P.A. Zucali

Advances in the biology of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.

Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials.

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500u2009mgu2009m−2 and carboplatin AUC 5u2009mgu2009ml−1u2009min−1 intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those ⩾70 years old. A total of 178 patients with an ECOG performance status of ⩽2 were included. Median age was 65 years (range 38–79), with 48 patients ⩾70 years (27%). Grade 3–4 haematological toxicity was slightly worse in ⩾70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease control (60.4 vs 66.9%, P=0.47), time to progression (7.2 vs 7.5 months, P=0.42) and survival (10.7 vs 13.9 months, P=0.12). Apart from slightly worse haematological toxicity, there was no significant difference in outcome or toxicity between age groups. The PC regimen is effective and well tolerated in selected elderly patients with MPM.

Second-line chemotherapy in malignant pleural mesothelioma: Results of a retrospective multicenter survey

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.

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Background:The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).Methods:Eligible patients received pemetrexed 500u2009mgu2009m−2, carboplatin area under the plasma concentration–time curve (AUC) 5u2009mgu2009ml−1 per minute and bevacizumab 15u2009mgu2009kg−1, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.Results:Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.Conclusion:The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.

Reproducibility of the WHO classification of thymomas: Practical implications

BACKGROUNDnThe 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.nnnMETHODSnFour 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.nnnRESULTSnIn 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.nnnCONCLUSIONSnIn 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.

Phase I and pharmacodynamic study of high-dose NGR–hTNF in patients with refractory solid tumours

Background:NGR–hTNF exploits the peptide asparagine–glycine–arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR–hTNF was previously established at 45u2009μgu2009m−2 as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60–325u2009μgu2009m−2). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (Ktrans) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both Cmax (P<0.0001) and area under the plasma concentration–time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment Ktrans values (P<0.0001), which inversely correlated with NGR–hTNF Cmax (P=0.03) and baseline Ktrans values (P<0.0001). Lower sTNF-R2 levels and greater Ktrans decreases after first cycle were associated with improved survival.Conclusion:asparagine–glycine–arginine–hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.

Comorbidity, postoperative morbidity and survival in patients undergoing radical surgery for malignant pleural mesothelioma.

OBJECTIVESnWe examined a series of malignant pleural mesothelioma (MPM) patients who underwent radical surgery to explore relationships among comorbidity, postoperative morbidity and survival.nnnMETHODSnA retrospective analysis was carried out of all MPM patients operated on in a single centre from 2000 to 2015. The Charlson Comorbidity Index (CCI) was used to classify patients according to their underlying condition. Postoperative complications were scored according to WHO-derived criteria. Survival comparisons were performed by Cox analysis.nnnRESULTSnNinety-one patients underwent extrapleural pneumonectomy (EPP), 47 underwent pleurectomy decortication (PD) and 25 underwent palliative pleurectomy. The mean CCI of PD patients was significantly higher compared with that of EPP patients (P= 0.044). The frequency of grade 3+ complications was similar between EPP and PD (27 vs 26%). However, EPP patients had a 6-fold higher frequency of pleural sepsis (24 vs 4%, P= 0.002) occurring up to 695 days postoperatively. Median overall survival was 19 months (95% CI 13-25) after EPP, 30 months (95% CI 20-35) after PD and 13 months (95% CI 5-32) after palliative pleurectomy. At multivariate analysis, CCI (P< 0.001), histology (P= 0.014) and pleural sepsis (P= 0.001), but not complete resection, were significantly associated with survival. There was a trend in favour of PD over palliative resection after adjusting for histology and CCI.nnnCONCLUSIONSnThe CCI is an independent predictor of survival in MPM patients undergoing radical surgery. Owing to its significant frequency and adverse impact, pleural sepsis may contribute to a reduced life expectancy after EPP. Surgical treatment of MPM remains debatable.

The "old drug" DTIC as a second/third line chemotherapy in advanced soft tissue sarcomas (STS)

9032 Background: There is not a standard second line chemotherapy in advanced STS. DTIC is one of the most active drugs in the treatment of STS with a response rate (RR) of 17%. As a second line chemotherapy the data available confirm these interesting results. Therefore we conducted a retrospective analysis about 44 patients (pts) treated in our Institute with DTIC as second/third line therapy between May 1997 and October 2003. The aim of our analysis was to evaluate the RR, the progression free survival (PFS) and the median duration of response.nnnMETHODSnAbout 44 pts anlysed, 36 were evaluable; 8 pts, after first cycle, were treated elsewhere. The median age was 55,5 (range 24-75). The 75% of pts (27/36) were metastatic and the 72% (26/36) had a disease grading 2-3. DTIC was done as second line chemotherapy in 70% of pts(25/36). The 75% of pts (27/36) and the 25% (9/36) had respectively progressive and relapsed disease before to start the treatment. DTIC was given every 21 days with three different schedules: DTIC 800 mg/sqm day 1 (20 pts); DTIC 400 mg/sqm days 1 and 2 (6 pts); DTIC 300 mg/sqm days 1, 2 and 3 (10 pts).nnnRESULTSnAmong 36 evaluable pts, 3 (8%) achieved partial response (PR) and 7 (19%) stable disease (SD), with an overall disease control of 28%. No complete response was observed. As second line therapy DTIC achieved 2/25 PR and 5/25 SD. The median PFS and the median duration of response were respectively 2 and 8 months. The progression free rate at 3 and 6 months was respectively 33% (SE 7.86%) and 25% (SE 7.2%). No grade 3-4 hematologic and non-hematologic toxicity according to W.H.O. was observed.nnnCONCLUSIONSnOur results suggest that DTIC as a second/third line therapy yields a satisfactory disease control in progressive STS; its activity seems to be comparable to other treatments, such as the high dose of ifosfamide or ET-743, but with a lower toxicity profile. The increse of dose-intensity to obtain a better RR is questionable considering cost-benefit ratio in terms of toxicities and overall survival. No significant financial relationships to disclose.

1557PDGTF2I MUTATIONS ARE FREQUENT IN THYMIC EPITHELIAL TUMORS

ABSTRACT Aim: To investigate the molecular aberrations of thymic epithelial tumors (TETs) which, currently, are largely unknown, hampering progress in diagnosis, prognostication and targeted therapy. Methods: Frozen tumor and normal blood were available for 28 TETs with a high proportion of cancer cell content (>80%). Exome capture was performed using Sure Select All Exon (Agilent) and TruSeq Exome Enrichment kit (Illumina) in 21 and 35 samples, respectively. Sequencing was performed using Genome Analyzer-II (Illumina) and HiSeq2000 (Illumina) in 21 and 35 samples, respectively. Reads were aligned using Novoalign (Novocraft) and somatic mutations were detected comparing exome sequencing of tumor and normal DNA of each patients using VarScan2. A single nucleotide missense mutation of GTF2I was the most common in TETs, and was confirmed in an independent cohort of 268 formalin fixed paraffin embedded TETs. Results: Thymic carcinomas had a higher number of mutations than thymomas with a mean of 43.5 and 17.4, respectively (p=0.001). In thymic carcinomas (11), genes with recurrent mutations included TP53 (4), CYLD (3), BAP1 (2), CDKN2A (2) and PBRM1 (2). A single nucleotide mutation of GTF2I (chr7:74146970T/A) was observed in 35% of thymomas (17). The mutation was missense (leucine to histidine), not previously described in cancer or as a polymorphism in dbSNP137 database. The mutation was predicted to alter the structure of the protein or its function according to Poliphen2 and SIFT algorithms. The presence of GTF2I mutation was confirmed in an extended cohort of 268 TETs: 82% of A (56), 74% of AB (54), 32% of B1 (28), 22% of B2 (32), 21% of B3 thymomas (62) and 8% of thymic carcinomas (36). The mutation was more frequent in stages I-II (57%) than in stages III-IV (19%; p Conclusions: GTF2I mutation is frequent in thymic epithelial tumors, especially in A-AB histotypes and is associated with a better outcome. Disclosure: All authors have declared no conflicts of interest.