 0.39 ng/μl, CL = 0.31–0.47) revealed differences among the four procedures. Qubit 2.0 ss-DNA kit gave higher cfDNA concentration values for all the samples analyzed. In detail, Qubit ssDNA assay revealed higher sensitivity in the quantification of small amounts of pure ss-DNA and ds-DNA, while NanoDrop allowed the assessment of the purity of cfDNA samples. Conclusions The NanoDrop and Qubit 2.0 measurements were analyzed in order to define their correlation with qPCR cfDNA assessment, showing good correlation values with the qPCR that should be considered the “gold standard”. In our proposal, the sequential combination of NanoDrop and Qubit ssDNA methods should be adopted for a cost-effective preliminary assessment of total circulating cfDNA in melanoma and prostate cancer patients, and only discordant values should undergo qPCR assessment.

2017 - BRAF ,NRASandC-KITAdvanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival [Articolo su rivista]
Ponti, Giovanni; Manfredini, Marco; Greco, Stefano; Pellacani, Giovanni; Depenni, Roberta; Tomasi, Aldo; Maccaferri, Monia; Cascinu, Stefano
abstract

The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management.

2017 - Desmoplastic melanoma: a challenge for the oncologist [Articolo su rivista]
Manfredini, Marco; Pellacani, Giovanni; Losi, Lorena; Maccaferri, Monia; Tomasi, Aldo; Ponti, Giovanni
abstract

To evaluate clinical, pathologic and genetic features of desmoplastic melanoma (DM).MATERIALS & METHODS: Analysis of all DM records from 1991 to 2015. RESULTS: The most common location of DMs was the head and neck (69%); median age and follow-up were 60.5 and 7.3 years, respectively. A familial predisposition for DMs and others malignancies was analyzed. Thin Breslow thickness (<4.5 mm) was associated with an intraepidermal component or a previous lentigo maligna, whereas high Breslow thickness (>4.5 mm) was observed in 'pure' DM. CONCLUSION: DM could progress from an early phase, characterized by an intraepidermal component, to late phase, characterized by a dermal nodule. This hypothesis correlates with melanoma genetic and NF1 mutation, which could be an early event in the progression of DM.

2016 - BRAFp.V600E, p.V600K, and p.V600R Mutations in Malignant Melanoma: Do They Also Differ in Immunohistochemical Assessment and Clinical Features? [Articolo su rivista]
Ponti, Giovanni; Tomasi, Aldo; Maiorana, Antonino; Ruini, Cristel; Maccaferri, Monia; Cesinaro, Anna M; Depenni, Roberta; Manni, Paola; Gelsomino, Fabio; Giusti, Francesca; Garagnani, Lorella; Pellacani, Giovanni
abstract

Although the detection of BRAF p.V600E mutation by immunohistochemistry was clearly described in melanoma, discordant evidences were reported for the detection of p.V600K and p.V600R mutations. The aim of the study was to evaluate the efficacy of BRAFp.V600E, p.V600K, and p.V600R detection by immunohistochemistry in melanoma.

2016 - Congenital Glioblastoma multiforme and eruptive disseminated Spitz nevi [Articolo su rivista]
Mandel, Victor Desmond; Persechino, Flavia; Berardi, Alberto; Ponti, Giovanni; Ciardo, Silvana; Rossi, Cecilia; Pellacani, Giovanni; Farnetani, Francesca
abstract

Background: Glioblastoma multiforme (GBM) is the deadliest malignant primary brain tumor in adults. GBM develops primarily in the cerebral hemispheres but can develop in other parts of the central nervous system. Its congenital variant is a very rare disease with few cases described in literature. Case presentation: We describe the case of a patient with congenital GBM who developed eruptive disseminated Spitz nevi (EDSN) after chemotherapy. Few cases of EDSN have been described in literature and this rare clinical variant, which occurs predominantly in adults, is characterized by multiple Spitz nevi in the trunk, buttocks, elbows and knees. There is no satisfactory treatment for EDSN and the best therapeutic choice is considered the clinical observation of melanocytic lesions. Conclusion: We recommend a close follow-up of these patients with clinical observation, dermoscopy and reflectance confocal microscopy (RCM). However, we suggest a surgical excision of the lesions suspected of being malignant.

2016 - Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome [Articolo su rivista]
Longo, Caterina; Pellacani, Giovanni; Tomasi, Aldo; Mandel, Victor Desmond; Ponti, Giovanni
abstract

Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors.

2016 - Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Martorana, Davide; Mandel, Victor Desmond; Loschi, Pietro; Pollio, Annamaria; Pecchi, Annarita; Dealis, Cristina; Seidenari, Stefania; Tomasi, Aldo
abstract

Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple cafè-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease.

2016 - Microsatellite instability, immunohistochemistry and germline mismatch repair gene mutations for the diagnosis of Muir-Torre syndrome in immunosuppressed patients [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Sestini, Roberta; Gorelli, Greta; Tomasi, Aldo
abstract

Although rare sebaceous tumors and keratoacanthomas are clinical criteria for Muir-Torre syndrome (MTS), they can also be found in the context of immunosuppression. We present here two patients who underwent organ transplantation in which immunosuppression unmasked MTS through the early appearance of the cutaneous sebaceous neoplasms. In all of their sebaceous tumors we detected microsatellite instability (MSI) e loss of mutS protein homolog 2 (MSH2) and 6 (MSH6) expression at immunohistochemistry (IHC). Although in the absence of visceral MTS phenotype, we performed the sequencing analysis for mismatch repair genes (MMR) identifying two novel MSH2 and MSH6 germline mutations. The combination of MSI and IHC status can therefore be considered useful for the recognition of MTS, even in case of incomplete MTS phenotype and/or in immunosuppressed patients. It would allow a costeffective approach to identify individuals who should undergo MMR genes direct sequencing.

2016 - Muir-Torre Syndrome and founder Mismatch Repair genes mutations: A long gone historical genetic challenge [Articolo su rivista]
Ponti, Giovanni; Manfredini, Marco; Tomasi, Aldo; Pellacani, Giovanni
abstract

A "cancer predisposing syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoachantomas associated to visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized as due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carring sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostics strategies for Lynch/Muir-Torre syndromes.

2016 - M09Quantification of circulating cell-free DNA by fluorimetry (Qubit) and spectrophotometry (NanoDrop) in patients with malignant melanoma and prostate cancer [Abstract in Atti di Convegno]
Ponti, G.; Maccaferri, M.; Depenni, R.; Mandrioli, M.; Pellacani, G.; Manfredini, M.; Ozben, T.; Ruini, C.; Iattoni, E.; Cerioli, D.; Cascinu, S.; Tomasi, A.
abstract

Quantification of circulating cell-free DNA by fluorimetry (Qubit) and spectrophotometry (NanoDrop) in patients with malignant melanoma and prostate cancer

2016 - Oral mucosal stigmata in hereditary-cancer syndromes: From germline mutations to distinctive clinical phenotypes and tailored therapies [Articolo su rivista]
Ponti, Giovanni; Tomasi, Aldo; Manfredini, Marco; Pellacani, Giovanni
abstract

Numerous familial tumor syndromes are associated with distinctive oral mucosal findings, which may make possible an early diagnosis as an efficacious marker for the risk of developing visceral malignancies. In detail, Familial Adenomatous Polyposis (FAP), Gardner syndrome, Peutz-Jeghers syndrome, Cowden Syndrome, Gorlin Syndrome, Lynch/Muir-Torre Syndrome and Multiple Endocrine Neoplasia show specific lesions of the oral mucosa and other distinct clinical and molecular features. The common genetic background of the above mentioned syndromes involve germline mutations in tumor suppressor genes, such as APC, PTEN, PTCH1, STK11, RET, clearly implied in both ectodermal and mesodermal differentiation, being the oral mucosal and dental stigmata frequently associated in the specific clinical phenotypes. The oral and maxillofacial manifestations of these syndromes may become visible several years before the intestinal lesions, constituting a clinical marker that is predictive for the development of intestinal polyps and/or other visceral malignancies. A multidisciplinary approach is therefore necessary for both clinical diagnosis and management of the gene-carriers probands and their family members who have to be referred for genetic testing or have to be investigated for the presence of visceral cancers.

2016 - Quantification of circulating cell-free DNA by fluorimetry (Qubit) and spectrophotometry (NanoDrop) in patients with malignant melanoma and prostate cancer [Abstract in Rivista]
Ponti, Giovanni; Maccaferri, M; Depenni, Roberta; Mandrioli, Mauro; Pellacani, Giovanni; Manfredini, M; Ozben, T; Ruini, C; Iattoni, Elena; Cerioli, Davide; Cascinu, Stefano; Tomasi, Aldo
abstract

n.d.

2016 - Role of microsatellite instability, immunohistochemistry and Mismatch Repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre Syndrome. [Articolo su rivista]
Ponti, Giovanni; Manfredini, Marco; Pellacani, Giovanni; Tomasi, Aldo
abstract

Sebaceous tumours and keratoacanthomas are uncommon neoplasms that constitute important clinical criteria for Muir-Torre Syndrome (MTS) diagnosis. In MTS patients, the increased risk of developing synchronous or metachronous visceral malignancies is characterized by autosomal dominant inheritance. However, there are further conditions, other than MTS, that increase the risk of sebaceous neoplasms, e.g. iatrogenic immunosuppression. In this latter scenario, the sebaceous tumours can present Microsatellite instability (MSI) and loss of Mismatch-Repair (MMR) proteins, characteristic of hereditary syndromes, even in the absence of MMR germline mutations. In this paper we examine transplant probands in which the immunosuppressive therapies unmask the MTS cutaneous phenotypes, showing microsatellite instability (MSI) and loss of MMR protein expression, as demonstrated by immunohistochemistry (IHC). Furthermore, mismatch repair genes (MMR) sequencing analysis identified the presence of germline mutations in MTS-suspected individuals, in the absence of a visceral MTS phenotype. It is well known that immunosuppression plays a central role in the development of sebaceous tumours in both MTS and in non-syndromic settings. Sebaceous skin tumours MSI status and IHC profiles can be influenced by epigenetic or iatrogenic factors, however they constitute valuable tools and a cost-effective approach to screen individuals who otherways should undergo MMR genes direct sequencing in the context of immunosuppression. In this complex setting, the choice of the immunosuppressive drug becomes a critical decision for the management of both MTS and sporadic transplant patients, that may benefit from the administration of immunosuppressive drugs, resulting in a low impact on skin cancerogenesis.

2016 - Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Sammaria, Giuliano; Manfredini, Marco
abstract

There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral benign and malignant neoplasms. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant systemic disease with almost complete penetrance and high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1. The syndrome is characterized by unusual skeletal changes and high predisposition to the development of multiple basal cell carcinomas, odontogenic keratocysts tumors and other visceral tumors. The Gorlin syndrome, clinically defined as distinct syndrome in 1963, existed during Dynastic Egyptian times, as revealed by a costellation of skeletal findings compatible with the syndrome in mummies dating back to 3000years ago and, most likely, in the ancient population of Pompeii. These paleogenetic and historical evidences, together with the clinical and biomolecular modern evidences, confirm the quite benign behavior of the syndrome and the critical value of the multiple and synchronous skeletal anomalies in the recognition of these rare and complex genetic disease.

2016 - Wall paintings facies and their possible genetic correlates in the ancient Pompeii: A bio-anthropologic message from the past? [Articolo su rivista]
Ponti, Giovanni; Manfredini, Marco; Ruini, Cristel
abstract

The figurative arts and precisely the ancient Pompeian wall paintings portraits can provide an additional source of information in supplementing bio-anthropological studies. There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to distinctive facial features. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant syndrome characterized by unusual skeletal changes, such as macrocephaly, facial asymmetry, hypertelorism, frontal and parietal bossing caused by germline mutations of the gene PTCH1. The Gorlin syndrome, clinically defined in 1963, existed during Dynastic Egyptian times, as revealed by a spectrum of skeletal findings compatible with the syndrome in mummies dating back to three thousand years ago and, most likely, in the ancient population of Pompeii. In the present research, we discuss the potential relationship between Pompeian wall paintings portrait and the cranio-metric bone changes revealed among the Pompeian skull collections assuming that the ancient portraits can constitute an important tool that should be strictly integrated with osteologic and biomolecular data in order to argue a syndromic diagnosis in ancient population.

2015 - A novel CYLD germline mutation in Brooke-Spiegler syndrome. [Articolo su rivista]
Guardoli, D; Argenziano, G; Ponti, Giovanni; Nasti, S; Zalaudek, I; Moscarella, E; Lallas, A; Piana, S; Specchio, F; Martinuzzi, C; Raucci, M; Pellacani, Giovanni; Longo, Caterina
abstract

BACKGROUND: Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by the development of multiple adnexal neoplasms including spiradenomas, cylindromas, trichoepitheliomas and major and minor salivary glands neoplasms. This syndrome encompasses a wide variability of clinical phenotypes depending on the variable number of tumours present in the given patient. OBJECTIVE: Somatic mutations in adjunct to CYLD germline mutations may play a central role in the development of the tumour phenotype and in the genotype-phenotype correlations. METHODS: Blood sample and paraffin embedded tissue biopsied from three cylindromas, one trichoepithelioma and one spiradenomas were collected after obtaining informed consent from our patient and genomic DNA was isolated. RESULTS: We found out a novel germline mutation in the CYLD gene in exon 15 that resulted in the deletion of one nucleotide. This gives rise to a premature translational termination codon at amino acid position 693 prior to four Cys-X-X-Cys pairs and one of the two catalytic domains of ubiquitin carboxy-terminal hydrolases. In only one cylindroma we detected the same germline mutation (c.2070delT/p.F690FfsX3) in addition to two somatic events (I645V and R936X). The presence of this unique mutation could be linked to the peculiar phenotype of our patient who presented an attenuated form of BSS, an autosomal dominant inheritance with low penetrance and no additional visceral tumours. CONCLUSIONS: The overall phenotype of our patient may support the hypothesis that somatic mutations in adjunct to CYLD germline mutations may play a central role in the development of the tumour phenotype and in the genotype-phenotype correlations.

2015 - BRAFV600E mutated and wild type melanomas: dermoscopy and reflectance confocal microscopy characterization [Poster]
Manfredini, Marco; Ponti, Giovanni; Mandel, Victor Desmond; Persechino, Flavia; Ruini, Cristel; Maccaferri, Monia; Pellacani, Giovanni
abstract

The advent of modern molecular approaches was of crucial importance for the identification of melanoma genetic signatures, opening new horizons in the treatment of metastatic disease with molecular targeted therapies. Similarly the melanoma diagnosis is aided by reflectance confocal microscopy (RCM): a promising technique that allows non-invasive imaging from the skin surface to the upper dermis with quasi-histologic resolution. The most common melanoma mutation involves the gene BRAF and it is represented by the BRAFV600E, however, V600K, V600R and V600D mutations are also known. Because different genetic aberrations categorize melanoma subtypes with distinct clinical characteristics, it is reasonable to hypothesize that a distinctive molecular signature corresponds to specific morphologic patterns. A comparison between the dermoscopic patterns of BRAF p.V600E, BRAF p.V600K and wild-type BRAF primary melanomas was assessed from a collection of 12 lesions (4 primary melanomas per each BRAFV600 mutated status and 4 wt). In 9 cases the RCM images were available and the frequency of the RCM descriptors was examined. The RCM analysis showed that the presence of plump bright cells, collagen bundles and inflammatory cells in the dermis were frequently observed even when dermoscopy showed no regression features. Our study showed that regression phenomena and the associated dermoscopic and RCM descriptors could help the clinician to discriminate between the different BRAF mutated status, providing key information for patient screening, management and follow-up.

2015 - Confocal microscopy characterization of BRAFV600E mutated melanomas [Articolo su rivista]
Ruini, Cristel; Manfredini, Marco; Pellacani, Giovanni; Mandel, Victor Desmond; Tomasi, Aldo; Ponti, Giovanni
abstract

Thanks to modern techniques, molecular signatures for melanoma are now identifiable and have opened new horizons in the treatment of metastatic disease with molecular-targeted therapies. We distinguish different melanoma subtypes on the basis of genetic mutations such as BRAFV600E and we can therefore hypothesize the existence of corresponding morphological patterns that might be detected in vivo by noninvasive diagnostic tools such as dermoscopy and confocal microscopy. Eight BRAFV600E mutated melanomas (six primary and two metastases) were collected, matched in terms of age, sex, and thickness wild-type controls, and analyzed. In this preliminary study, regression, corresponding to fibrosis and melanophages in the dermis, was the predominant pattern and was also observed confocally when dermoscopy showed no peppering. In particular, confocal microscopy could not only detect regression but also provided a semiquantitative analysis of its grade through the count of melanophages. Confocal microscopy can be proposed as a useful tool in the preliminary screening and characterization of BRAFV600E mutated melanomas, providing new insights for patients' screening and follow-up.

2015 - Distinctive clinical and dermoscopic features of BRAFp.V600K mutated melanomas. [Articolo su rivista]
Ponti, Giovanni; Manfredini, M; Tomasi, Aldo; Pellacani, Giovanni
abstract

dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma have been recently analyzed by Pozzobon et al. in an interesting study published in your journal. The authors found out that peppering pattern was significantly increased among BRAF mutant melanoma, being present in the 68% of their cases series, with OR 1.68 (CI 95%1.089-2.581, p=0.015).1 The intend of this letter is to underline the dermoscopic features and the distinctive clinical features of BRAF p.V600K melanoma (the second most common BRAF V600 mutation detected in 5 to 30% of cases), that might be slightly different from from BRAF p.V600E melanoma.

2015 - Fordyce granules and hyperplastic mucosal sebaceous glands as distinctive stigmata in Muir-Torre syndrome patients: characterization with reflectance confocal microscopy [Articolo su rivista]
Ponti, Giovanni; Meschieri, Andrea; Pollio, Annamaria; Ruini, Cristel; Manfredini, Marco; Longo, Caterina; Mandel, Victor Desmond; Ciardo, Silvana; Tomasi, Aldo; Giannetti, Luca; Pellacani, Giovanni
abstract

Background: The Muir-Torre syndrome (MTS), a variant of Lynch syndrome (LS), is characterized by the presence of sebaceous skin adenomas and/or carcinomas and keratoacanthomas associated with visceral malignancies. Fordyce granules (FGs) are oral mucosal lesions previously found in association with LS. The aim of this study was to analyze the specific frequency of FGs in sporadic individuals and gene carriers patients with MTS of known mismatch repair genes mutations. The secondary aim was to characterize FGs by means of reflectance confocal microscopy (RCM). Methods: A total of 13 patients belonging to nine different genetically unrelated MTS kindreds (MLH1 gene mutation n = 2; MSH2 gene mutation n = 11) and 140 genetically unrelated healthy controls were examined. Depending on the clinical examination of the oral mucosa surface, subjects were categorized as either FGs positive or FGs negative. Results: FGs were diagnosed in 13 of 13 (100%) of MMR gene carriers patients with MTS vs. 9 of 140 (6.4%) controls. The most common site for FGs in MTS was the vestibular oral mucosa, compared with the gingival mandibular and retromandibular pad in controls. RCM examination found multiple sebaceous acinar cells that appear as round or oval hyper-refractive globules and that create a lobular aspects of the sebaceous glands defined as 'moruliform' or 'berry-like' structures. Conclusions: Clinical and RCM evidences of our study suggest that an activation of the sebaceous glands system occurs in patients with MTS. Fordyce granules and intra-oral sebaceous hyperplasia may constitute an additional clinical parameter, which may be adopted to distinguish individuals with highest likelihood of being affected from MTS.

2015 - Giuseppe Mariani: the Biography on the fiftieth anniversary of his death [Articolo su rivista]
Farnetani, Francesca; Manfredini, Marco; Mandel, Victor Desmond; Ponti, Giovanni
abstract

[No abstract available]

2015 - Giuseppe Moscati: a man, a physician and a scientist [Articolo su rivista]
Ponti, Giovanni; D'Onofrio, Felice; Ruini, Cristel; Muscatello, Umberto; Tomasi, Aldo
abstract

The life of Giuseppe Moscati (1880-1927) as a man, as a physician and as a scientist may be framed within the cultural climate of Positivism, which spread over the last years of the 19th century and the beginning of the 20th Century. His activity contributed to patients' care improvement; in addition to meticulous drug regimens, he also prescribed a methodology of spiritual care, involving meditation and self-control as part of an holistic approach to healthcare. Our review deals with his published researches, highlighting the innovative findings on the juvenile diabetes treatment and extensive clinical changes consequent upon nephritis. This extraordinary man put considerable emphasis on primary care and holistic health in Italy, pioneering a new patient-centred, and holistic approach to medicine.

2015 - Leonardo Martinotti: the biography on the fiftieth anniversary of his death [Articolo su rivista]
Farnetani, Francesca; Manfredini, Marco; Mandel, Victor Desmond; Ponti, Giovanni
abstract

[No abstract available]

2015 - Mismatch Repair Gene Deficiency and Genetic Anticipation in Lynch Syndrome [Articolo su rivista]
Ponti, Giovanni; Ruini, Cristel; Tomasi, Aldo
abstract

Lynch syndrome; mismatch repair genes

2015 - Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome [Articolo su rivista]
Ponti, Giovanni; E., Castellsagué; C., Ruini; Percesepe, Antonio; Tomasi, Aldo
abstract

...

2015 - The long road to the use of microscope in clinical medicine in vivo: From early pioneering proposals to the modern perspectives of optical biopsy [Articolo su rivista]
Ponti, G.; Muscatello, U.
abstract

For a long period the scientists did not recognized the potentialities of the compound microscope in medicine. Only few scientists recognized the potentialities of the microscope for the medicine; among them G. Campani who proposed the utilization of his microscope to investigate the skin lesions directly on the patient. The proposal was illustrated in a letter Acta Eruditorum of 1686. The recent development of optical techniques, capable of providing in-focus images of an object from different planes with high spatial resolution, significantly increased the diagnostic potential of the microscope directly on the patient.

2014 - Brooke-Spiegler syndrome tumor spectrum beyond the skin: a patient carrying germline R936X CYLD mutation and a somatic CYLD mutation in Brenner tumor [Articolo su rivista]
Ponti, Giovanni; Ruini, Cristel; Girolomoni, Giampiero; Pellacani, Giovanni; Farnetani, Francesca; Pastorino, Lorenza; Ghiorzo, Paola; Witkowski Alex, M.; Bianchi Scarrà, Giovanna; Tomasi, Aldo; Loschi, Pietro; Nasti, Sabina
abstract

Brooke–Spiegler syndrome is a hereditary disorder characterized by predisposition to the development of skin appendage tumors and the major and minor salivary glands neoplasms. The role of the CYLD mutation in visceral neoplasms is still unclear, except for parathyroid tumor. We report the case of a 46 year-old patient with multiple cylindromas and trichoepiteliomas, a Brenner tumor of the ovary, and a negative family history for Brooke-Spiegler phenotype. Genetic analysis revealed R936X germline mutation in the proband but not in her relatives. The same somatic mutation was found in the Brenner tumor, together with a novel missense CYLD mutation (D889N), which has never been reported in the literature to our knowledge. A founder effect for R936X has been hypothesized due to its high; surprisingly in our case this mutation seems to be recognized as a de novo mutation. Future studies involving a greater number of cases are necessary to understand possible genotype/phenotype correlations, through the clinical analysis of the familial tumor spectrum.

2014 - Dermoscopy of small melanomas: just a miniaturized dermoscopy? [Articolo su rivista]
Ferrari, C; Seidenari, Stefania; Borsari, S; Fabiano, A; Bassoli, Sara; Giusti, F; Ponti, Giovanni; Magnoni, Cristina
abstract

BACKGROUND AND OBJECTIVE: Small melanomas (MMs) are usually MMs in an initial growth phase, deserving attention by the clinician aiming at an early diagnosis. The aim of this study was to identify clues for early diagnosis of small MM, by comparing the dermoscopic features of MMs smaller than 4 mm (micromelanomas) to those of larger MMs. MATERIALS AND METHODS: The database consisted in the dermoscopic images of 482 MMs which were retrieved and measured digitally. The ABCD and the 7-point criteria were evaluated on the whole data base by 3 expert dermoscopists, whereas the main dermoscopic pattern was assessed only on micromelanomas. The dermoscopic aspects were correlated to clinical and histological ones. RESULTS: Most 7-point and ABCD scores and criteria referring to micromelanomas differed from those of the whole MM data base. Lesion asymmetry, number of colors, blue-whitish veil, atypical vessels, irregular globules/dots and regression increased according to MM diameter. An inverse trend was observed for atypical network and irregular pigmentation, which were more frequently observed in micromelanomas than in larger ones. Among the 22 micromelanomas, 12 lesions were in situ, whereas the other 10 were 0.2-2 mm thick. The clinical and dermoscopic characteristics of the 2 groups were similar. CONCLUSIONS: Micromelanomas are not a rarity. However, the clinician should be aware of the fact that the majority of them lack most of the dermoscopic features presented by larger lesions. This article is protected by copyright. All rights reserved.

2014 - Erratum: Molecular targeted approaches for advanced BRAF V600, N-RAS, c-KIT, and GNAQ melanoma (Disease Markers) [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Loschi, Pietro; Luppi, Gabriele; Gelsomino, Fabio; Longo, Caterina
abstract

ND

2014 - Giuseppe Moscati (1880-1927): a holistic approach to medicine [Articolo su rivista]
Ponti, Giovanni; Tomasi, Aldo
abstract

Giuseppe Moscati was a physician, medical school professor and a pioneer in the field of biochemistry and Italian studies on diabetes. He was declared a Catholic saint in 1987. In order to respond better to both the physical and spiritual needs of his patients, he developed his own holistic approach to healthcare involving meticulous drug regimens, meditation and discipline.

2014 - High Magnification Digital Dermoscopy of Basal Cell Carcinoma: A Single-centre Study on 400 cases. [Articolo su rivista]
Seidenari, S; Bellucci, C; Bassoli, S; Arginelli, F; Magnoni, Cristina; Ponti, Giovanni
abstract

The aim of this study was to assess the frequency of classic dermoscopic basal cell carcinoma (BCC) features and the sensitivity of new descriptors, such as light brown nests (homogeneous and structured) only visible employing a high magnification digital videomicroscope. A retrospective analysis of 2,024 highly magnified digital images referring to 400 BCCs was performed by 3 independent observers, who assessed 11 classic BCC descriptors and the new ones. Light brown nests were detected in 40.5% of BCCs. Homogeneous ones were observable in 17.8%, and structured nests in 32.8%. Light brown nests were visible in 14.3% of non-pigmented lesions, whereas in the pigmented groups these were observed in 42-54% of the cases. We suggest that brown nests described in this study may improve early recognition of superficial BCCs and of non-pigmented or slightly pigmented ones that may lack classic dermoscopic patterns.

2014 - Hypomelanosis of Ito with a trisomy 2 mosaicism: a case report [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Percesepe, Antonio; Guarneri, Carmelo; Guerra, Azzurra; Mandel, Victor Desmond; Kisla, Elif; Cevikel, Piril; Neri, Claudia; Menozzi, Cristina; Seidenari, Stefania
abstract

Introduction: Hypomelanosis of Ito is a rare neurocutaneous disorder, characterized by streaks and swirls of hypopigmentation following the lines of Blaschko that may be associated to systemic abnormalities involving the central nervous system and musculoskeletal system. Despite the preponderance of reported sporadic hypomelanosis of Ito, few reports of familial hypomelanosis of Ito have been described. Case presentation: A 6-month-old Caucasian girl presented with unilateral areas of hypomelanosis distributed on the left half of her body and her father presented with similar mosaic hypopigmented lesions on his upper chest. Whereas both blood karyotypes obtained from peripheral lymphocyte cultures were normal, a 16% trisomy 2 mosaicism was found in cultured skinfibroblasts derived from a hypopigmented skin area of her father. Conclusions: Familial cases of hypomelanosis of Ito are very rare and can occur in patients without systemic involvement. Hypomelanosis of Ito constitutes a non-specific diagnostic definition including different clinical entities with a wide phenotypic variability, either sporadic or familial. Unfortunately, a large number of cases remain misdiagnosed due to both diagnostic challenges and controversial issues on cutaneous biopsies in the pediatric population.

2014 - Molecular Targeted Approaches for Advanced BRAF V600, N-RAS, c-KIT, and GNAQ Melanomas [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Loschi, Pietro; Luppi, Gabriele; Gelsomino, Fabio; Longo, Caterina
abstract

The introduction of a newly developed target therapy for metastatic melanomas poses the challenge to have a good molecular stratification of those patients who may benefit from this therapeutic option. Practically, BRAF mutation status (V600E) is commonly screened although other non-V600E mutations (i.e., K-R-M-D) could be found in some patients who respond to therapy equally to the patients harboring V600E mutations. Furthermore, other mutations, namely, N-RAS, KIT, and GNAQ, should be sequenced according to distinct melanoma specific subtypes and clinical aspects. In our report, a practical flow chart is described along with our experience in this field.

2014 - Muir-Torre syndrome or phenocopy? The value of the immunohistochemical expression of mismatch repair proteins in sebaceous tumors of immunocompromised patients [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Ruini, Cristel; Percesepe, Antonio; Longo, Caterina; Mandel, Victor Desmond; Crucianelli, Francesca; Gorelli, Greta; Tomasi, Aldo
abstract

Primary and secondary immunodepressive conditions are associated with an increased incidence of sebaceous tumors. Microsatellite instability (MSI) and lack of expression of mismatch repair (MMR) proteins, typical markers of Muir-Torre/Lynch heredo-familial settings, can be recognized also in immunocompromised patients. We aimed to carry on a systematic examination of clinical, immunohistochemical, biomolecular features of sebaceous tumors arising in immunocompromised and immunocompetent patients between 1986 and 2012. Microsatellite screening, immunohistochemical analysis and genetic testing were performed for hMLH1, hMSH2 and hMSH6. Methylation status of MMR genes was checked in cases with immunohistochemistry (IHC) loss of MMR proteins expression and no germline mutations. Fifteen patients had a personal history of visceral carcinomas fulfilling diagnostic criteria for Muir-Torre syndrome. In this cohort, IHC analysis, MSI status and genetic testing were in agreement, showing eight MSH2 and two MLH1 germline mutations. Five patients were immunosuppressed and their sebaceous tumors showed a lack of MSH2/MSH6 expression, although just one case with positive family history for visceral cancer harbored a germline mutation. In immunosuppressed patients, loss of IHC for MMR proteins is not necessarily secondary to MMR germline mutations. IHC false positives are probably due to epigenetic alterations. MSI and lack of expression of MMR proteins can be recognized also in immunocompromised patients without MMR germline mutations.

2014 - Multiple primary melanomas versus single melanoma of the head and neck: a comparison of genetic, diagnostic, and therapeutic implications [Articolo su rivista]
Pollio, Annamaria; Tomasi, Aldo; Pellacani, Giovanni; Ruini, Cristel; Mandel, Victor Desmond; Fortuna, Giulio; Seidenari, Stefania; Ponti, Giovanni
abstract

Single primary and multiple primary melanomas (MPMs) of the head and neck region may be confused at first glance because of the common clinical and dermoscopic patterns. An inaccurate diagnosis may lead the clinician to a wrong diagnostic and therapeutic pathway because MPMs occurring in familial or sporadic settings are often involved in individual cancer susceptibility. We investigated the clinical, demographic, histological, and survival differences between MPMs and single melanoma occurring in the head and neck region. A retrospective analysis of medical and histologic records from 217 melanomas of the head and neck region was carried out. Malignant neoplasms affecting MPMs patients were also reported. Mutational analysis of specific genes was carried out when clinical data and family history were suggestive for a familial/hereditary setting. Two hundred and five out of 217 (94.5%) patients were affected by single primary melanoma and 12 (5.5%) by MPMs of the head and neck region. Individuals affected by MPMs were distinguished by a significantly higher mutation frequency and a higher prevalence of malignant neoplasms such as renal cancer. Genetic testing showed germline mutations affecting MITF E318K, CDKN2A genes. Our data highlight the importance of strict cancer surveillance in individuals with MPMs and the role of appropriate genetic counseling and testing in selected patients. Finally, personalized clinical and instrumental screening and follow-up strategies should also be based on mutational status. A heightened level of suspicion is required in the clinical management of mutation carriers.

2014 - NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies [Articolo su rivista]
Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; DE SANTIS, Giorgio; Pollio, Annamaria; Tauro, Maria Neri; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo
abstract

Background/aim: Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Patients and methods: Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Results: Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. Conclusion: This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1.

2014 - Skeletal and cranio-facial signs in Gorlin syndrome from ancient Egypt to the modern age: Sphenoid asymmetry in a patient with a novel PTCH1 mutation [Articolo su rivista]
Ponti, Giovanni; Ruini, Cristel; Pastorino, Lorenza; Loschi, Pietro; Pecchi, Annarita; Malagoli, Marcella; Mandel, Victor Desmond; Boano, Rosa; Conti, Andrea; Pellacani, Giovanni; Tomasi, Aldo
abstract

Gorlin syndrome is an autosomal dominant disorder linked to PTCH1 mutation, identified by a collection of clinical and radiologic signs. We describe the case of a family in which father and son fulfilled clear cut diagnostic criteria for Gorlin syndrome including multiple basal cell carcinomas, keratocystic odontogenic tumors, atypical skeletal anomalies and a novel PTCH1 germline mutation (c.1041delAA). Craniofacial and other skeletal anomalies displayed at 3D and helical CT scan were: macrocephaly, positional plagiocephaly, skull base and sphenoid asymmetry, bifidity of multiple ribs and giant multilocular odontogenic jaw cysts. Extensive multilamellar calcifications were found in falx cerebri, tentorium, falx cerebelli and in the atlanto-occipital ligament. The inclusion of bifid ribs as a novel major criteri may be useful for the recognition and characterization of misdiagnosed cases.

2014 - Stem cell properties in cell cultures from different stage of melanoma progression. [Articolo su rivista]
Magnoni, Cristina; S., Guidice; Pellacani, Giovanni; G., Bertazzoni; Longo, Caterina; E., Veratti; D., Morini; L., Benassi; S., Al Jalbout; C., Vaschieri; P., Azzoni; DE POL, Anto; S., Seidenari; Tomasi, Aldo; Ponti, Giovanni
abstract

Cutaneous Melanoma is an extremely heterogeneous human cancer. The most aggressive melanoma may contain deregulated cells with undifferentiated/stem cell-like phenotype. A critical mechanism by which melanoma cells enhance their invasive capacity is the dissolution of the intercellular adhesions and the acquisition of mesenchymal features as a part of an epithelial-to-mesenchimal transition (EMT). The aim of this study was to clarify the role of stem cell-like population in human melanomas through the in vitro analysis of melanocytic cell cultures, obtained from distinct histotypes of primary and metastatic malignant melanoma. Patients with advanced melanoma larger than 2cm diameter and/or wider than 300mm2 surface were enrolled. The melanoma cells were isolated from skin biopsies of lentigo melanoma (LM), superficial spreading (SS), nodular melanoma (NM) and metastatic melanoma (MM) and maintained in different media in order to evaluate the colony-forming unit assay, alkaline phosphatase and toluidine blue stain and the cell ability to differentiate into osteogenic and adipogenic lineages. Immunohistochemistry and flow cytometry analysis were performed in order to evaluate antigenic markers CD90, CD73, CD105, CD146, CD20, CD166 and nestin. This study confirms that melanoma can include an heterogeneous cell population with both abilities to self-renew and to give rise to differentiated progeny. Melanoma cells displayed the intra-tumoral heterogeneity and dynamic antigen phenotypes. Histologically, the transitions from normal skin to DN to LM to NM to MM was associated with a gradual increase in the expression of CD146, CD20, CD133, Nestin and CD73 by melanoma cells. These molecular evidences could be a milestone for the development of novel biomolecular targeted-therapy approaches.

2013 - Are the neck malignant melanomas different from the ones affecting the head? Clinicopathologic, dermoscopic and prognostic findings [Articolo su rivista]
Ponti, Giovanni; Pollio, Annamaria; Tomasi, Aldo; Borsari, Stefania; Magnoni, Cristina; Mandel, Victor Desmond; Loschi, Pietro; Ruini, Cristel; Seidenari, Stefania
abstract

Background: Malignant melanomas of the head and neck are usually considered as a unique entity in comparison to other body sites. However, no characterization of neck melanoma has been performed so far, despite the clear anatomic and histological differences. Aim: We investigated clinical, demographic, histological and dermoscopic differences between face, scalp and neck melanoma. Materials and methods: A retrospective analysis of medical and histologic records from 116 melanomas of the head and neck area collected between January 2003 and January 2008 was performed. Body site, gender, age, number of lesions, age at first melanoma diagnosis, size, Clark level, association with nevi, presence or absence of mitoses and/or ulceration, presence of synchronous and/or metachronous melanoma were recorded. Moreover, digital dermoscopy images of 92 melanomas of the head and neck area were analyzed for main dermoscopic patterns and lesion diameter. Results: Significant differences in Breslow thickness, ex-naevo origin and tumor size among neck and face-scalp melanomas were observed. Neck MM patients were younger than those with MM of face and scalp. In contrast to scalp and face, no patient died from neck melanoma. Dermoscopic patterns were similar to those of trunk-limbs MM, and no lesion showed a lentigo maligna pattern which was observed in most lesions of the face. Conclusion: Melanomas of the neck must be distinguished from face and scalp melanomas because of younger age, different dermoscopic patterns and ex-naevo origin and better prognosis. These data should be taken into account both from an epidemiological and clinical point of view.

2013 - Can noninvasive imaging tools potentially predict the risk of ulceration in invasive melanomas showing blue and black colors? [Articolo su rivista]
Longo, Caterina; F., Farnetani; E., Moscarella; B., de Pace; S., Ciardo; Ponti, Giovanni; S., Piana; Am, Cesinaro; C., Cota; G., Argenziano; C., Rosendahl; Pellacani, Giovanni; I., Zalaudek
abstract

The aim of this study was to evaluate the reflectance microscopy and histopathologic correlates of dermoscopic blue and black color (BB) in a series of melanomas. We searched our database for dermoscopic images of histopathologically diagnosed pigmented nodular melanomas (pNM), superficial spreading melanomas with a nodular component (SSM+Nod), and melanoma metastasis (METs). All cases were assessed for the presence of dermoscopic BB. Confocal microscopy findings were then compared with those of histopathology. A total of 17 BB-positive tumors including eight pNMs, five SSM+Nod, and four METs were included in the study. We identified two different dermoscopic patterns associated with black color, namely, large black blotches and irregular black dots/globules, which corresponded to two different confocal and histopathologic findings. Black blotches resulted from a total filling of the epidermis by an upward migration of melanocyte nests and pagetoid melanocytes as single cells and clusters, whereas black dots/globules also corresponded to the upward migration of melanocyte nests in the epidermis and pagetoid spread, but with sparing of intervening areas of epidermis. Interestingly, two pNM and two METs showing black color lacked any epidermal involvement and, instead, they were characterized by upward-bulging dermal masses of atypical melanocytes covered by an highly attenuated epidermis. In both cases, black color corresponded to pigment-containing melanocytes in close proximity to the surface of the skin. Our study suggests that black color results not only from epidermal melanin but also from a dense dermal proliferation of pigmented melanocytes under a thinned epidermis. It seems reasonable to suggest that a bulging proliferation of dermal melanocytes beneath a thin epidermal layer could precede ulceration. As ulceration is a very significant prognostic factor, speculation arising from this study that dermoscopic black color may in some cases indicate incipient ulceration is worthy of further study.

2013 - Cancer-associated genodermatoses: Skin neoplasms as clues to hereditary tumor syndromes. [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; S., Seidenari; A., Pollio; Muscatello, Umberto; Tomasi, Aldo
abstract

Characteristic skin neoplasms are associated with a large number of hereditary tumor syndromes and their knowledge and early detection may facilitate the diagnosis of the underlying malignancies. We will review the clinical and dermatopathological aspects of cutaneous and visceral lesions and the recent progresses in understanding the etiology, pathogenesis and therapies of selected tumor syndromes. The skin neoplasms we chose to consider are multiple neurofibromas in neurofibromatosis, cylindromas and trichoepitheliomas in Broke-Spiegler syndrome, sebaceous tumors and keratoacanthomas in Muir-Torre syndrome, Gardner fibromas in Gardner syndrome, multiple basal cell carcinomas in nevoid basal cell carcinoma (Gorlin) syndrome, multiple tricholemmomas in Cowden syndrome, multiple fibrofolliculomas in Birt-Hogg-Dubé syndrome and multiple leiomyomas in hereditary leiomyomatosis and renal cell cancer. Hereditary cancers have distinct biological and clinical features as compared to their sporadic counterparts; for this reason, we are now able to experiment new treatment approaches involving not only tumor detection and prevention, but also tailored therapeutic strategies focusing on the peculiar druggable molecular targets.

2013 - Clinical utility gene card for: Gorlin syndrome - update 2013. [Articolo su rivista]
Muzio, Ll; Pastorino, L; Levanat, S; Musani, V; Situm, M; Ponti, Giovanni; Bianchi Scarra, G.
abstract

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2013 - Erratum: Microscopic margins of resection influence primary gastrointestinal stromal tumor survival (Onkologie (2012) 35 (645-648)) [Articolo su rivista]
Catena, F.; Di Battista, M.; Ansaloni, L.; Pantaleo, M.; Fusaroli, P.; Di Scioscio, V.; Santini, D.; Nannini, M.; Saponara, M.; Ponti, G.; Persiani, R.; Delrio, P.; Coccolini, F.; Di Saverio, S.; Biasco, G.; Lazzareschi, D.; Pinn, A.
abstract

2013 - Fluorescence in-situ hybridization and dermoscopy in the assessment of controversial melanocytic tumors. [Articolo su rivista]
Ponti, Giovanni; Ruini, C; Massi, D; Pellacani, Giovanni; Tomasi, Aldo; Paglierani, M; Loschi, Pietro; Seidenari, Stefania
abstract

Although the 'gold standard' for melanoma diagnosis remains histopathological analysis, presently dermoscopists play a significant role in the diagnostic process. However, even a combined approach may not allow a clear-cut judgment on equivocal melanocytic lesions. Fluorescence in-situ hybridization (FISH) can offer assistance in the evaluation of chromosome abnormalities associated with malignancies, and its role is emerging in melanoma diagnosis. The aim of this study was to evaluate the diagnostic role of the FISH in the assessment of controversial lesions, defined as those lesions showing discrepancies between dermatoscopic and histological evaluations. Twenty clinically and histologically ambiguous melanocytic lesions were selected. After the first histopathologic diagnosis, a second pathologist examined the specimens in a blinded review for a second opinion and to identify the most suitable areas to hybridize using probes specific to RREB1, MYB, and CCND1 genes and the centromere of chromosome 6. The first histopathological evaluation led to the diagnosis of melanoma in seven cases, whereas the second identified eight cases of malignant melanoma and was in agreement with the first in 65% of cases and with dermoscopy in 40% of cases. Cytogenetic abnormalities detected by FISH are markers of malignancy that can be useful in the characterization of difficult-to-diagnose melanocytic tumors, when the dermatologist and the pathologist have a different opinions.

2013 - Hereditary trichilemmal cysts: a proposal for the assessment of diagnostic clinical criteria [Articolo su rivista]
Seidenari, Stefania; Pellacani, Giovanni; Nasti, Sabina; Tomasi, Aldo; Pastorino, Lorenza; Ghiorzo, Paola; Ruini, Cristel; BIANCHI-SCARRÀ, Giovanna; Pollio, Annamaria; Mandel, Victor Desmond; Ponti, Giovanni
abstract

Trichilemmal cysts (TCs) can occur as sporadic lesions or in hereditary-familial settings with autosomal dominant transmission. These entities have not been widely analyzed in their peculiar aspects yet. The aim of this study was to describe a cohort of patients with diagnosis of TCs through a clinical and biomolecular characterization, intended to highlight some effective diagnostic criteria for their identification. Among 149 cases of this study, 24 cases of TCs (16.1%) arose in patients with at least one first-degree relative with diagnosis of TCs. Peculiar findings concerning hereditary lesions included the multiple presentation with an early onset age. On the basis of clinical evaluation, we propose a panel of clinical and histologic criteria for the diagnosis of hereditary TCs, which includes: (i) the diagnosis of TCs in at least two first-degree relatives or in three first- or second-degree relatives in two consecutive generations; (ii) at least one of the patients with TCs diagnosed <45 years; and (iii) the diagnosis of multiple or giant (>5-cm lesions) or rare histopathologic features (proliferating and ossifying) TCs.

2013 - High-resolution imaging of basal cell carcinoma: a comparison between multiphoton microscopy with fluorescence lifetime imaging and reflectance confocal microscopy. [Articolo su rivista]
Manfredini, Marco; Arginelli, F; Dunsby, C; French, P; Talbot, C; König, K; Pellacani, Giovanni; Ponti, Giovanni; Seidenari, S.
abstract

AIMS: The aim of this study was to compare morphological aspects of basal cell carcinoma (BCC) as assessed by two different imaging methods: in vivo reflectance confocal microscopy (RCM) and multiphoton tomography with fluorescence lifetime imaging implementation (MPT-FLIM).METHODS: The study comprised 16 BCCs for which a complete set of RCM and MPT-FLIM images were available. The presence of seven MPT-FLIM descriptors was evaluated. The presence of seven RCM equivalent parameters was scored in accordance to their extension. Chi-squared test with Fisher's exact test and Spearman's rank correlation coefficient were determined between MPT-FLIM scores and adjusted-RCM scores.RESULTS: MPT-FLIM and RCM descriptors of BCC were coupled to match the descriptors that define the same pathological structures. The comparison included: Streaming and Aligned elongated cells, Streaming with multiple directions and Double alignment, Palisading (RCM) and Palisading (MPT-FLIM), Typical tumor islands, and Cell islands surrounded by fibers, Dark silhouettes and Phantom islands, Plump bright cells and Melanophages, Vessels (RCM), and Vessels (MPT-FLIM). The parameters that were significantly correlated were Melanophages/Plump Bright Cells, Aligned elongated cells/Streaming, Double alignment/Streaming with multiple directions, and Palisading (MPT-FLIM)/Palisading (RCM).CONCLUSION: According to our data, both methods are suitable to image BCC's features. The concordance between MPT-FLIM and RCM is high, with some limitations due to the technical differences between the two devices. The hardest difficulty when comparing the images generated by the two imaging modalities is represented by their different field of view.

2013 - Is confocal microscopy a valuable tool in diagnosing nodular lesions? A study on 140 cases. [Articolo su rivista]
Longo, Caterina; Farnetani, Francesca; S., Ciardo; Cesinaro, A. M.; E., Moscarella; Ponti, Giovanni; I., Zalaudek; G., Argenziano; Pellacani, Giovanni
abstract

BACKGROUND: Nodular lesions poses diagnostic challenge since nodular melanoma may simulate all kind of melanocytic and non-melanocytic lesions. Reflectance confocal microscopy is a novel technique that allows the visualization of skin at nearly histologic resolution although limited laser depth penetration hamper the visualization of deep dermis. METHODS: 140 nodules were retrospectively evaluated by means of confocal microscopy in blind from histopathologic diagnosis. At the end of the study the patients' codes were broken and the evaluations were matched with histopathologic diagnosis before performing statistical analysis. OBJECTIVE: We sought to assess whether the diagnostic accuracy of confocal microscopy compared to histopathology for the diagnosis of nodular lesions, and to identify possible limitations of this technique RESULTS: The study consisted of 140 nodular lesions (23 "pure" nodular melanomas, 9 melanoma metastasis, 28 BCCs, 6 invasive SCC, 32 naevi, 14 Seborrheic keratosis, 17 dermatofibroma, 5 vascular lesions and 6 other lesions). Confocal microscopy correctly diagnosed 121 out of 140 lesions (86,4%); eight out of 140 (5,7%) lesions revealed discordance between histopathology and confocal microscopy. Eight out of 140 (5,7%) cases were not evaluable by means of confocal microscopy due to the presence of ulceration or hyperkeratosis and three cases showed a non specific pattern. Interestingly, confocal microscopy reached a 96.5% sensitivity and 94.1% specificity (AUC: 0.970) (CI95%: 0.924-1.015) (p<0.001) for the diagnosis of melanoma. LIMITATIONS: The study is retrospective and lesions were not included on the basis of their diagnostic difficulty CONCLUSIONS: Despite the limited laser depth penetration of confocal microscopy, this imaging tool represents an effective instruments in diagnosing nodular lesions; however, fully ulcerated lesions or when a marked hyperkeratosis is present, biopsy should be always performed. Prospective studies on difficult to diagnose nodules should be performed to further analyze the pros and contra of RCM in skin cancer diagnosis.

2013 - Malignant and benign tumors associated to multiple primary melanomas: just the starting block for the involvement of MITF, PTEN and CDKN2A in multiple cancerogenesis? [Articolo su rivista]
A., Pollio; Tomasi, Aldo; Seidenari, Stefania; Pellacani, Giovanni; M., Rodolfo; S., Frigerio; A., Maurichi; D., Turchetti; S., Bassoli; C., Ruini; Ponti, Giovanni
abstract

Background: Multiple primary melanomas (MPMs) could represent an interesting field of investigation for possible linkage between multiple cancer phenotypes and genetic background. In this setting, the co-existence of MPMs and malignant/benign neoplasms in a group of MPMs patients has been highlighted and the corresponding germ-line mutations have been traced. Methods: The study evaluated the prevalence of benign and malignant neoplasms in a group of 49 MPMs patients and compared the data with 49 age- and gender-matched single primary melanoma (SPM) controls. Genetic testing was performed when a germ-line mutation was suspected. Results: A statistically significant prevalence (P<0.0001) of benign and malignant neoplasms were found among MPMs patients. Of 27 diagnosed malignancies, basal cell carcinoma was the most frequent (n=10, 37.1%), followed by colorectal adenocarcinoma (n=4, 14.8%), prostate adenocarcinoma (n=3, 11.1%), breast adenocarcinoma (n=2, 7.4%), papillary thyroid carcinoma (n=2, 7.4%), pancreas adenocarcinoma (n=2, 7.4%), renal cell carcinoma (n=2, 7,4%), oral squamous carcinoma (n=1, 3.7%), liver adenocarcinoma (n=1, 3.7%), large B lymphoma (n=1, 3.7%), multiple myeloma (n=1, 3.7%), urinary bladder carcinoma (n=1, 3.7%), stomach carcinoma (n=1, 3.7%). Ten different benign neoplasms arising in various organs were also reported. Germline mutations involving PTEN, MITF E318K, CDKN2A, MC1R were detected. Conclusions: Close cancer surveillance should be recommended in MPMs patients. Clinicians should select the appropriate population for genetic testing and refer those patients for genetic counseling. Tailored clinical and instrumental screenings and follow-up strategies have to be based on the patient’s mutation status.

2013 - Microsatellite Instability and Mismatch Repair protein expression in Sebaceous tumors, Keratocanthoma and Basal Cell Carcinomas with sebaceous differentiation in Muir-Torre Syndrome. [Articolo su rivista]
Ponti, Giovanni; Longo, Caterina
abstract

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2013 - Multiphoton laser tomography and fluorescence lifetime imaging of melanoma: morphologic features and quantitative data for sensitive and specific non-invasive diagnostics. [Articolo su rivista]
Seidenari, S; Arginelli, F; Dunsby, C; French, Pm; König, K; Magnoni, Cristina; Talbot, C; Ponti, Giovanni
abstract

Multiphoton laser tomography (MPT) combined with fluorescence lifetime imaging (FLIM) is a non-invasive imaging technique, based on the study of fluorescence decay times of naturally occurring fluorescent molecules, enabling a non-invasive investigation of the skin with subcellular resolution. The aim of this retrospective observational ex vivo study, was to characterize melanoma both from a morphologic and a quantitative point of view, attaining an improvement in the diagnostic accuracy with respect to dermoscopy. In the training phase, thirty parameters, comprising both cytological descriptors and architectural aspects, were identified. The training set included 6 melanomas with a mean Breslow thickness±S.D. of 0.89±0.48 mm. In the test phase, these parameters were blindly evaluated on a test data set consisting of 25 melanomas, 50 nevi and 50 basal cell carcinomas. Melanomas in the test phase comprised 8 in situ lesions and had a mean thickness±S.D. of 0.77±1.2 mm. Moreover, quantitative FLIM data were calculated for special areas of interest. Melanoma was characterized by the presence of atypical short lifetime cells and architectural disorder, in contrast to nevi presenting typical cells and a regular histoarchitecture. Sensitivity and specificity values for melanoma diagnosis were 100% and 98%, respectively, whereas dermoscopy achieved the same sensitivity, but a lower specificity (82%). Mean fluorescence lifetime values of melanocytic cells did not vary between melanomas and nevi, but significantly differed from those referring to basal cell carcinoma enabling a differential diagnosis based on quantitative data. Data from prospective preoperative trials are needed to confirm if MPT/FLIM could increase diagnostic specificity and thus reduce unnecessary surgical excisions.

2013 - Multiple tumor phenotypes and malignant melanoma: the role of genetic testing for MITF, PTEN and CDKN2A. [Abstract in Atti di Convegno]
Ponti, Giovanni; Depenni, R; Luppi, G; Ruini, C; Gelsomino, F; Loschi, P; Tomasi, Aldo; Spallanzani, A; Pellacani, Giovanni
abstract

It is well known that synchronous and/or metachronous multiple primary melanomas (MPMs) occur in clearly hereditary settings as well as in familial and sporadic settings. However, no evidence exists about their co-occurrence in patients with multiple cancer phenotypes, a setting in which genetic susceptibility plays a significant role. Inside the multiple tumor phenotypes, multiple primary melanomas occurring in familial or sporadic settings constitute an interesting case study for the analysis of cancer susceptibility. In this study, we focused on the co-existence of MPMs and other types of tumors evaluating the genetic characterization underlying the context of high susceptibility to the development of multiple cancer phenotypes. We retrospectively evaluated the prevalence of benign and malignant neoplasms occurred in a group of 49 patients with multiple primary melanomas (MPMs) and compared the results with a group of 58 randomly age- and gender matched controls with single primary melanoma (SPM) and a group of 52 age- and gender randomly matched healthy patients. Mutational analysis of specific genes was performed when clinical data and family history were suggestive for familial/hereditary setting. Individuals affected by MPMs were distinguished by a statistically significant higher mutation frequency and a higher prevalence of other neoplasms. Of 27 diagnosed malignancies, basal cell carcinoma was the most frequent (n=10, 37.1%), followed by colorectal adenocarcinoma (n=5, 18.5%) and prostate adenocarcinoma (n=3, 11.1%). In addition to malignances, we also detected 10 benign tumors. Genetic testing revealed germline mutations affecting PTEN, MITF E318K, CDKN2A, MC1R genes. Our data highlight the importance of strict cancer surveillance in individuals with MPMs and the role of appropriate genetic counseling and testing in selected patients. Selected candidates should undergo genetic testing, not only for CDKN2a, CDK4, MC1R, but also for MITF E318K and PTEN, in ordeto plan personalized clinical and instrumental screenings and follow-up strategies; the latter must be assessed basing on mutational status: it is prudent to have a heightened level of suspicion in the clinical management of mutation carriers.

2013 - Proteomic analysis of PTCH1+/- fibroblast lysate and conditioned culture media isolated from the skin of healthy subjects and Nevoid Basal Cell Carcinoma Syndrome (NBCCS) patients. [Poster]
Pastorino, L.; Bertazzoni, G.; Monari, Emanuela; Cuoghi, A.; Bergamini, Stefania; Bellei, E.; Ruini, C.; Ghiorzo, P.; Bianchi Scarrà, G.; Pellacani, Giovanni; Loschi, P.; Pollio, A.; Tomasi, Aldo; Farnetani, F.; Ponti, Giovanni
abstract

PTCH1 mutations lead to complex syndromes such as the Gorlin Syndrome (GS) also named Nevoid basal Cell Carcinoma Syndrome (NBCCS, OMIM #109400) is a rare autosomal dominant disorder characterized by striking predisposition to the development of multiple basal cell carcinomas (BCCs), keratocystic odontogenic tumors (KOCTs) of the jaws, palmar and/or plantar pits and developmental defects. A variety of other benign or malignant tumors i.e., ovarian fibroma, medulloblastoma, rhabdomyosarcoma, cardiac fibroma and ameloblastoma can be found. The mechanisms underlying the increased predisposition to the development of BCCs in the context of Gorlin-Goltz syndrome is linked to molecular pathways that differ from sporadic cases. Patients with Gorlin syndrome tend to develop multiple BCCs at an early age: moreover, the tumors typically arise on non-sunexposed skin. Fibroblasts of patients with Gorlin Syndrome may display properties determining BCC development. The aim of this study was to compare the proteomic profile of cultured fibroblast and fibroblast conditioned culture media of PTCH1+ and non-mutated fibroblasts. Proteomic analyses was performed using Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry in PTCH1+ fibroblast conditioned media isolated from not affected sun-protected skin areas of Gorlin patients and from healthy subjects. The protein profiles were obtained using Copper pre-activated IMAC30 ProteinChip array. 12 protein cluster peaks, >5 kDa, had statistically significant differences in their peak intensities between PTCH1+ and PTCH1- subject groups (p<0.05). Protein profiles in the fibroblast conditioned media revealed statistically significant differences between two different types (missense vs nonsense) of PTCH1 mutations. These differences could be useful as signatures to identify PTCH1 gene carriers at high risk for the development of NBCCS-associated malignancies, and to develop novel experimental molecular tailored therapies based on these druggable targets. These protein peaks profiles provided better understanding of the complex skin cancer microenvironment and could be useful to select patients at risk to develop multiple and aggressive BCCs and/or other NBCCS-associated malignancies.

2013 - Proteomic Analysis of PTCH1+/- Fibroblast Lysate and Conditioned Culture Media Isolated from the Skin of Healthy Subjects and Nevoid Basal Cell Carcinoma Syndrome Patients. [Articolo su rivista]
Ponti, Giovanni; Bertazzoni, G; Pastorino, L; Monari, Emanuela; Cuoghi, Aurora; Bergamini, Stefania; Bellei, Elisa; Benassi, Luisa; Azzoni, Paola; Petrachi, Tiziana; Magnoni, Cristina; Pellacani, Giovanni; Loschi, P; Pollio, A; Witkowski, Am; Tomasi, Aldo
abstract

Background. The pathogenesis underlying the increased predisposition to the development of basal cell carcinomas (BCCs) in the context of Gorlin-Goltz syndrome is linked to molecular mechanisms that differ from sporadic BCCs. Patients with Gorlin syndrome tend to develop multiple BCCs at an early age and present with tumors of non-sun-exposed skin. The aim of this study was to compare the proteomic profile of cultured fibroblast and fibroblast conditioned culture media of PTCH1+ and nonmutated fibroblasts. Results. Proteomic analysis was performed using Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry in PTCH1+ fibroblast conditioned media isolated from not affected sun-protected skin areas of Gorlin patients and from healthy subjects. 12 protein cluster peaks, >5 kDa, had significant differences in their peak intensities between PTCH1+ and PTCH1- subject groups. We detected a strongly MMP1 overexpression in PTCH1+ fibroblasts obtained from NBCCS patients with respect to healthy donors. Conclusion. Protein profiles in the fibroblast conditioned media revealed statistically significant differences between two different types (missense versus nonsense) of PTCH1 mutations. These differences could be useful as signatures to identify PTCH1 gene carriers at high risk for the development of NBCCS-associated malignancies and to develop novel experimental molecular tailored therapies based on these druggable targets.

2013 - Relationship between histological and computer based assessment of melanoma diameter and thickness in head & neck vs. trunk melanoma. [Articolo su rivista]
Seidenari, Stefania; A., Fabiano; S., Al Jalbout; S., Bassoli; S., Borsari; Magnoni, Cristina; Tomasi, Aldo; Vinceti, Marco; Ponti, Giovanni
abstract

BackgroundDiameter represents a controversial parameter in the diagnosis of melanoma (MM). The ABCD rule considers it an important diagnostic parameter, while some authors decrease its relevance. Also, its measurement is not always reliable, histological methods being usually used. The current study aims to compare histological and digital measurements and to evaluate the correlation between MM head- and trunk diameter and thickness. Methods The study population was subdivided according to diameter subgroups considering head- and trunk-limbs lesions separately. Digital diameters measured by an automatic software referring to 477 MM images were compared to diameters reported on the pathologist’s records. Clinical and histological information was also considered, and the correlation between diameter and thickness was assessed. Odds ratios (OR) were computed for different diameter subgroups. Results Mean digital diameters of head MMs and trunk limbs MMs exceeded histological measurements by 11% and 20%, respectively. In head MMs, no correlation between diameter and thickness was observable, whereas in the trunk-limbs group a direct relationship between thickness and diameter was noticed. ORs for non in situ vs in situ andfor ≥ 1 mm vs < 1 mm thick were low for small lesions, increasing for larger ones, indicating that the latter are more likely to be thick. ConclusionMM diameter should be assessed digitally to avoid tissue shrinkage after biopsy and imprecise in vivo measurements. Although nearly 10% of MMs might escape an early diagnosis based only on the D of the ABCD rule, MM diameter may be related to its thickness.The evaluation with a computer vision system should be recommended for small pigmented lesions (<6mm) in order to reduce the percentage of misdiagnosed smaller MMs and to better evaluate the parameter E of the ABCDE rule (Evolving lesion).

2013 - Sphenoid asymmetry associated to other skeletal anomalies in a clear cut case of PTCH1 mutated Gorlin-Goltz syndrome: a novel finding? [Poster]
Ruini, Cristel; Pastorino, Lorenza; Malagoli, Marzio; Bruno, Walter; Ghiorzo, Paola; BIANCHI-SCARRÀ, Giovanna; Loschi, Pietro; Pellacani, Giovanni; Tomasi, Aldo; Farnetani, Francesca; Mandel, Victor Desmond; Ponti, Giovanni
abstract

Gorlin-Goltz syndrome is an autosomal dominantly inherited disorder linked to PTCH1 mutation, recognized by a collection of clinical and radiologic signs (macrocephaly, frontal bossing, multiple intracranial calcifications including falx cerebri and atlanto-occipital ligament). We describe here a the case of a family with clear cut criteria for Gorlin-Goltz syndrome presenting the association of cranio-facial and skeletal anomalies together with a peculiar sphenoid variant. Two patients, father and son, were examined because of multiple basal cell carcinomas and keratocystic odontogenic tumours. Other suggestive findings were multiple positive family history, typical skeletal anomalies and a novel PTCH1 germline mutation (c.1041delAA). Craniofacial and other skeletal anomalies displayed at 3D and helical CT scan were: macrocephaly, skull base asymmetry (positional plagiocephaly), mandibular prognathism, mandibular condylar deformation with hyperplasia of the coronoid process, bifidity of multiple ribs and giant multilocular odontogenic jaw cysts. Extensive multilamellar calcifications were found in falx cerebri, tentorium, falx cerebelli and in the apical segment of the atlanto-occipital ligament. Thoracic anomalies included bifid left 3rd, 4th, 5th and 6th rib, dismorphic body of the 3rd thoracic vertebra, dorsolumbar scoliosis, sacrum acutum. Interestingly, 3D-CT scan showed asymmetry of both sphenoid wings with thickening of the left wing sphenoid wing together with irregularity of the architecture of trabecular bone with alternating osteolytic and sclerotic areas. Abnormalities of the sphenoid bone are not very common, and consist of differently aggressive entities: some of them are typical of the pediatric age in few hereditary and congenital disorders. The application of new criteria (i.e. peculiar calcifications of ligaments and sphenoid asymmetry) to a wider case series can lead to the early diagnosis of Gorlin syndrome, especially in pediatric patients, when the full phenotype is not yet expressed. The inclusion of bifid ribs as a novel major criteria and the recognition of peculiar cranial anomalies such as sphenoid asymmetry, well detected at volume CT reconstruction, might be useful for the recognition and characterization of misdiagnosed cases.

2013 - The somatic affairs of BRAF: tailored therapies for advanced malignant melanoma and orphan non-V600E (V600R-M) mutations. [Articolo su rivista]
Ponti, Giovanni; Pellacani, Giovanni; Tomasi, Aldo; Gelsomino, F.; Spallanzani, A.; Depenni, R; Al Jalbout, S.; Simi, L.; Garagnani, L.; Borsari, S.; Conti, A.; Ruini, C.; Fontana, A.; Luppi, G.
abstract

BRAF V600R-M-D are uncommon mutations, not included in the experimental protocols of BRAF selective inhibitors. We report the evaluation of correlations among different types of BRAF somatic mutations in melanoma and their management with BRAF inhibitors. 21 patients with BRAF mutated metastatic melanoma were enrolled in the protocol with BRAF inhibitors for compassionate use at the University of Modena. Hot spot V600E mutations were found in 19 patients. V600R mutation and double (V600E -V600M) mutation were identified in two melanomas. In one case, V600K mutation was found. Two screening failures were noted. Mean progression free survival at follow-up of to 8 weeks, was 7.6 months. Five patients had a very short follow-up and the experimental protocol is still ongoing, so we cannot provide complete follow-up data. However, all of them are still under treatment and disease progression free. An objective response with few side effects was observed in all patients. in vitro studies with the aim of testing drug sensitivity.

2012 - Ameloblastoma: a neglected criterion for nevoid basal cell carcinoma (Gorlin) syndrome. [Articolo su rivista]
Ponti, Giovanni; L., Pastorino; A., Pollio; S., Nasti; Pellacani, Giovanni; M. D., Mignogna; Tomasi, Aldo; C. D., Forno; Longo, Caterina; G., Bianchi Scarrà; G., Ficarra; Seidenari, Stefania
abstract

Ameloblastomas are considered to be aggressive and locally invasive neoplasms derived from odontogenic epithelium with a tendency for recurrence and bone destruction. Although the relationship between nevoid basal cell carcinoma syndrome (NBCCS) and ameloblastoma is less frequent, it might constitute a peculiar stigmata of this hereditary disorder. The objective of the current study was to evaluate whether a combined clinical and biomolecular approach could be useful for the identification of NBCCS among patients with a diagnosis of ameloblastoma. The authors collected ameloblastoma tumors recorded in the databases of the Pathology Departments of the University of Modena during the period 1991-2011. Family trees were drawn for all 41 patients affected by these specific odontogenic tumors. Two patients with ameloblastoma were also affected by multiple basal cell carcinomas and odontogenic keratocysts tumors (OKCTs) achieving the requested clinical criteria for the diagnosis of NBCCS. The clinical diagnoses were confirmed by the identification of two different novel PTCH1 germline mutations (c.2186A > T [p.K729 M]; c.931insA) in those unrelated patients. Clinical ameloblastoma findings can be used as screening for the identification of families at risk of NBCCS. Ameloblastomas diagnosis warrants the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS. Thus, we propose the inclusion of ameloblasoma as criterion for the identification of NBCCS.

2012 - Ameloblastoma as criterion for Nevoid Basal Cell Carcinoma (Gorlin) Syndrome identification [Poster]
Ponti, Giovanni; Pastorino, L; Pollio, A; Nasti, S; Pellacani, Giovanni; Mignogna, Md; Del Forno, C; Bianchi Scarrà, G; Ficarra, G; Greco, M; Arginelli, F; Seidenari, S.
abstract

Introduction & Objectives: Ameloblastomas are considered to be aggressive and locally invasive neoplasms derived from odontogenic epithelium and with a tendency for recurrence and bone destruction. Although the relationship between NBCCS and ameloblastoma is infrequent it constitutes a peculiar stigmata of this hereditary disorder. The objective of the current study was to evaluate whether a combined clinical and biomolecular approach could be useful for the identification of NBCCS among patients with a diagnosis of ameloblastoma. Material and Methods: The authors collected ameloblastoma tumors recorded in the databases of the Pathology Departments of the University during the period 1991-2011. Family trees were drawn for 41 patients affected by these peculiar odontogenic tumors. Results: Two patients with ameloblastoma were also affected by multiple basal cell carcinoma and OKCTs, thus meeting the clinical criteria for the diagnosis of NBCCS. This was confirmed by the identification of two different novel PTCH1 germline mutations (c.2186A>T [p.K729M]; c.931insA) in those unrelated patients. Conclusions: The clinical characterization of the ameloblastoma can be used as screening for the identification of families at risk of NBCCS. Ameloblasomas diagnosis warrants the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS. We propose the inclusion of ameloblasoma as criterion for the identification of NBCCS.

2012 - Brooke-Spiegler syndrome: report of two cases not associated with a mutation in the CYLD and PTCH tumor-suppressor genes. [Articolo su rivista]
Ponti, Giovanni; Nasti, S; Losi, Lorena; Pastorino, L; Pollio, A; Benassi, L; Giudice, S; Bertazzoni, G; Veratti, E; Azzoni, Paola; Bianchi Scarrà, G; Seidenari, S.
abstract

Brooke-Spiegler syndrome represents an autosomal dominant disease characterized by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically) spiroadenomas. Patients with Brooke-Spiegler syndrome are also at risk of developing tumors of the major and minor salivary glands. Patients with Brooke-Spiegler syndrome have various mutations in the CYLD gene, a tumor-suppressor gene located on chromosome 16q. To date, 68 unique CYLD mutations have been identified. We describe two families with Brooke-Spiegler syndrome, one with familial cylindromatosis and one with multiple familial trichoepithelioma, which showed wide inter-family phenotypic variability. Analysis of germline mutations of the CYLD and PTCH genes was performed using peripheral blood. In addition, formalin-fixed paraffin-embedded tumor samples were analyzed for PTCH somatic mutations and cylindroma cell cultures were obtained directly from patients for further growth and analysis. Clinically, the major features of Brooke-Spiegler syndrome include the presence of heterogeneous skin tumors and wide inter- and intra-familial phenotypic variability. Histopathologically, both cylindromas and trichoepitheliomas were found in affected individuals. Mutations or loss of heterozygosity was not found in CYLD and PTCH genes. In CYLD and PTCH mutation-negative patients, other genes may be affected and further studies are needed to clarify whether these patients may be affected by de novo germline mutations.

2012 - Caso di Neurofibromatosi diagnosticata a 71 anni [Poster]
Olezzi, Daniela; Sacco, Antonio; Curci, Marco; Martini, Mia; Neri, Federica; Ponti, Giovanni; Mandel, Victor Desmond; Puviani, Mario
abstract

Introduzione: La neurofibromatosi di tipo 1 (NF1) è una malattia genetica a trasmissione autosomica dominante caratterizzata da mutazioni a carico del gene NF1, localizzato sul cromosoma 17q11.2. La sindrome ha un’incidenza di 1 su 3500 ed è caratterizzata da diverse manifestazioni a livello cutaneo, osseo, oculare e nervoso. La diagnosi di NF1 si basa sui criteri clinici che includono macchie caffè-latte, neurofibromi, lentigginosi a livello della regione ascellare o inguinale, glioma del nervo ottico e noduli di Lisch. Dal punto di vista delle funzioni cognitive si possono riscontrare disturbi del linguaggio e ritardo mentale. I pazienti con neurofibromatosi hanno un rischio di sviluppare tumori da 3 a 4 volte maggiore rispetto alla popolazione generale; in particolare, il tumore di Wilms, tumori gastrointestinali stromali (GIST), rabdomiosarcomi, meningiomi, gliomi del nervo ottico e feocromocitomi. Molto raramente la diagnosi clinica e biomolecolare di NF1 viene posta in età avanzata essendo le manifestazioni cliniche della sindrome relativamente precoci e talora presenti fin dalla nascita. Tuttavia, sono riportati in letteratura casi di neurofibromi plessiformi ad esordio molto tardivo. Case Report: Riportiamo il caso di un paziente di 71 anni, ricoverato con la diagnosi di stato di male parziale motorio ed esiti di ematoma cerebrale su base ischemica, che veniva valutato in consulenza dermatologica per il rilievo di numerose lesioni cutanee esofitiche a livello del tronco. Tali lesioni di differente diametro e morfologia erano clinicamente compatibili con la diagnosi di neurofibromi, che veniva confermata successivamente all’esame istologico. Il paziente si mostrava poco collaborante e scarsamente orientato nel tempo e nello spazio. All’esame obiettivo venivano rilevate, inoltre, lentiggini ascellari bilaterali, numerose chiazze caffè-latte, scoliosi ed ipoacusia bilaterale. L’anamnesi familiare era negativa per il rilievo di neurofibromi e altri segni riconducibili a tale patologia. Attualmente è in corso lo studio genetico per la ricerca mutazionale a carico del gene NF1. Conclusioni: La diagnosi tardiva di NF1 nel paziente che presentiamo può essere addotta in parte alla comparsa in età avanzata del fenotipo cutaneo ed in parte al disagiato contesto familiare che non ha contribuito all’attuazione di adeguate strategie diagnostiche e di follow-up clinico-strumentale. Tale caso clinico ci rammenta che la diagnosi di Neurofibromatosi può essere posta anche in pazienti con anamnesi familiare completamente negativa per la comparsa di mutazioni de novo. E’ noto che il 50% dei pazienti con diagnosi di NF1 non presenta storia familiare per tale patologia.

2012 - Diagnosis of BCC by multiphoton laser tomography. [Articolo su rivista]
Seidenari, S.; Arginelli, F.; Bassoli, S.; Cautela, J.; Cesinaro, A. M.; Guanti, M.; Guardoli, D.; Magnoni, Cristina; Manfredini, M.; Ponti, Giovanni; König, K.
abstract

BACKGROUND/PURPOSE: Multiphoton Laser Tomography (MPT) is a non-linear optical technique that gives access to morphology and structure of both cells and extracellular matrix of the skin through the combination of autofluorescence imaging and second harmonic generation (SHG). The aim of this study was to identify MPT descriptors on ex vivo specimens of basal cell carcinoma (BCC) to assess the sensitivity and specificity of these criteria for the diagnosis of BCC and its differentiation from other skin tumours, inflammatory diseases and healthy skin.METHODS: In the preliminary study, MPT images referring to 24 BCCs and 24 healthy skin samples were simultaneously evaluated by three observers for the identification of features characteristic of BCC. In the main study, the presence/absence of the descriptors identified in the preliminary study was blindly evaluated on a test set, comprising 66 BCCs, 66 healthy skin samples and 66 skin lesions, including 23 nevi, 8 melanomas, 17 skin tumours and other skin lesions by 3 independent observers.RESULTS: In the preliminary study, three epidermal descriptors and six descriptors for BCC were identified. The latter included aligned elongated cells, double alignment of cells, cell nests with palisading and phantom islands. From the test set, 56 BCCs were correctly diagnosed, whereas in 10 cases the diagnosis was 'other lesions'. However, it was always possible to exclude the diagnosis of BCC in healthy skin and other lesion samples. Thus, overall sensitivity of the method was 84.85, whereas a specificity of 100% was observed with respect to both healthy skin and 'other lesions'.CONCLUSIONS: This study describes new morphological descriptors of BCC enabling its characterization and its distinction from healthy skin and other skin lesions in ex vivo samples, and demonstrates for the first time that MPT represents a sensitive and specific technique for the diagnosis of BCC.

2012 - Diagnostic and pathogenetic role of café-au-lait macules in nevoid basal cell carcinoma syndrome [Articolo su rivista]
Ponti, Giovanni; Tomasi, Aldo; Pastorino, Lorenza; Ruini, Cristel; Guarneri, Carmelo; Mandel, Victor Desmond; Seidenari, Stefania; Pellacani, Giovanni
abstract

Café au lait spots (CALS) are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1), together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver-Russell, LEOPARD, Ataxia-Telangiectasia). A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS) with known PTCH1 germline mutation (C.1348-2A&gt;G) who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age), while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences.

2012 - Feasibility of in vivo confocal microscopy in diagnosing nodular lesions. [Abstract in Rivista]
Longo, Caterina; Ciardo, S.; Farnetani, F.; Cesinaro, A.; Ponti, Giovanni; Pellacani, Giovanni
abstract

abstract

2012 - High resolution diagnosis of common nevi by multiphoton laser tomography and fluorescence lifetime imaging. [Articolo su rivista]
Arginelli, F; Manfredini, M; Bassoli, S; Dunsby, C; French, P; König, K; Magnoni, Cristina; Ponti, Giovanni; Talbot, C; Seidenari, S.
abstract

BACKGROUND: Multiphoton Laser Tomography (MPT) has developed as a non-invasive tool that allows real-time observation of the skin with subcellular resolution. MPT is readily combined with time resolved detectors to achieve fluorescence lifetime imaging (FLIM). The aim of our study was to identify morphologic MPT/FLIM descriptors of melanocytic nevi, referring to cellular and architectural features. METHODS: In the preliminary study, MPT/FLIM images referring to 16 ex vivo nevi were simultaneously evaluated by 3 observers for the identification of morphologic descriptors characteristic of melanocytic nevi. Proposed descriptors were discussed and the parameters referring to epidermal keratinocytes, epidermal melanocytes, dermo-epidermal junction, papillary dermis and overall architecture were selected. In the main study, the presence/absence of the specified criteria were blindly evaluated on a test set, comprising 102 ex vivo samples (51 melanocytic nevi, 51 miscellaneous skin lesions) by 2 observers. RESULTS: Twelve descriptors were identified: "short-lifetime cells in the stratum corneum", "melanin-containing keratinocytes", "dendritic cells", "small short-lifetime cells" in the upper and lower layers", "edged papillae", "non-edged papillae", "junctional nests of short-lifetime cells", "dermal cell clusters", "short-lifetime cells in the papilla", "monomorphic and regular histoarchitecture", "architectural disarray". CONCLUSION: Identified descriptors for benign melanocytic lesions proved sensitive and specific, enabling the differentiation between melanocytic nevi and non-melanocytic lesions.

2012 - Italian Euromelanoma Day Screening Campaign (2005-2007) and the planning of melanoma screening strategies. [Articolo su rivista]
Seidenari, S.; Benati, E.; Ponti, Giovanni; Borsari, S.; Ferrari, C.; Albertini, G.; Altomare, G.; Arcangeli, F.; Aste, N.; Bernengo, M. G.; Bongiorno, M. R.; Borroni, G.; Calvieri, S.; Chimenti, S.; Cusano, F.; Fracchiolla, C.; Gaddoni, G.; Girolomoni, G.; Guarneri, B.; Lanzoni, A.; Lombardi, M.; Lotti, T.; Mariotti, A.; Marsili, F.; Micali, G.; Parodi, A.; Peris, K.; Peserico, A.; Quaglino, P.; Santini, M.; Schiavon, S.; Tonino, C.; Trevisan, G.; Tribuzi, P.; Valentini, P.; Vena, G. A.; Virgili, A.
abstract

Although no study has definitively shown that unfocused screening of skin cancer is effective, many campaigns have been organized with the aim of increasing awareness on melanoma risk factors. The objective of this study was to analyse the results of the Skin Cancer Screening Day in Italy during the period 2005-2007, to determine the priorities for melanoma control plans in a Mediterranean country. A total of 5002 patients were screened by dermatologists in 31 cities. Individuals who considered themselves to have many naevi and those with a family history of melanoma showed a higher number of common and atypical naevi. Ten melanomas, 20 basal cell carcinomas and two squamous cell carcinomas were histopathologically confirmed. Our observations provide the following suggestions for melanoma prevention strategies: (a) an unfocused campaign is suitable to inform the public about the importance of self-examination of the skin, but is not useful to identify a larger number of melanomas; and (b) melanoma screening campaigns should focus on a selected population, which meets rigorous risk criteria to maintain higher cost-effectiveness. The financial support to effective melanoma screening programmes could be increased, especially in southern populations where lower levels of self-surveillance and socioeconomic conditions represent risk factors for late identification of melanoma.

2012 - Microscopic margins of resection influence primary gastrointestinal stromal tumor survival. [Articolo su rivista]
Catena, F; Di Battista, M; Ansaloni, L; Pantaleo, M; Fusaroli, P; Di Scioscio, V; Santini, D; Nannini, M; Saponara, M; Ponti, Giovanni; Persiani, R; Delrio, P; Coccolini, F; Di Saverio, S; Biasco, G; Lazzareschi, D; Pinna, A.
abstract

Background: Primary gastrointestinal stromal tumors (GISTs) are stromal tumors that arise from the gastrointestinal tract. Both surgical resection and molecular therapy are crucial in the treatment of these tumors. This study analyzes the outcomes of 151 patients with GIST treated at 3 institutions. These institutions comprise the GISTologist Study Group and provided follow-up data. Patients and Methods: 151 patients with primary GIST were admitted and treated at the St. Orsola-Malpighi University Hospital in Bologna, Italy, the Catholic University Hospital in Rome, Italy, and the Modena University Hospital and National Cancer Institute in Naples, Italy, over the past 11 years. Patient data as well as tumor and therapy variables were studied to identify factors predicting survival with a focus on the microscopic margins of resection. Results: All 151 patients had primary disease without metastasis and underwent complete resection of gross disease. The 5-year disease-free survival rate was 77%. Disease-free survival was predicted by tumor size, mitotic count, and margins of resection. Recurrence of disease after resection was predominantly intra-abdominal. Conclusions: Tumor size, mitotic count, and microscopic margins of resection predict disease-free survival in patients with primary GIST.

2012 - Multiphoton laser tomography and fluorescence lifetime imaging of basal cell carcinoma: morphologic features for non-invasive diagnostics [Articolo su rivista]
Seidenari, Stefania; Arginelli, Federica; Dunsby, C; French, P; König, K; Magnoni, Cristina; Manfredini, Marco; Talbot, C; Ponti, Giovanni
abstract

Multiphoton laser tomography (MPT) combined with fluorescence lifetime imaging (FLIM) is a non-invasive imaging technique, which gives access to the cellular and extracellular morphology of the skin. The aim of our study was to assess the sensitivity and specificity of MPT/FLIM descriptors for basal cell carcinoma (BCC), to improve BCC diagnosis and the identification of tumor margins. In the preliminary study, FLIM images referring to 35 BCCs and 35 healthy skin samples were evaluated for the identification of morphologic descriptors characteristic of BCC. In the main study, the selected parameters were blindly evaluated on a test set comprising 63 BCCs, 63 healthy skin samples and 66 skin lesions. Moreover, FLIM values inside a region of interest were calculated on 98 healthy skin and 98 BCC samples. In the preliminary study, three epidermal descriptors and 7 BCC descriptors were identified. The specificity of the diagnostic criteria versus 'other lesions' was extremely high, indicating that the presence of at least one BCC descriptor makes the diagnosis of 'other lesion' extremely unlikely. FLIM values referring to BCC cells significantly differed from those of healthy skin. In this study, we identified morphological and numerical descriptors enabling the differentiation of BCC from other skin disorders and its distinction from healthy skin in ex vivo samples. In future, MPT/FLIM may be applied to skin lesions to provide direct clinical guidance before biopsy and histological examination and for the identification of tumor margins allowing a complete surgical removal.

2012 - Mutazioni somatiche di BRAF in pazienti affetti da melanoma maligno metastatico ed efficacia clinica degli approcci terapeutici a bersaglio molecolare con inibitori di BRAF [Poster]
Ponti, Giovanni; Pellacani, Giovanni; Simi, Lisa; Depenni, Roberta; Spallanzani, Andrea; Gelsomino, Fabio; Pollio, Annamaria; Borsari, Stefania; Fabiano, Antonella; Mandel, Victor Desmond; Tomasi, Aldo; Luppi, Gabriele
abstract

L’introduzione di terapie a bersaglio molecolare ha rivoluzionato la prognosi dei pazienti affetti da melanoma in stadio avanzato. Attualmente è possibile determinare lo status molecolare del melanoma analizzando geni quali C-KIT, BRAF ed N-RAS per la scelta di strategie terapeutiche mirate. Mutazioni di BRAF si riscontrano in circa il 50% dei melanomi: tra queste la V600E e la V600K sono maggiormente frequenti e ben studiate nei pregressi protocolli di sperimentazione fase II/III con inibitori di BRAF. Questi ultimi (Dabrafenib e Vemurafenib) hanno dimostrato chiara efficacia nell’indurre risposte obiettive nel melanoma avanzato. Con il presente lavoro presentiamo le preliminari valutazioni delle correlazioni tra tipologie di mutazioni somatiche del gene BRAF riscontrate in una coorte di melanomi in stadio IV e le risposte cliniche a tale inibitori selettivi. A partire dal giugno 2011, 19 pazienti (10 M; 9F; età media 55 anni) affetti da melanoma stage IV BRAF+ sono stati arruolati in protocolli terapeutici con Dabrafenib (150 mg 2 volte/die) o Vemurafenib (960 mg 2volte/die) presso l’Università di Modena. Il restaging strumentale della malattia veniva eseguito a 8 settimane dall’inizio della terapia. Sono state riscontrate mutazione hot spot V600E (c.1799T&gt;A) in 18 pazienti, in due differenti pazienti sono state individuate le rare mutazioni V600M (c.1798G&gt;A) e V600R (c.1790T&gt;G). In un melanoma è stata evidenziata una doppia mutazione (V600E; V600M) ed il relativo paziente, trattato con Dabrafenib, ha presentato una rapida regressione delle importati lesioni metastatiche. In due casi la ricerca mutazionale in BRAF, risultata inizialmente negativa, è stata poi riscontrata in una successiva analisi. I dati clinici preliminari evidenziano una risposta obiettiva già nelle primissime settimane di terapia, buona tolleranza con scarsi effetti collaterali sia nei pazienti con mutazioni V600E che in quelli con le rare mutazioni V600 M e V600R. Il periodo di sopravvivenza medio libero da progressione dei 15 pazienti con follow-up di almeno 8 settimane è stato di 7 mesi. In 9 pazienti persiste la risposta terapeutica ad oggi. La doppia mutazione di BRAF potrebbe costituire un fattore prognostico positivo per la risposta agli inibitori di BRAF. Nei casi negativi alla ricerca mutazionale, dovrebbe essere routinariamente impiegate indagini più approfondite atte ad evidenziare non solo la presenza della comune V600E ma anche delle varianti meno comuni degli esoni 11 e 15.

2012 - Neoadjuvant treatment with Bevacizumab and FOLFOX-6 in patients with liver metastasis from colorectal cancer: preliminary results of a Phase II study. [Poster]
Bertolini, F; Malavasi, N; Dealis, C; Zironi, S; Depenni, R; Fontana, A; Sternieri, R; Ponti, Giovanni; Luppi, G; Conte, Pierfranco
abstract

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2012 - Neoplasie maligne e benigne associate al melanoma multiplo: coinvolgimento di MITF, PTEN and CDKN2A nella cancerogenesi melanocitaria multipla. [Poster]
A., Pollio; S., Seidenari; Pellacani, Giovanni; M., Rodolfo; S., Frigerio; A., Maurichi; D., Turchetti; A., Elmakky; L., Pastorino; M. D., Mignogna; Tomasi, Aldo; Ponti, Giovanni
abstract

Background: Il fenotipo melanomi multipli è un interessante modello di ricerca per lo studio e l’identificazione di mutazioni germinali che sottendono alla maggiore suscettibilità neoplastica cutanea e viscerale, individuale e familiare. L’analisi della storia clinica di gruppo di paziente affetti da melanoma multiplo ha evidenziato una non trascurabile incidenza di neoplasie polidistrettuali associate al fenotipo melanoma multiplo. Materiali e metodi: Lo studio ha analizzato in modo retrospettivo la presenza di neoplasie benigne e maligne in un gruppo di 49 pazienti con diagnosi di melanoma multiplo rapportate ad un gruppo controllo di 49 pazienti con diagnosi di melanoma singolo selezionato per medesima età, sesso e durata del follow-up. I test genetici mutazionali sono stati eseguiti in tutti i pazienti il cui quadro clinico dava adito al sospetto di una mutazione germinale sottesa. Risultati: Una prevalenza statisticamente signficativa (P<0.0001) di neoplasie benigne e maligne è stata evidenziata nel gruppo di pazienti affetti da melanoma multiplo rispetto al gruppo controllo. Le neoplasie maligne riscontrate sono state 27 di cui la più frequente è stata il carcinoma basocellulare cutaneo (n=10, 37.1%), seguito dall’adenocarcinoma del colon-retto (n=4, 14.8%), dall’adenocarcinoma della prostata (n=3, 11.1%), dal carcinoma mammario (n=2, 7.4%), dal carcinoma papillifero della tiroide (n=2, 7.4%), dall adenocarcinoma pancreatico (n=2, 7.4%), dal carcinoma renale (n=2, 7,4%), dal carcinoma orale (n=1, 3.7%), dall’adenocarcinoma del fegato(n=1, 3.7%), dal linfoma a cellule B (n=1, 3.7%), dal mieloma multiplo (n=1, 3.7%), dal carcinoma vescicale (n=1, 3.7%) ed infine dal carcinoma dello stomaco (n=1, 3.7%). Nel gruppo controllo non è stata riportata alcuna neoplasia maligna associata. Dieci neoplasie benigne sono state riportate a carico di più organi tra i pazienti con melanoma multiplo. I test genetici hanno svelato mutazioni germinali a carico di geni quali PTEN, MITF E318K, CDKN2A, MC1R. In tre pazienti con melanomi multipli e storia personale e/o individuale di neoplasie renali a cellule chiare è stata rilevata coesistenza di mutazioni germinali di CDKN2A, MC1R e MITF . Conclusioni: Una sorveglianza oncologica accurata è raccomandabile nei pazienti affetti da melanoma multiplo. È compito del clinico selezionare in base alla storia clinica riportata i pazienti da candidare ai test genetici per un ulteriore approfondimento diagnostico. Infatti il managment clinico del paziente può essere direttamente influenzato dal tipo di mutazione diagnosticata sia per quanto concerne la terapia che la pianificazione del follow-up.

2012 - Novel PTCH1 mutations in patients with keratocysic odontogenic umors as first hint to NBCC (Gorlin) detection [Poster]
Fabiano, Antonella; Ponti, Giovanni; Pastrino, L; Pellacani, Giovanni; Longo, Caterina; Bassoli, S; Bianchi Scarrà, G; Seidenari, S.
abstract

Keratocystic odontogenic tumors (KCOTs) are cystic tumors that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is a rare autosomal dominantly inherited disease mainly characterized by multiple basal cell carcinomas, KCOTs of the jaws and a variety of other tumors. PTCH1 mutation can be found both in sporadic or NBCCS associated KCOTs. The aim of the current study was to assess whether a combined clinical and bio-molecular approach could be suitable for the detection of NBCCS among patients with a diagnosis of keratocystic odontogenic tumors (KCOTs). The authors collected keratocystic odontogenic tumors recorded in the database of the Pathology Department of the University of Modena and Reggio Emilia during the period 1991-2011. Through interviews and examinations, family pedigrees were drawn for all patients affected by these odontogenic lesions.We found out that 18 of the 70 patients with KCOTs and/or multiple basal cell carcinomas actually met the clinical criteria for the diagnosis of NBCCS. A wide inter- and intra-familial phenotypic variability was evident in the families. Ameloblastomas (AMLs) were reported in two probands that are also carriers of the PCTH1 germline mutations. Nine germline mutations in the PTCH1 gene, 5 of them novel, were evident in 14 tested probands.The clinical evaluation of the keratocystic odontogenic tumors can be used as screening for the detection of families at risk of NBCCS. Keratocystic odontogenic lesions are uncommon, and their discovery deserves the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS.

2012 - Novel PTCH1 mutations in patients with keratocystic odontogenic tumors as first hint to Gorlin-Goltz syndrome detection [Abstract in Rivista]
A., Fabiano; Ponti, Giovanni; L., Pastorino; Longo, Caterina; G., Bianchi Scarrà; S., Seidenari; Pellacani, Giovanni
abstract

abstract

2012 - Novel PTCH1 Mutations in Patients with Keratocystic Odontogenic Tumors Screened for Nevoid Basal Cell Carcinoma (NBCC) Syndrome. [Articolo su rivista]
L., Pastorino; A., Pollio; PELLACANI, Giovanni; C., Guarneri; P., Ghiorzo; LONGO, Caterina; W., Bruno; F., Giusti; S., Bassoli; G., Bianchi Scarrà; C., Ruini; S., Seidenari; TOMASI, Aldo; PONTI, Giovanni
abstract

Keratocystic odontogenic tumors (KCOTs) are cystic tumors that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is a rare autosomal dominantly inherited disease mainly characterized by multiple basal cell carcinomas, KCOTs of the jaws and a variety of other tumors. PTCH1 mutation can be found both in sporadic or NBCCS associated KCOTs. The aim of the current study was to assess whether a combined clinical and bio-molecular approach could be suitable for the detection of NBCCS among patients with a diagnosis of keratocystic odontogenic tumors (KCOTs). The authors collected keratocystic odontogenic tumors recorded in the database of the Pathology Department of the University of Modena and Reggio Emilia during the period 1991-2011. Through interviews and examinations, family pedigrees were drawn for all patients affected by these odontogenic lesions. We found out that 18 of the 70 patients with KCOTs and/or multiple basal cell carcinomas actually met the clinical criteria for the diagnosis of NBCCS. A wide inter- and intra-familial phenotypic variability was evident in the families. Ameloblastomas (AMLs) were reported in two probands that are also carriers of the PCTH1 germline mutations. Nine germline mutations in the PTCH1 gene, 5 of them novel, were evident in 14 tested probands. The clinical evaluation of the keratocystic odontogenic tumors can be used as screening for the detection of families at risk of NBCCS. Keratocystic odontogenic lesions are uncommon, and their discovery deserves the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS.

2012 - Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma [Articolo su rivista]
Ponti, Giovanni; Tomasi, Aldo; Pellacani, Giovanni
abstract

ABSTRACT: The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for melanomas development and progression, such as BRAF, CKIT and PTEN: the consequent results are, in fact, essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies. We present here the case of a 66 year-old male patient, diagnosed with an advanced melanoma in June 2011, and treated with Dabrafenib for double mutant metastatic disease. The patient was referred to our attention for a large exophytic malignant melanoma on the left shoulder. After complete surgical excision and elective lymph node dissection for presence of metastatic sentinel lymph node, the patient has started high-dose interferon alfa- 2b injections as adjuvant therapy for a complete negative staging. The treatment was interrupted in August 2011 due to the appearance of metastatic lymph nodes. Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder. Mutational study of the tumor revealed a double BRAF mutation on V-600E and V600M. This finding incited us to enroll the patient in compassionate Dabrafenib clinical trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost surprisingly for the rapidity of the effect, one week later the lesion on the shoulder has reduced its size by 60% and one month later it has completely disappeared from sight. CT scan of June 2012 documented the astonishing clinical response.

2012 - Patched homolog 1 gene mutation (p.G1093R) induces nevoid basal cell carcinoma syndrome and non-syndromic keratocystic odontogenic tumors: A case report. [Articolo su rivista]
Ponti, Giovanni; A., Pollio; L., Pastorino; Pellacani, Giovanni; Magnoni, Cristina; S., Nasti; G., Fortuna; Tomasi, Aldo; G. B., Scarrà; Seidenari, Stefania
abstract

Mutations in the Patched homolog 1 (PTCH1) gene lead to an autosomal dominant disorder known as nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome (GS). Several PTCH1 mutations have been observed in NBCCS associated with keratocystic odontogenic tumors (KCOTs), including non-syndromic KCOTs. The missense mutation c.3277G>C (p.G1093R) in exon 19 of the PTCH1 gene has only been reported in non-syndromic KCOTs. The present study reports for the first time a familial case (father and daughter) of NBCCS and KCOTs, carrying the same c.3277G>C (p.G1093R) germline mutation. This observation suggests that this missense mutation is involved in the pathogenesis of NBCCS as well as in a subset of non-syndromic KCOTs. The identification of a missense mutation may lead to an earlier diagnosis of NBCCS.

2012 - p16 immunohistochemistry of multiple primary melanomas as screening to identify Familial Melanoma Syndrome [Articolo su rivista]
Ponti, Giovanni; G., Luppi; Losi, Lorena; A. M., Cesinaro; Sartori, Giuliana; Maiorana, Antonino; Pellacani, Giovanni; Longo, Caterina; E., Boni; P., Pepe; Giannetti, Alberto; Seidenari, Stefania; M. T., Landi
abstract

The Authors describe the use of p16 immunohistochemistry in multiple primary melanomas as screening to identify Familial Melanoma Syndrome.

2012 - The dermoscopic variability of pigment network in melanoma in situ. [Articolo su rivista]
Seidenari, S; Ferrari, C; Borsari, S; Bassoli, Sara; Cesinaro, Am; Giusti, F; Pellacani, Giovanni; Ponti, Giovanni; Zalaudek, I; Argenziano, G.
abstract

To define the dermoscopic aspects of the network in melanoma in situ (MIS), using both standard and newly introduced network descriptors. Fifty-four histologically confirmed MIS with a reticular pattern, 108 atypical reticular naevi and 108 typical reticular naevi were evaluated for the presence of 11 network descriptors. The ABCD-score and the seven-point score were calculated, and the diameter of the lesions was measured by means of a dedicated software. Clinical data including age, sex and skin site were also considered. The prevalence of different dermoscopic features was calculated to allow (i) the identification of lesions to be excised and (ii) the distinction between MIS and dermoscopically atypical naevi. In dermoscopically atypical lesions (MIS and atypical naevi), the frequency of all descriptors significantly differed from those of typical naevi. With respect to atypical naevi, MIS more frequently showed larger size, an atypical network involving more than half of the lesion, the contemporary presence of more than one type of network and more extended reticular grey-blue regression areas located both in the centre and at the periphery of the lesion. The list of network descriptors proposed by us can be used for the identification of lesions that should be subjected to surgery. For the distinction between MIS and atypical naevi, the extension of an atypical network, the presence of more than one type of network, the distribution of reticular grey-blue areas and the lesion diameter must be considered.

2012 - Unicystic ameloblastoma associated with the novel K729M PTCH1 mutation in a patient with nevoid basal cell carcinoma (Gorlin) syndrome. [Articolo su rivista]
Ponti, Giovanni; Pollio, A.; Mignogna, M. D.; Pellacani, Giovanni; Pastorino, L.; Bianchi Scarrà, G.; Di Gregorio, C.; Magnoni, Cristina; Azzoni, P.; Greco, M.; Seidenari, S.
abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a very wide spectrum of clinical signs and symptoms. Here, we report an unusual case of NBCCS in a 38-year-old man with an early onset of clinical signs and symptoms and an associated unicystic ameloblastoma, histopathologically showing basaloid differentiation and intraluminal growth. The odontogenic tumor was surgically enucleated and recurred at the follow-up at 14 months. The proband and his child were identified as gene carriers of the novel K729M PTCH1 missense mutation; other first- and second-degree relatives presented clinical features of NBCCS. Only five other cases of association between ameloblastoma and NBCCS have been reported so far, suggesting that PTCH1 missense mutation might take part in the pathogenesis of keratocystic odontogenic tumors (KCOTs) as well as ameloblastomas.

2012 - Value and prognostic significance of mitotic rate in a retrospective series of pT1 cutaneous malignant melanoma patients [Articolo su rivista]
Ponti, Giovanni; A., Pollio; A. M., Cesinaro; Pellacani, Giovanni; Magnoni, Cristina; Seidenari, Stefania
abstract

INTRODUCTION: Patients affected by thin melanomas (≤1mm) generally have a good prognosis; however, some have a recurrence and eventually die of the disease. The seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, introduced mitotic rate (MR) as one of the primary criteria for staging thin melanoma. MATERIALS AND METHODS: In this study, we sought to determine the prognostic value of mitotic rate in a retrospective cohort of localized primary cutaneous melanoma patients. RESULTS: In total, 286 cases of pT1 primary malignant melanoma occurring in the period 2003-2008 were evaluated. Mitotic counts were re-assessed on standard sections of cases without mitosis and with at least 1 mitosis at diagnosis; 5-year follow-up and recurrence-free survival were available for all patients. Of the 56 radically treated pT1b melanoma patients, 4 (7.1%) had recurrent disease. These data support the efficacy of the incorporation of mitogenicity into AJCC staging for localized cutaneous melanoma and indicate the difficulties in the accuracy and reproducibility of the mitotic count system.

2012 - Variegated Dermoscopy of in situ Melanoma. [Articolo su rivista]
S., Seidenari; S., Bassoli; S., Borsari; C., Ferrari; F., Giusti; Ponti, Giovanni; C., Tomasini; Magnoni, Cristina
abstract

Background: Melanomas in situ (MIS) are difficult to diagnose, lacking well-established dermoscopic descriptors. Objective: The aim of this study was to improve the identification of early melanomas describing the variegated dermoscopic features of MIS and their correlation with demographic and clinical aspects. Methods: Dermoscopic images of 114 histologically proven MIS were evaluated by 3 expert dermoscopists and classified into their main dermoscopic patterns. Dermoscopic features were also considered for their correlation with clinical parameters. Results: Eight different dermoscopic subtypes of MIS were identified: reticular grey-blue (27.2%), reticular (21.1%), multicomponent (20.2%), island (10.5%), spitzoid (7%), inverse network (6.1%), 'net-blue globules' (5.3%) and globular (2.6%). Clinical characteristics of lesions and patients varied according to the different dermoscopic groups. Conclusion: We hypothesize that the different dermoscopic subgroups of MIS correspond to lesions with a different origin and, possibly, various patterns of growth and a different biological behaviour.

2011 - Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. [Articolo su rivista]
Ponti, Giovanni; Losi, Lorena; Martorana, D; Priola, M; Boni, E; Pollio, A; Neri, Tm; Seidenari, S.
abstract

BACKGROUND: Neurofibroma occurs as isolated or multiple lesions frequently associated with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting 1 in 3500 individuals. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. NF1 is a fully penetrant gene exhibiting a mutation rate some 10-fold higher compared with most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of lesions.METHODS: 110 patients with at least two neurofibroma lesions recorded in the files of the Pathology Department of the University of Modena during the period 1999-2010, were included in this study. Through interviews and examination of clinical charts, pedigrees were drawn for all patients who were affected by at least two neurofibromas. We attempted to delineate the clinical features of NF1 and the mutational spectrum in the cohort of 11 NF1 families identified. For each proband, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, more frequently, by denaturing high performance liquid chromatography (DHPLC). Two GIST tumors of NF1 patients were tested for somatic NF1 mutations.RESULTS: NF1 germline mutations were identified in 7 (68%) patients. A novel mutation, c.3457_3460delCTCA in exon 20, was detected in two unrelated patients and was associated with different clinical features. No NF1 somatic mutations were detected in the GIST tumors. A wide phenotypic and genotypic variability was registered, both in the spectrum of skin lesions and visceral neoplasms, even among members of the same family who had different clinical manifestations. A proclivity to multiple tumors arising in the same subject, and a higher tumor burden per family were the most relevant findings observed in patients affected with the NF1 mutation.CONCLUSIONS: We report a novel NF1 mutation and we contribute data for the refinement of the NF1 genotype-phenotype spectrum.

2011 - Grey-blue regression in melanoma in situ-evaluation on 111 cases. [Articolo su rivista]
S., Bassoli; S., Borsari; C., Ferrari; F., Giusti; Pellacani, Giovanni; Ponti, Giovanni; S., Seidenari
abstract

As fibrosis and melanosis are often seen in malignant melanoma, the presence of dermoscopic signs of regression may represent a clue for the diagnosis of malignancy. Our aim was to assess the frequency and extent of 11 dermoscopic features of regression evaluating dermoscopic images of 111 melanomas in situ (MIS). Regression structures (grey-blue areas, white areas, peppering, and/or blue-whitish veil) were present in 80.1% of the lesions. Approximately 80% of the lesions showed regression of dermoscopic structures and light brown areas. Most lesions showed the presence of grey-blue areas (74.7%), whereas peppering was observable in 30.6% of MIS. Areas of fibrosis were mainly observable as structureless areas with a pinkish hue (50.4%). Based on our data, the reticular pattern of blue regression and light brown areas can be considered a significant discriminator and a reliable predictor of MIS.

2011 - Quantitative evaluation of healthy epidermis by means of multiphoton microscopy and fluorescence lifetime imaging microscopy [Articolo su rivista]
Benati, E.; Bellini, V.; Borsari, S.; Dunsby, C.; Ferrari, C.; French, P.; Guanti, M.; Guardoli, D.; Koenig, K.; Pellacani, Giovanni; Ponti, Giovanni; Schianchi, S.; Talbot, C.; Seidenari, S.
abstract

BACKGROUND/PURPOSE: Multiphoton microscopy (MPM) enables the assessment of unstained living biological tissue with submicron resolution, whereas fluorescence lifetime imaging microscopy (FLIM) generates image contrast between different states of tissue characterized by various fluorescence decay rates. The aim of this study was to compare the healthy skin of young individuals with that of older subjects, as well as to assess the skin at different body sites, by means of MPM and FLIM. METHODS: Nineteen elderly patients were examined on the outer side of the forearm, whereas 30 young individuals were assessed on the dorsal and volar sides of the forearm and on the thigh. RESULTS: Cell and nucleus diameters, cell density and FLIM vary according to the epidermal cell depth and the skin site. In elderly subjects, epidermal cells show morphologic alterations in shape and size, with smaller cell and nucleus diameters; the number of basal cells is decreased, whereas the mean fluorescence lifetimes at both the upper and the lower layers increase. CONCLUSION: This study provides quantitative and qualitative data on normal epidermis at different skin sites at different ages and represents a reference for the clinician attempting to understand the effectiveness of MPM and FLIM in discriminating diseased states of the skin from normal ones.

2010 - Cytogenetic abnormalities and clinical features in a patient cohort affected by three or more synchronous or metachronous primitive malignancies. [Articolo su rivista]
Ponti, Giovanni; Luppi, G; Giacobbi, F; Corradini, G; Temperani, Paola; Losi, Lorena; Ferrara, L; Pagano, M; Seidenari, Stefania; Tagliafico, Enrico; Torelli, Giuseppe; Conte, Pierfranco
abstract

The multiple cancers (MC) phenotype represents an intriguing entity from both the clinical and the biomolecular points of view. Multiple cancers can arise in a patient either synchronously or metachronously and are frequently detected in hereditary disorders. Here we report the clinical and cytogenetic characterization of 48 patients developing at least three malignancies outside the context of a known genetic condition and 30 control individuals. Medical and pathology reports were registered, blood was collected for cytogenetic studies, and the standard G-banding technique was used for chromosomal analysis of the lymphocyte cultures. Chromosomal analysis of the peripheral blood cultures revealed high cytogenetic instability in 83% of patients' karyotypes that displayed structural rearrangements most often involving chromosomes X, 1, 6, and 7. Peculiar telomeric associations and marker chromosomes were detected in patients with a suspected cancer family history. The MC condition can be observed over a wide clinical range, which includes either apparently sporadic cases or families with a strong history of tumors. These findings indicate that Xq, 6p, and 7q are likely to harbor genes of importance in cancer development, and the present cytogenetic mapping may be crucial for further molecular genetic investigations to recognize a predictive cytogenetic signature useful to detect patients with a high risk of multiple malignancies.

2010 - Gastrointestinal stromal tumor and other primary metachronous and synchronous neoplasms as a suspicious criterion for syndromic setting [Articolo su rivista]
Ponti, Giovanni; Luppi, G; Martorana, D; Rossi, G; Losi, Lorena; Bertolini, Federica; Sartori, G; Pellacani, Giovanni; Seidenari, Stefania; Boni, E; Neri, Tm; Silini, E; Tamburini, E; Maiorana, Antonino; Conte, Pierfranco
abstract

Gastrointestinal stromal tumors (GISTs) may be sporadic or inherited. Although KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic and inherited GISTs, a small subset of GISTs are negative for both. Besides the classical Familial GIST Syndrome, GIST can occur as part of multi-neoplastic disease. The present study was designed to analyze the synchronous and metachronous tumors developed among GIST patients assessed by our institution for GIST Syndrome setting recognition. Patients (n=141) with primary GIST (77 men and 64 women) were recruited between 1988 and 2007 and their clinical and pathological records were reviewed. Mutation analysis of KIT, PDGFRA, NF1 and MMR genes was performed on somatic and peripheral blood DNA. GISTs occurred associated with other primary malignancies in 46 of 141 (32.6%) patients. The most common neoplasms were gastrointestinal and genitourinary. A novel exon 6 germline large deletion of NF1 was identified in the NF1/GIST kindred. The development of GIST associated with other neoplasms is common and diagnosis of peculiar benign associated-neoplasms warrants the search for familial cancer susceptibility. In particular, syndromic or familial settings have to be suspected in the presence of neurofibroma or lung chordoma in C-KIT and PDGFRA negative GIST patients.

2010 - Leser-Trélat syndrome in patients affected by six multiple metachronous primitive cancers. [Articolo su rivista]
Ponti, Giovanni; Luppi, G.; Losi, L.; Giannetti, A.; Seidenari, S.
abstract

Leser-Trélat syndrome is characterized by the eruptive appearance of multiple seborrheic keratoses in association with underlying malignant disease. Usually, the sign of Leser-Trélat is associated with adenocarcinoma, most frequently of the colon, breast, or stomach, but also of the lung, kidney, liver, and pancreas. Herein, we present a case that we believe is the first report of the sign of Leser-Trélat in association with occult gastric adenocarcinoma and the anamnestic oncologic history of five other multiple primitive cancers. Epidermal growth factor receptor (EGFR) immunohistochemical expression analysis of multiple seborrheic keratoses revealed an intense membranous staining in the basal keratinocytes and in all the upper epidermal layers. Patients with the sign of Leser-Trélat should undergo a diagnostic screening programme for malignant disease along with patients with known Leser-Trélat syndrome who present with a recent acute and florid eruption of their seborrheic keratoses. We propose the importance of combining the molecular features of multiple seborrheic keratoses with EGFR immunohistochemistry analyses to determine the likelihood of Leser-Trélat syndrome and the consequent high risk of underlying multiple visceral malignancies.

2010 - Reticular grey-blue areas of regression as a dermoscopic marker of melanoma in situ. [Articolo su rivista]
Seidenari, Stefania; Ferrari, Chiara; Borsari, Stefania; Benati, Elisa; Ponti, Giovanni; Bassoli, Sara; Giusti, Francesca; Schianchi, Simona; Pellacani, Giovanni
abstract

BACKGROUND: By dermoscopy, regression structures are substantially defined by the presence of white and blue areas in the lesion image. As fibrosis and melanosis are often seen in malignant melanoma (MM), the presence of dermoscopic signs of regression may represent a clue for the diagnosis of malignancy.OBJECTIVES: To assess the frequency and extent of dermoscopic signs of regression in melanoma in situ (MIS) and to describe its dermoscopic features.METHODS: Dermoscopic images of 85 MIS, 85 invasive MMs and 85 dermoscopically equivocal lesions with a histological diagnosis of naevus were evaluated by three dermatologists, who assessed the presence of 11 parameters of regression.RESULTS: The number of regression parameters per lesion increased according to melanoma thickness. White areas, the grey-blue veil and widespread blue areas were more frequent in invasive MMs than in the other two lesion groups, whereas light brown areas and regression of dermoscopic structures were more frequent in MIS. Peppering was observable in the same percentage of MIS and invasive MMs. Blue areas were more frequently structureless in equivocal lesions and invasive MMs, whereas the reticular pattern prevailed in MIS.CONCLUSIONS: Frequency, morphology, extent and distribution of regression vary according to melanoma thickness and diameter. Lesions with reticular blue regression and light brown areas should undergo surgical excision for the suspicion of MIS. Moreover, the identification of the reticular pattern of blue regression can be considered a significant discriminator and a reliable predictor of MIS.

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 - "Collision" metastasis from unknown primary squamous cell carcinoma and papillary microcarcinoma of thyroid presenting as lateral cervical cystic mass [Articolo su rivista]
Mattioli, F; Masoni, F; Ponti, Giovanni; Rossi, G; Masoni, Francesco; ALICANDRI CIUFELLI, Matteo; Presutti, Livio
abstract

We report an unusual case of "collision metastasis". In a single lymph node, we found a metastatic mass composed of two immunohistochemically distinct components originating from two primary tumors: a papillary microfollicular thyroid cancer and an unknown primary squamous cell carcinoma. The clinical features and immunohistochemical profile are reported. Collision phenomena in oncology are extremely rare and pose diagnostic and management challenges which are discussed.

2009 - Complete pathological response in a patient with multiple liver metastases from colon cancer treated with Folfox-6 chemotherapy plus bevacizumab: a case report [Articolo su rivista]
N., Malavasi; Ponti, Giovanni; R., Depenni; F., Bertolini; S., Zironi; G., Luppi; P. F., Conte
abstract

The complete pathological response after primary chemotherapy could represent an important prognostic factor in patients affected by colorectal liver metastases. In recent studies, increasing complete pathological response seems to be correlated with longer overall survival periods and it is recognized as an important prognostic factor in patients treated with pre-operative chemotherapy. The correlation of radiological information on residual neoplastic disease after neoadjuvant treatment, obtained with CT and PET, has to be evaluated; in fact the complete disappearance of liver metastasis on radiological imaging does not always mean a complete disappearance of tumor tissue on histological examination; when it is documented with surgical procedures and confirmed by pathologist's examination, we can consider the complete pathological response. In recent years the addition of monoclonal antibodies to conventional chemotherapy may further increase the proportion of patients referred for surgery; bevacizumab before surgery has been shown to be feasible and safe, although concerns still exist regarding possible post-surgical and wound healing complications or bleeding. The limitation of the radiologic assessment of response as a surrogate for pathological response is even more relevant when antiangiogenic treatments are used. Excellent responses to bevacizumab-containing regimens do occur and referral to surgical oncology is a crucial step for documentation of complete pathological response.

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

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

2008 - Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer [Articolo su rivista]
Ponti, Giovanni; Losi, Lorena; Pellacani, Giovanni; L., Wannesson; A. M., Cesinaro; T., Venesio; C., Petti; Seidenari, Stefania
abstract

Background Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed. Objectives To characterize clinically and/or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods Patients with HNPCC with a diagnosis of MM were studied by immunohistochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, beta-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM. Results Nine cutaneous MMs were detected in the tumour spectrum of eight families with HNPCC. The median age at diagnosis was 46 years. In one HNPCC family the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM. Conclusions Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM.

2008 - The impact of histopathologic diagnosis on the proper management of testis neoplasms. [Articolo su rivista]
Ponti, Giovanni; Ponzoni, M.; Ferreri, A. J.; Foppoli, M.; Mazzucchelli, L.; Zucca, E.
abstract

BACKGROUND: A 45-year-old man underwent a right orchiectomy for a rapidly growing testicular mass. After histologic and imaging examinations the patient was diagnosed with stage I (T1N0M0) seminoma. Approximately 2 months after surgery the patient began to complain of abdominal pain and a CT scan revealed a bulky retroperitoneal mass. The patient did not receive the planned prophylactic radiotherapy and was treated with combined cisplatin, etoposide and bleomycin chemotherapy; after the completion of this treatment he achieved complete remission. Three years later, and while still undergoing follow-up, the patient developed multiple neurological motor deficits.INVESTIGATIONS: Brain MRI and CT-guided biopsy.DIAGNOSIS: Diffuse large B-cell lymphoma of the testis, relapsing in the central nervous system.MANAGEMENT: High-dose methotrexate alone or in combination with high-dose cytarabine.

2008 - Wnt pathway, angiogenetic and hormonal markers in sporadic and familial adenomatous polyposis-associated juvenile nasopharyngeal angiofibromas (JNA) [Articolo su rivista]
Ponti, Giovanni; Losi, Lorena; Pellacani, Giovanni; G. B., Rossi; Presutti, Livio; Mattioli, Francesco; Villari, Domenico; L., Wannesson; ALICANDRI CIUFELLI, Matteo; P., Izzo; M., De Rosa; P., Marone; Seidenari, Stefania
abstract

Juvenile nasopharyngeal angiofibroma (JNA) is a rare, invasive, and locally destructive tumor of the nasopharynx. The Writ pathway, angiogenctic and hormonal factors are involved in the pathophysiology of JNA; it can result in an extracolonic manifestation of familial adenomatous polyposis (FAP) or in a sporadic tumor. All patients who underwent resection of JNA between 1991 and 2006 at the University of Modena and Reggio Emilia were studied to identify immunohistochemical markers of associated FAP syndrome. Paraffin-embedded JNA samples were analyzed immunohistochemically for the expression of adenomatous polyposis coli (APC), beta-catenin, E-cadherin, androgen receptor, and vascular endothelial growth factors receptor (VEGFR(2)). In one out of the 4 (25%) young patients affected by JNA the diagnosis of FAP syndrome linked to APC mutation was made. All of the sporadic and familial JNA tumors showed nuclear staining of beta-catenin, whereas altered APC expression was seen only in FAP-associated JNA. All cases were stained with VEGFR(2). A combined clinical, immunohistochemical, and biomolecular screening may be useful for the identification of FAP among patients with a diagnosis of JNA. The Writ pathway can be involved in the JNA pathogenesis either by somatic mutations of beta-catenin or by germline APC mutations. As the VEGFR has an important impact on the pathogenesis of JNA, we suggest that a targeted therapy with monoclonal antibodies against VEGFR might lead to a specific chemoprevention and treatment of these tumors and their recurrences.

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 - BRAF mutations in multiple sebaceous hyperplasias of patients belonging to MYH-asociated polyposis pedigrees [Articolo su rivista]
Ponti, Giovanni; T., Venesio; Losi, Lorena; Pellacani, Giovanni; L., Bertario; P., Sala; Pedroni, Monica; C., Petti; S., Maffei; L., Varesco; E., Lerch; A., Baggio; Bassoli, Sara; Longo, Caterina; Seidenari, Stefania
abstract

The characteristics of sebaceous gland hyperplasia (SGH) consist of yellowish or skin-colored papules and nodules. Chronic sun exposure and immunosuppressed conditions are the main environmental risk factors, whereas chronological aging regulated by hormones and molecular changes are the intrinsic risk factors. We have evaluated the contribution of BRAF, K-Ras, and N-Ras mutations to the pathogenesis of SGHs in four patients belonging to three MYH-associated polyposis (MAP) pedigrees. MAP is an autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. Immunohistochemistry of mismatch repair and APC proteins was performed. DNA isolated from blood lymphocytes and formalin-fixed or paraffin-em bedded SGHs was PCR amplified and sequenced. In the SGH patients, we detected T1796A heterozygous substitution (V600E) in the BRAF gene. Compound biallelic germline MYH mutations (Y165C/G382D, R168H/379delC, and Y90X/ delGGA464) were detected in the MAP patients. In contrast to the majority of melanocytic lesions, activating hotspot mutations in BRAF have not been involved so far in the pathogenesis of SGH. BRAF mutation is not a specific marker of melanocytic cancerogenesis, and it can also be involved in SGHs. In both melanocytic and non-melanocytic skin tumors, BRAF mutation is linked to early tumorigenesis events.

2007 - Diagnosi di tre o più tumori a carico di uno stesso individuo come criterio per l'identificazione di famiglie con Sindrome eredo-familiare di predisposizione al cancro [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

abstract

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.

2006 - Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis [Articolo su rivista]
C., Di Gregorio; M., Frattini; S., Maffei; Ponti, Giovanni; Pedroni, Monica; Venesio, T; Bertario, L; Varesco, L; Risio, M; PONZ DE LEON, Maurizio; Losi, Lorena
abstract

BACKGROUND &amp; AIMS: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene.METHODS: The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies.RESULTS: In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa.CONCLUSIONS: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis.

2006 - Inherited predisposition to skin cancer. [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

Inherited predisposition to skin cancer.

2006 - Mutazioni somatiche di BRAF in iperplasie sebacee multiple di pazienti affetti da MAP (MYH-Associated Polyposis). [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

nd

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 - Ruolo delpathway Wnt e dei markers ormonali ed angiogenetici nella patogenesi dell'angiofibroma nasofaringeo [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

abstract

2006 - Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or Keratoacanthomas [Articolo su rivista]
Ponti, Giovanni; Losi, Lorena; Pedroni, Monica; E., Lucci Cordisco; C., Di Gregorio; Pellacani, Giovanni; Seidenari, Stefania
abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal-dominant disorder characterized by predisposition to colorectal cancer and extracolonic malignancies, frequent multiple primary tumors in the same patient, and early age of cancer onset. A main clinical variant of Lynch syndrome, Muir-Torre syndrome (MTS) is characterized by the association between one or more visceral malignancies, with at least one sebaceous skin tumor or keratoacanthoma. In our study, we have screened a cohort of 538 HNPCC patients, related to 57 HNPCC families, to detect sebaceous skin tumors and keratoacanthomas and the role of mismatch repair (MMR) genes, MLH1, MSH2, and MSH6, in their pathogenesis. Among the 57 HNPCC families, we have identified four MTS families and one suspected MTS family, in which sebaceous carcinoma was found in one HNPCC mutation carrier subject who did not show visceral malignancy. In four of these families, linked to two MLH1 mutations and to two MSH2 mutations, biomolecular characterization showed concordance among immunohistochemistry analysis and gene mutations. The evidences of our investigations show that MLH1 and MSH2 gene mutations have an equivalent etiopathological role both for Lynch syndrome and for MTS; hence, we propose a broadened clinical criteria for definition of Lynch syndrome that will include sebaceous adenoma, carcinoma, and keratoacanthoma.

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 - Correlazioni genotipo-fenotipo in soggetti portatori di mutazioni in eterozigosi del gene MYH [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

Correlazioni genotipo-fenotipo in soggetti portatori di mutazioni in eterozigosi del gene MYH

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 - 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 - 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.

2005 - Muir-Torre syndrome [Articolo su rivista]
Ponti, Giovanni; PONZ DE LEON, Maurizio
abstract

Muir-Torre syndrome is an autosomal-dominant skin condition of genetic origin, characterised by tumours of the sebaceous gland or keratoacanthoma. that are associated with visceral malignant diseases. The cutaneous characteristics of Muir-Torre syndrome are sebaceous adenoma, epithelioma, carcinoma, or multiple keratoacanthomas, whereas visceral malignant diseases include colorectal, endometrial, urological, and upper gastrointestinal tumours. Although Muir-Torre syndrome has a striking familial association and features of autosomal-dominant transmission, it can arise in individuals without a family history or any known mutations. Clinical and biomolecular evidence has suggested that there are two types of Muir-Torre syndrome. The most common is a variant of hereditary non-polyposis colorectal cancer, which is characterised by defects in mismatch repair genes and early-onset tumours. The second type does not show deficiency in mismatch repair and its pathogenesis remains undefined. Diagnosis of these rare sebaceous lesions warrants the search for associated internal malignant diseases: the peculiarity of skin lesions and their biomolecular characterisation with microsatellite instability analysis and immunohistochemistry could be used to identify familial Muir-Torre syndrome, allowing clinicians to tailor a personalised programme to screen for skin and visceral malignant diseases in high-risk individuals.

2005 - Ruolo dei geni MYH ed MLH1 nella Sindrome di Muir-Torre [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

Relazione

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.

2004 - Variabilità fenotipica e caratterizzazione biomolecolare in otto famiglie con diagnosi di Muir-Torre. [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

nd

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

Rivista della Società Italiana di Anatomia Patologica e Citopatologia Diagnostica

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

Abstract

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

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

2003 - Gestione dei familiari: forme familiari e forme sporadiche. [Relazione in Atti di Convegno]
Ponti, Giovanni
abstract

Gestione dei familiari: forme familiari e forme sporadiche.

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

Abstract

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

abstract

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

Abstract

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

Not avaivable

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

Atti del convegno

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

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

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

Atti del convegno

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

nd

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

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

2002 - 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

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.

2000 - A faster diagnosis of colorectal cancer in symptomatic patients is not related to a more favourable prognosis [Abstract in Rivista]
Riegler, G; De Lisa, F; Ponti, Giovanni; Caravelli, G; Selvaggi, F; Riccio, G; Esposito, I; Carratù, R.
abstract

Abstract

2000 - A faster diagnosis of colorectal cancer in symtomatic patients is not related to a more favourable prognosis. [Abstract in Rivista]
Riegler, G; Delisa, F; Ponti, Giovanni; Caravelli, G; Selvaggi, F; Riccio, G; Esposito, I; Carratù, R; Borgheseri, P; Rossi, Gb; De Palma, G; Russo, P; Piscitelli, A; Baldi, V; Guardascione, F; Di Giorgio, P; D'Avenia, E; Montanaro, F; Parente, E; Saffiotti, O; Bozzi, M.
abstract

Supplement to Gastroenterology

1999 - Prevalence of HNPCC in a series of consecutive patients on the first endoscopic diagnosis of colorectal cancer: A multicenter study [Articolo su rivista]
Riegler, G.; Savastano, A.; Selvaggi, F.; Ciociano, R.; Martino, R.; Riccio, G.; Iorio, R.; Ponti, G.; Carratu, R.; Borgheresi, P.; De Filippo, G.; Rossi, G. B.; Tempesta, A. M.; De Palma, G. D.; Catanzano, C.; Russo, P.; Bianco, M. A.; Piscitelli, A.; Di Carlo, V.; Baldi, V.; Avagliano, P.; Guardascione, F.; Petrelli, G.; Di Giorgio, P.; De Luca, L.; D'Avenia, E.; Cattaneo, D.; Montanaro, F.; Maisto, T.; Parente, E.; Vincenti, R.; Saffiotti, O.; Di Cesare, D.; Bozzi, M.; Beatrice, M.
abstract

Background and Study Aims: It is difficult to measure the prevalence of hereditary non-polyposis colorectal cancer (HNPCC) in geographical areas that do not have tumor registers, as is the case in the present study, and it was therefore decided to assess the prevalence in Italy using different methods. Patients and Methods: The pedigree was established for 485 of 501 colorectal cancer patients diagnosed with colorectal carcinomas. Patients were included consecutively in 13 gastroenterology centers; they had not taken part in prevention examinations. Information was collected regarding the neoplastic pathology observed in the families, confirmed in 90% of cases among 3515 first-degree relatives and in 79.5% of cases among 7068 second-degree relatives. Results: In the 3515 first-degree relatives (1002 parents, 1560 siblings and 953 children), 61 colorectal carcinomas, 29 carcinomas in the digestive tract outside the colon, and 99 carcinomas in other locations were reported. Only five of the 485 patients (1%) satisfied the Amsterdam criteria (three cancers, two of which were in first-degree relatives in different generations and one in a relative younger than 50). When broadening the criteria that we are proposing (satisfying only two of the three Amsterdam criteria), the prevalence would increase to 3% (15 cases). Conclusions: Modifying the criteria makes it easier to identify new mutations or confirm the existence of those already known, as well as allowing preventative treatment in relatives who are apparently healthy.

1997 - Multiple adenomas can be considered a HNPCC definition criterium. [Abstract in Rivista]
Riegler, G; D'Angella, G; Caravelli, G; Arimoli, A; Ciociano, R; Ponti, Giovanni; Carratù, R.
abstract

ISSN: 1125-8055