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Objectives: Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC)., Patients and Methods: GEM (1000 mg/m 2 ) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS)., Results: In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients., Conclusions: The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit., Competing Interests: Declaration of Competing Interest All the authors declare no competing interests. None of the authors have received funding for this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients., Methods: Vinorelbine 25 mg/m(2) was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity., Results: Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as > 2L treatment. The median age was 69 years (range 45-80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR(0 vs. 1-2) 0.50; 95%CI: 0.3-0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR(FL-PFS>6 ms vs. <6 ms) 0.50; 95%CI: 0.3-0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients., Conclusions: Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥ 6 months., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas., Methods: Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss' kappa-coefficient was used to assess the pathologists' overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test., Results: In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists., Conclusions: In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management. Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies., (Published by Elsevier Ireland Ltd.)

The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The role of second-line therapy in patients with malignant pleural mesothelioma (MPM) progressing after first-line pemetrexed-based chemotherapy (PBC) is currently undefined. Recent case series have suggested a possible role of re-treatment with PBC. In this observational study, the activity and safety of this therapeutic option was assessed in a consecutive series of cases. Patients with complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 3 months after first-line PBC were retreated with PBC, either as second-line (2L) or further-line (>2L) therapy. Descriptive analyses of progression-free survival (PFS), overall survival (OS), response rate and toxicity are reported. Between October 2004 and July 2009, 31 patients (21 males and 10 females) received re-treatment with PBC as 2L (18 patients) or beyond 2L therapy (13 patients). Median age was 65 years (range 37-81). Fifteen patients were re-treated with pemetrexed alone, and 16 with a pemetrexed/platinum combination. An objective response was achieved in 6 patients (one CR and 5 PRs), for a response rate of 19%. Nine patients (29%) had SD after treatment. Overall, the disease control rate (DCR) was 48%. Median PFS and overall survival (OS) after re-treatment with PBC were 3.8 months and 10.5 months, respectively. PFS and OS after re-treatment with PBC were correlated with PFS achieved after first-line PBC (FL-PFS). Patients with a FL-PFS >12 months had a median PFS after re-treatment of 5.5 months, while patients with a FL-PFS ≤12 months had a median PFS after re-treatment of 2.5 months; no patient in this group was progression-free at 1 year. Toxicity was mild, with grade 3 or 4 hematological toxicity occurring in 9.7% of patients. In conclusion, re-treatment with PBC should be considered as second-line therapy in MPM patients achieving a durable (>12 months) disease control with first-line PBC. Further prospective evaluation of this therapeutic option is warranted., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Methylation of tumor suppressor genes is among the most frequent alterations in patients with malignant pleural mesothelioma (MPM). The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15(INK4B), p16(INK4A), RASSF1A and NORE1A in MPM. Samples of 79 MPM patients were analyzed using a methylation-specific PCR method. Associations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined. The analysis documented methylation in 30 cases (38%). The methylation frequency for individual genes was 19% for p15(INK4B) (n=15), 11.4% for p16(INK4A) (n=9), 20.2% for RASSF1A (n=16) and 5.1% for Nore1A (n=4). In the whole series methylation was associated to an increased proliferation index (P=0.05). In patients treated with extrapleural pneumonectomy, methylated MPM showed a trend to a poorer OS in comparison to unmethylated cases (median OS 16 months vs. 35 months, P=0.06, HR=2.01, 95% CI 0.95-4.30). In the overall population, methylation did not correlate to patient outcome but a trend to an improved survival was detectable in ummethylated MPM treated with extrapleural pneumonectomy. This result suggests the need to select homogeneously treated and staged patients with MPM to address whether their methylation profile may impact on patient's survival.