Faculty Bibliography

PURPOSE: Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)-based immunotherapy for MM. Experimental design: We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM severe combined immunodeficient (SCID) mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments. RESULTS: CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, mAb TP41.2 significantly reduced MM cell motility, migration, and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival. CONCLUSION: These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM. Clin Cancer Res; 18(19); 5352-63. (c)2012 AACR.

Background: Covered stents have become part of the armamentarium for treating various esophageal pathologies. A recently available, low profile, fully covered metal stent with symmetrical flares (FCMSF) may offer improved deployment and resistance to migration. Methods: A retrospective review of 58 esophageal FCMSF placed in 47 consecutive patients by a single thoracic surgeon between March 2010 and February 2012 was performed. Pathologies included benign and malignant stricture and leak. Stents were placed endoscopically under general anesthesia using a 6 mm deployment system; bidirectional maneuverability was possible. Dysphagia score (0-4) was prospectively recorded. Leak treatment was assessed with postoperative esophagrams. Results: Mean age was 62.0 years. Sixteen of 58 stents (28%) were placed urgently/emergently. All patients had successful stent deployment with 0% stent-related hospital morbidity/mortality. Overall post-operative morbidity occurred following 12/58 stents, including arrhythmia, pneumonia, pneumothorax, urinary retention, hemodynamic instability, and COPD exacerbation. In patients with stricture (n = 29), mean dysphagia scores were reduced from 3.0 preoperatively to 1.2 post-operatively (p < 0.001). for leak, stent therapy (+/- drainage) avoided formal esophageal operation in 94% (17/18). Fifteen stents were removed during follow-up, 4 after migration. Mean overall survival was 2.3 +/- 2.6 months for stricture (21/35 remain alive) and 8.7 +/- 9.6 months for leak (16/18 remain alive). Mean duration of stent therapy was 4.9 +/- 4.8 months for stricture (29/35 remain in situ) and 3.5 +/- 3.2 months for leak (10/20 remain in situ). Mean hospital stay was 3.9 +/- 7.0 days. Discussion: FCMSF are an effective therapy for both esophageal strictures and leaks. The symmetrical covered flares likely contribute to the low observed migration rate

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

BACKGROUND: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma. METHODS: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson chi2 test or two-tailed Fisher's exact test). RESULTS: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p