CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey.

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management. METHODS: The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS). RESULTS: In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001). CONCLUSIONS: Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.

XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study.

Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29-4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity.

Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m(2) in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero. RESULTS: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3-34.7]. In all, 29 (39%) (95% CI 28-48) patients reported stable disease. The median survival was estimated at 14 months. CONCLUSION: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.

Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients.

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.

[Invasion of the chest wall in primary lung neoplasms]. / L'invasione della parete toracica nelle neoplasie polmonari primitive.

The authors analyse a series of 5 patients who underwent pulmonary and parietal resection between 1990 and 1993 due to non.microcytoma bronchogenic carcinoma with invasion of the thoracic wall. The patients comprised four men and one woman aged between 45 and 69 years old. Thoracic pain was present in two patients. Pulmonary resection with extrapleural stripping was performed in two patients whereas a block resection from one to five ribs and the corresponding intercostal spaces was performed in the other three patients. The authors' approach is not to perform these operations according to rigid protocols but to adapt them according to the local status of tumour invasion. Therefore to resort to extrapleural resection when there is a free cleavage plane between parietal pleura and rib wall; resection in block of the wall where the carcinoma has infiltrated the endothoracic fascia or deeper. The authors do not report any major complications and record a postoperative mortality rate of 0%. In two cases the thoracic wall was reconstructed using a sheet of Gore-Tex which did not provoke rejection phenomena. Radiotherapy was carried out in cases with positive lymph nodes. The series presented here is too recent to provide significant data regarding survival. However, the only factor seen to influence prognosis in the five patients was the presence or otherwise of lymph node metastasis, irrespective of the histological type and operation performed. The five year survival rate of T3N0M0 patients is in fact similar to that of T2N0M0 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical observations on the treatment of ischemic cardiac disease with a calcium antagonist: nifedipine]. / Osservazioni cliniche sul trattamento della cardiopatia ischemica con un calcio-antagonista: la Nifedipina.

Results obtained wih Nifedipine in 146 coronary patients, 85 of them suffering from coronaro-sclerosis with rest and effort stenocardic attacks, and 61 with post-infarctual stenocardic signs, are reported. In 76% of patients in the first group and in 85% of those in the second, pain symptomatology disappeared rapidly; ECGs also showed attenuation and modification, particularly among angina patients. The drug also led to a reduction in hypertension.