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Mesothelioma: HELP
Articles by Anish Thomas
Based on 20 articles published since 2010
(Why 20 articles?)
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Between 2010 and 2020, Anish Thomas wrote the following 20 articles about Mesothelioma.
 
+ Citations + Abstracts
1 Guideline Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. 2018

Kindler, Hedy L / Ismaila, Nofisat / Armato, Samuel G / Bueno, Raphael / Hesdorffer, Mary / Jahan, Thierry / Jones, Clyde Michael / Miettinen, Markku / Pass, Harvey / Rimner, Andreas / Rusch, Valerie / Sterman, Daniel / Thomas, Anish / Hassan, Raffit. ·Hedy L. Kindler and Samuel G. Armato III, The University of Chicago, Chicago, IL · Nofisat Ismaila, American Society of Clinical Oncology · Mary Hesdorffer, Mesothelioma Applied Research Foundation, Alexandria, VA · Raphael Bueno, Harvard Medical School, Boston, MA · Thierry Jahan, University of California San Francisco, San Francisco, CA · Clyde Michael Jones, Baptist Cancer Center Physicians Foundation, Memphis, TN · Markku Miettinen, Anish Thomas and Raffit Hassan, Center for Cancer Research, National Cancer Institute, Bethesda, MD · Harvey Pass and Daniel Sterman, New York University Langone Medical Center · and Andreas Rimner and Valerie Rusch, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #29346042.

ABSTRACT: Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

2 Review Scientific Advances and New Frontiers in Mesothelioma Therapeutics. 2018

Mutti, Luciano / Peikert, Tobias / Robinson, Bruce W S / Scherpereel, Arnaud / Tsao, Anne S / de Perrot, Marc / Woodard, Gavitt A / Jablons, David M / Wiens, Jacinta / Hirsch, Fred R / Yang, Haining / Carbone, Michele / Thomas, Anish / Hassan, Raffit. ·School of Environment and Life Sciences, College of Science and Technology, Cockcroft Building, University of Salford, Salford, United Kingdom. · Department of Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota. · National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. · Pulmonary and Thoracic Oncology, CHU de Lille, Univ Lille, Lille, France; French National Network of Clinical Expert Centres for Malignant Pleural Mesothelioma Management. · Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. · Division of Thoracic Surgery, University of Toronto, Toronto, Ontario, Canada. · Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. · International Association for the Study of Lung Cancer, Aurora, Colorado. · International Association for the Study of Lung Cancer, Aurora, Colorado; Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado. · Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii. · Development Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. · Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: hassanr@mail.nih.gov. ·J Thorac Oncol · Pubmed #29966799.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium, and rarely, the tunica vaginalis. The incidence of MPM is expected to increase worldwide in the next two decades. However, even with the use of multimodality treatment, MPM remains challenging to treat, with a 5-year survival rate of less than 5%. The International Association for the Study of Lung Cancer has gathered experts in different areas of mesothelioma research and management to summarize the most significant scientific advances and new frontiers related to mesothelioma therapeutics.

3 Review New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. 2013

Mossman, Brooke T / Shukla, Arti / Heintz, Nicholas H / Verschraegen, Claire F / Thomas, Anish / Hassan, Raffit. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405-0068, USA. brooke.mossman@uvm.edu ·Am J Pathol · Pubmed #23395095.

ABSTRACT: Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.

4 Review Immunotherapies for non-small-cell lung cancer and mesothelioma. 2012

Thomas, Anish / Hassan, Raffit. ·Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ·Lancet Oncol · Pubmed #22748269.

ABSTRACT: Non-small-cell lung cancer and mesothelioma are thoracic malignancies, which in their advanced stages are incurable and have poor prognosis. Advances in our understanding of immune responses to tumours, tumour immunosuppression mechanisms, and tumour-specific shared antigens enabled successful early clinical trials of several specific and non-specific immunotherapies. For non-small-cell lung cancer, phase 3 clinical trial results of Toll-like receptor agonists show little promise. However, ongoing phase 3 trials are assessing melanoma-associated antigen A3 vaccine, liposomal BLP25, belagenpumatucel-L, and talactoferrin. In mesothelioma, immunotherapies being investigated include dendritic cell-based and Listeria-based vaccines, and allogeneic tumour cell and WT1 analogue peptide vaccines. Selection of appropriate patients and disease stages for immunotherapy, measurement of tumour-specific immune responses, and understanding the association between immune and clinical responses are some of the major challenges for the development of immunotherapies for these malignancies.

5 Clinical Trial Efficacy and Safety of Avelumab Treatment in Patients With Advanced Unresectable Mesothelioma: Phase 1b Results From the JAVELIN Solid Tumor Trial. 2019

Hassan, Raffit / Thomas, Anish / Nemunaitis, John J / Patel, Manish R / Bennouna, Jaafar / Chen, Franklin L / Delord, Jean-Pierre / Dowlati, Afshin / Kochuparambil, Samith T / Taylor, Matthew H / Powderly, John D / Vaishampayan, Ulka N / Verschraegen, Claire / Grote, Hans Juergen / von Heydebreck, Anja / Chin, Kevin / Gulley, James L. ·Thoracic and GI Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Division of Hematology and Oncology, University of Toledo College of Medicine, Toledo, Ohio. · Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota. · Department of Pneumology, Thoracic Oncology Unit, University Hospital of Nantes, Nantes, France. · Novant Health Oncology Specialists, Winston-Salem, North Carolina. · Institut Universitaire du Cancer-Oncopole, Toulouse, France. · Division of Hematology and Oncology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio. · Virginia Piper Cancer Institute, Minneapolis, Minnesota. · Knight Cancer Institute, Oregon Health & Science University, Portland. · Carolina BioOncology Institute, Huntersville, North Carolina. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. · Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus. · Merck KGaA, Darmstadt, Germany. · EMD Serono, Billerica, Massachusetts. · Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. ·JAMA Oncol · Pubmed #30605211.

ABSTRACT: Importance: Patients with malignant mesothelioma whose disease has progressed after platinum and pemetrexed treatment have limited options. Anti-programmed cell death 1 (PD-1) antibodies have antitumor activity in this disease, but little is known about the activity of anti-programmed cell death ligand 1 (PD-L1) antibodies in patients with mesothelioma. Objective: To assess the efficacy and safety of avelumab in a cohort of patients with previously treated mesothelioma. Design, Setting, and Participants: Phase 1b open-label study (JAVELIN Solid Tumor) in patients with unresectable mesothelioma that progressed after platinum and pemetrexed treatment, enrolled at 25 sites in 3 countries between September 9, 2014, and July 22, 2015. Interventions: Participants received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures: Prespecified end points included confirmed best overall response based on Response Evaluation Criteria In Solid Tumors, version 1.1; duration of response; progression-free survival (PFS); overall survival (OS); PD-L1 expression-based analyses; and safety. Results: Of 53 patients treated with avelumab, the median age was 67 (range, 32-84) years; 32 (60%) were male. As of December 31, 2016, median follow-up was 24.8 (range, 16.8-27.8) months. Twenty patients (38%) had 3 or more previous lines of therapy (median, 2; range, 1-8). The confirmed objective response rate (ORR) was 9% (5 patients; 95% CI, 3.1%-20.7%), with complete response in 1 patient and partial response in 4 patients. Responses were durable (median, 15.2 months; 95% CI, 11.1 to not estimable months) and occurred in patients with PD-L1-positive tumors (3 of 16; ORR, 19%; 95% CI, 4.0%-45.6%) and PD-L1-negative tumors (2 of 27; ORR, 7%; 95% CI, 0.9%-24.3%) based on a 5% or greater PD-L1 cutoff. Disease control rate was 58% (31 patients). Median PFS was 4.1 (95% CI, 1.4-6.2) months, and the 12-month PFS rate was 17.4% (95% CI, 7.7%-30.4%). Median OS was 10.7 (95% CI, 6.4-20.2) months, and the median 12-month OS rate was 43.8% (95% CI, 29.8%-57.0%). Five patients (9%) had a grade 3 or 4 treatment-related adverse event, and 3 (6%) had a grade 3 or 4 immune-related, treatment-related adverse event. There were no treatment-related deaths. Conclusions and Relevance: Avelumab showed durable antitumor activity and disease control with an acceptable safety profile in a heavily pretreated cohort of patients with mesothelioma. Trial Registration: ClinicalTrials.gov identifier: NCT01772004.

6 Clinical Trial Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging. 2015

Lindenberg, Liza / Thomas, Anish / Adler, Stephen / Mena, Esther / Kurdziel, Karen / Maltzman, Julia / Wallin, Bruce / Hoffman, Kimberly / Pastan, Ira / Paik, Chang Hum / Choyke, Peter / Hassan, Raffit. ·Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Molecular Imaging Program, National Cancer Institute, SAIC-Frederick, Inc, NCI-Frederick, Frederick, MD, USA. · Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA. · Morphotek, Exton, PA, USA. · Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Radiology and Imaging Sciences, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA. ·Oncotarget · Pubmed #25756664.

ABSTRACT: Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers. Considering the ongoing clinical development of amatuximab in these cancers, our objective was to characterize the biodistribution, and dosimetry of 111Indium (111In) radiolabelled amatuximab in mesothelin-expressing cancers. Between October 2011 and February 2013, six patients including four with malignant mesothelioma and two with pancreatic adenocarcinoma underwent Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) imaging following administration of 111In amatuximab. SPECT/CT images were obtained at 2-4 hours, 24-48 hours and 96-168 hours after radiotracer injection. In all patients, tumor to background ratios (TBR) consistently met or exceeded an uptake of 1.2 (range 1.2-62.0) which is considered the minimum TBR that can be visualized. TBRs were higher in tumors of patients with mesothelioma than pancreatic adenocarcinoma. 111In-amatuximab uptake was noted in both primary tumors and metastatic sites. The radiotracer dose was generally well-tolerated and demonstrated physiologic uptake in the heart, liver, kidneys and spleen. This is the first study to show tumor localization of an anti-mesothelin antibody in humans. Our results show that 111In-amatuximab was well tolerated with a favorable dosimetry profile. It localizes to mesothelin expressing cancers with a higher uptake in mesothelioma than pancreatic cancer.

7 Clinical Trial Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. 2014

Hassan, Raffit / Kindler, Hedy L / Jahan, Thierry / Bazhenova, Lyudmila / Reck, Martin / Thomas, Anish / Pastan, Ira / Parno, Jeff / O'Shannessy, Daniel J / Fatato, Penny / Maltzman, Julia D / Wallin, Bruce A. ·Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. hassanr@mail.nih.gov. · University of Chicago, Chicago, Illinois. · University of California, San Francisco, California. · University of California, San Diego, California. · Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Grosshansdorf, Stormarn, Germany. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · United BioSource Corp., Blue Bell, Pennsylvania. · Morphotek, Inc., Exton, Pennsylvania. ·Clin Cancer Res · Pubmed #25231400.

ABSTRACT: PURPOSE: Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM. EXPERIMENTAL DESIGN: In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety. RESULTS: Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off. CONCLUSIONS: Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.

8 Clinical Trial Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. 2014

Hassan, Raffit / Sharon, Elad / Thomas, Anish / Zhang, Jingli / Ling, Alexander / Miettinen, Markku / Kreitman, Robert J / Steinberg, Seth M / Hollevoet, Kevin / Pastan, Ira. ·Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. ·Cancer · Pubmed #24989332.

ABSTRACT: BACKGROUND: The primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response. METHODS: Chemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks. RESULTS: Twenty-four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose-limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P < .0001). CONCLUSIONS: SS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses.

9 Clinical Trial Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. 2013

Hassan, Raffit / Miller, Andrew C / Sharon, Elad / Thomas, Anish / Reynolds, James C / Ling, Alexander / Kreitman, Robert J / Miettinen, Markku M / Steinberg, Seth M / Fowler, Daniel H / Pastan, Ira. ·Laboratory of Molecular Biology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. ·Sci Transl Med · Pubmed #24154601.

ABSTRACT: Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy-refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed.

10 Article FDG-PET assessment of malignant pleural mesothelioma: Total Lesion volume and Total Lesion Glycolysis; the central role of volume. 2020

Reynolds, James C / Maass-Moreno, Roberto / Thomas, Anish / Ling, Alexander / Padiernos, Emerson B / Steinberg, Seth M / Hassan, Raffit. ·Radiology and Imaging Science, Clinical Center, National Institutes of Health, United States. · Radiology and Imaging Sciences, National Institutes of Health, Clinical Center, United States. · Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, United States. · Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, United States. · Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, United States. ·J Nucl Med · Pubmed #32284398.

ABSTRACT: Cancer Survival is related to tumor volume. FDG PET measurement of tumor volume holds promise but is not yet a clinical tool. Measurements come in two forms: the total lesion volume (TLV) based on the number of voxels in the tumor and secondly the total lesion glycolysis (TLG) which is the TLV multiplied by the average SUL per voxel of the tumor (SUL is the standardize uptake value normalized for lean mass). In this study we measured tumor volume in patients with malignant pleural mesothelioma (MPM).

11 Article Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression. 2020

Rathkey, Daniel / Khanal, Manakamana / Murai, Junko / Zhang, Jingli / Sengupta, Manjistha / Jiang, Qun / Morrow, Betsy / Evans, Christine N / Chari, Raj / Fetsch, Patricia / Chung, Hye-Jung / Xi, Liqiang / Roth, Mark / Filie, Armando / Raffeld, Mark / Thomas, Anish / Pommier, Yves / Hassan, Raffit. ·Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland. · Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: hassanr@mail.nih.gov. ·J Thorac Oncol · Pubmed #32004714.

ABSTRACT: INTRODUCTION: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial. METHODS: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4-methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O RESULTS: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 μM to greater than 50 μM and 0.039 μM to greater than 5 μM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression. CONCLUSIONS: BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.

12 Article Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. 2019

Hassan, Raffit / Morrow, Betsy / Thomas, Anish / Walsh, Tom / Lee, Ming K / Gulsuner, Suleyman / Gadiraju, Meghana / Panou, Vasiliki / Gao, Shaojian / Mian, Idrees / Khan, Javed / Raffeld, Mark / Patel, Snehal / Xi, Liqiang / Wei, Jun S / Hesdorffer, Mary / Zhang, Jingli / Calzone, Kathleen / Desai, Arpita / Padiernos, Emerson / Alewine, Christine / Schrump, David S / Steinberg, Seth M / Kindler, Hedy L / King, Mary-Claire / Churpek, Jane E. ·Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892; hassanr@mail.nih.gov mcking@uw.edu. · Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892. · Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD 20892. · Department of Medicine, University of Washington, Seattle, WA 98195. · Department of Genome Sciences, University of Washington, Seattle, WA 98195. · Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637. · Department of Respiratory Diseases, Aalborg University Hospital, 9000 Aalborg, Denmark. · Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892. · Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892. · Mesothelioma Applied Research Foundation, Washington, DC 20036. · Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892. · Office of the Clinical Director, CCR, NCI, NIH, Bethesda, MD 20892. · Department of Medicine, University of Washington, Seattle, WA 98195; hassanr@mail.nih.gov mcking@uw.edu. ·Proc Natl Acad Sci U S A · Pubmed #30975761.

ABSTRACT: Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (

13 Article Elevated Serum Megakaryocyte Potentiating Factor as a Predictor of Poor Survival in Patients with Mesothelioma and Primary Lung Cancer. 2018

Yu, Yunkai / Ryan, Bríd M / Thomas, Anish / Morrow, Betsy / Zhang, Jingli / Kang, Zhigang / Zingone, Adriana / Onda, Masanori / Hassan, Raffit / Pastan, Ira / Cao, Liang. ·Genetics Branch. · Laboratory of Human Carcinogenesis. · Thoracic and Gastrointestinal Oncology Branch. · Basic Science Program, Leidos Biomedical Research, Inc., Frederick, MD. · Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD. ·J Appl Lab Med · Pubmed #30370398.

ABSTRACT: Background: There is an urgent need for a companion assay to work with mesothelin-targeted therapeutic agents and for noninvasive and accurate prognostication of malignant mesothelioma (MM) patients. We report the development and validation of a blood-based assay for megakaryocyte potentiating factor (MPF) and the evaluation of its effectiveness for prognosis in MM and lung cancer patients. Methods: Using electrochemiluminescence technology, we developed a sensitive MPF assay and performed both analytical and clinical validations. Further, the effectiveness of the MPF assay in predicting prognosis was evaluated for 95 MM and 272 lung cancer patients. Results: We performed comprehensive analytical and clinical validation, including precision and accuracy, interference, preanalytical variables, sensitivity, and specificity for mesothelioma. In MM patients, increased serum MPF is a predictor of poor survival with a hazard ratio (HR) = 2.46 (log-rank Conclusions: The MPF assay has robust technical characteristics, with strong analytic and clinical validation. Clinical studies indicate that increased serum MPF is a predictor of poor survival for MM patients, throughout the course of the disease. Increased MPF is also associated with poor overall survival for patients with newly diagnosed lung cancer.

14 Article Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. 2018

Khanna, Swati / Graef, Suzanne / Mussai, Francis / Thomas, Anish / Wali, Neha / Yenidunya, Bahar Guliz / Yuan, Constance / Morrow, Betsy / Zhang, Jingli / Korangy, Firouzeh / Greten, Tim F / Steinberg, Seth M / Stetler-Stevenson, Maryalice / Middleton, Gary / De Santo, Carmela / Hassan, Raffit. ·Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. · University of Maryland Baltimore County, Baltimore, Maryland. · Koç University, Rumelifeneri, Sarıyer/İstanbul, Turkey. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. hassanr@mail.nih.gov. ·Clin Cancer Res · Pubmed #29602801.

ABSTRACT:

15 Article Patterns of care and survival among patients with malignant mesothelioma in the United States. 2017

Enewold, Lindsey / Sharon, Elad / Thomas, Anish. ·National Cancer Institute, Bethesda, MD, United States. Electronic address: lindsey.enewold@nih.gov. · National Cancer Institute, Bethesda, MD, United States. ·Lung Cancer · Pubmed #29191582.

ABSTRACT: BACKGROUND: Mesothelioma is a rare malignancy that is associated with poor survival. This study aimed to describe the patterns of care and subsequent survival among malignant mesothelioma patients in the United States, while adjusting for patient demographics and comorbidities. METHODS: A random sample of patients diagnosed with histologically confirmed mesothelioma in 2011, as reported to the National Cancer Institute's Surveillance Epidemiology and End Results program, were included. Logistic regression and Cox proportional hazard regression were utilized to identify factors associated with receipt of therapy and all-cause mortality, respectively, among patients with pleural mesothelioma. RESULTS: This study included 389 patients with pleural mesothelioma and 53 patients with non-pleural mesothelioma. Almost a third (29.3%) of the pleural patients and 21.5% of the non-pleural patients received no therapy. Additionally, approximately 60% of both patient groups received systemic therapy. Among pleural mesothelioma patients, receipt of therapy was less likely among older patients. Median survival was 9 months among the pleural patients and 18 months among the non-pleural patients. Receipt of either surgery or systemic therapy and particularly the combination of these two modalities was associated with better all-cause survival. Additionally, among pleural mesothelioma patients, younger age and lower socioeconomic status were found to be associated with better all-cause survival. Comorbidity score was not found to be associated with receipt of treatment nor was it independently associated with survival among pleural mesothelioma patients. CONCLUSION: These findings indicate the need for efforts to ensure equitable application of currently available therapies to all patients.

16 Article CTLA-4 blockade in mesothelioma: ineffective or reason for optimism? 2017

Thomas, Anish / Hassan, Raffit. ·Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. · Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: hassanr@mail.nih.gov. ·Lancet Oncol · Pubmed #28729153.

ABSTRACT: -- No abstract --

17 Article Clinical Features and Outcomes of Tunica Vaginalis Mesothelioma: A Case Series From the National Institutes of Health. 2017

An, Julie Y / Kim, David / Tanakchi, Sally / Semerjian, Alice M / Thomas, Anish / Boyle, Shawna L / Hassan, Raffit / Metwalli, Adam R. ·Urologic Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD. Electronic address: julie.an@mail.nih.gov. · School of Medicine and Health Sciences, The George Washington University, Washington, DC. · Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Department of Urology, The George Washington University, Washington, DC. · Thoracic and GI Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD. · Urologic Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD. Electronic address: shawna.boyle@nih.gov. · Urologic Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD. ·Clin Genitourin Cancer · Pubmed #28606736.

ABSTRACT: -- No abstract --

18 Article Malignant Mesothelioma Effusions Are Infiltrated by CD3 2016

Khanna, Swati / Thomas, Anish / Abate-Daga, Daniel / Zhang, Jingli / Morrow, Betsy / Steinberg, Seth M / Orlandi, Augusto / Ferroni, Patrizia / Schlom, Jeffrey / Guadagni, Fiorella / Hassan, Raffit. ·Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy. · San Raffaele Roma Open University and BioBIM (Interinstitutional Multidisciplinary BioBank), SR Research Center, IRCCS San Raffaele Pisana, Rome, Italy. · Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: hassanr@mail.nih.gov. ·J Thorac Oncol · Pubmed #27544053.

ABSTRACT: INTRODUCTION: The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. METHODS: Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells. Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, was evaluated in presence of autologous and allogeneic natural killer cells. RESULTS: Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1-positive, which was associated with slightly inferior overall survival compared to patients with PD-L1-negative tumors (median 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples testing positive, respectively. In nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced interferon-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab-mediated ADCC in the presence of autologous natural killer cells. CONCLUSIONS: Most pleural as well as peritoneal mesotheliomas express PD-L1. Malignant effusions in this disease are characterized by the presence of tumor cells and CD3-positive T cells that highly express PD-L1. In addition, mesothelioma tumor cells are susceptible to ADCC by the anti-PD-L1 antibody avelumab.

19 Article Distinctive clinical characteristics of malignant mesothelioma in young patients. 2015

Thomas, Anish / Chen, Yuanbin / Yu, Tinghui / Gill, Ammara / Prasad, Vinay. ·Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Office of Surveillance and Biometrics, Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA. · Meyer Orthopedic and Rehabilitation Hospital, Springfield, MO, USA. · Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. ·Oncotarget · Pubmed #26202904.

ABSTRACT: Although considered a disease of the elderly, a subset of patients with mesothelioma are young (<40 years). The goal of this study was to understand their characteristics and outcomes. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract mesothelioma cases (1990-2010). We modeled Kaplan-Meyer survival curves stratified by site of disease, and age of presentation. 2% (207 of 12345) of mesothelioma patients are young. Sex distribution is comparable among the young (51% males, 49% females); males predominated (78%, 22%) in the older cohort. Frequency of pleural and peritoneal mesothelioma are similar in the young (47%, 48% respectively); pleural disease predominated in the old (90%, 9%). Cancer-directed surgeries are more frequent in the young. Regardless of histologic subtype, young patients with pleural (11 vs. 8 months) and peritoneal (not reached vs. 10 months) mesothelioma had significantly improved overall survival. In multivariate analysis, younger age was an independent prognostic factor. Although rare, mesothelioma do occur in the young; their characteristics are distinct from those of older patients. Further studies are needed to understand the interplay between genetic susceptibility and mineral fiber carcinogenesis in the pathogenesis of mesothelioma in the young.

20 Article Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma. 2015

Kalra, Neetu / Zhang, Jingli / Thomas, Anish / Xi, Liqiang / Cheung, Mitchell / Talarchek, Jacqueline / Burkett, Sandra / Tsokos, Maria G / Chen, Yuanbin / Raffeld, Mark / Miettinen, Markku / Pastan, Ira / Testa, Joseph R / Hassan, Raffit. ·Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. neetu.kalra@gmail.com. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. zhangjingl@mail.nih.gov. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. anish.thomas@nih.gov. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. xil2@mail.nih.gov. · Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. mitchell.cheung@fccc.edu. · Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. jacqueline.talarchek@fccc.edu. · Molecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, 21702, USA. burketts@mail.nih.gov. · Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. mtsokos@bidmc.harvard.edu. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. ychenmd@gmail.com. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. mraff@mail.nih.gov. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. miettinenmm@mail.nih.gov. · Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. pastani@mail.nih.gov. · Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Joseph.Testa@fccc.edu. · Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. hassanr@mail.nih.gov. ·BMC Cancer · Pubmed #25952750.

ABSTRACT: BACKGROUND: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. METHODS: We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC. RESULTS: Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors. CONCLUSIONS: The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.