Video-assisted biopsy and talc pleurodesis for malignant pleural mesothelioma.

Malignant pleural mesothelioma is a disease of the pleural cavity that is strongly associated with asbestos exposure. In most cases it carries a poor prognosis. Patients often present with respiratory symptoms, caused by pleural effusion. Treatment, preferably in a multimodal setting, cannot provide cure, but can prolong survival and improve quality of life in selected cases.  Prior to eventual cytoreductive surgery, surgical intervention can provide histopathological proof of disease, and symptoms can be controlled with talc pleurodesis.  We present the case of a 67-year-old patient with malignant pleural mesothelioma who underwent video-assisted thoracoscopic biopsy and talc pleurodesis, and demonstrate our technique with a video tutorial showing how we performed the procedure.

Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma.

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.

Prognostic influence of tumor microenvironment after hypofractionated radiation and surgery for mesothelioma.

OBJECTIVE: Cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation, but programmed cell death pathways (programmed cell death 1 and programmed cell death ligand 1 [PD-1/PD-L1]) may provide a mechanism of tumor immune escape. We therefore reviewed the influence of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma (MPM). METHODS: Sixty-nine consecutive patients undergoing the protocol of Surgery for Mesothelioma after Radiation Therapy (SMART) between November 2008 and February 2016 were analyzed for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Comparison was made with a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n = 14) and no induction (n = 2) between March 2005 and October 2008. PD-L1 expression on tumor cells ≥1% was considered positive. CD8+ TILs and PD-1 expression were scored as a percentage of positive cells. RESULTS: PD-L1 was negative in 75% of MPM after completion of SMART. CD8+ TILs ranged between 0.24% and 8.47% (median 2%). CD8+ TILs ≥2% was associated with significantly better survival in epithelioid MPM (median survival 3.7 years vs 2.3 years in CD8+ TILs <2%; P = .02). PD-L1 positivity was associated with worse survival in biphasic MPM (median survival, 0.4 years vs 1.5 years in biphasic PD-L1 negative tumors; P = .07) after SMART. Multivariate analysis demonstrated that epithelioid MPM, nodal disease, and CD8+ TILs were independent predictors of survival after SMART. CONCLUSIONS: The influence of tumor microenvironment on survival differs between epithelioid and nonepithelioid MPM. CD8+ TILs is an independent factor associated with better survival in epithelioid MPM treated with SMART.

Quantitative relationships of exposure to chrysotile asbestos and mesothelioma mortality.

BACKGROUND: While asbestos has long been known to cause mesothelioma, quantitative exposure-response data on the relation of mesothelioma risk and exposure to chrysotile asbestos are sparse. METHODS: Quantitative relationships of mortality from mesothelioma and pleural cancer were investigated in an established cohort of 5397 asbestos textile manufacturing workers in North Carolina, USA. Eligible workers were those employed between 1950 and 1973 with mortality follow-up through 2003. Individual exposure to chrysotile fibres was estimated on the basis of 3420 air samples covering the entire study period linked to work history records. Exposure coefficients adjusted for age, race, and time-related covariates were estimated by Poisson regression. RESULTS: Positive, statistically significant associations were observed between mortality from all pleural cancer (including mesothelioma) and time since first exposure (TSFE) to asbestos (rate ratio [RR], 1.19; 95% confidence interval [CI], 1.06-1.34 per year), duration of exposure, and cumulative asbestos fibre exposure (RR, 1.15; 95% CI, 1.04-1.28 per 100 f-years/mL; 10-year lag). Analyses of the shape of exposure-response functions suggested a linear relationship with TSFE and a less-than-linear relationship with cumulative exposure. Restricting the analysis to years when mesothelioma was coded as a unique cause of death yielded stronger but less precise associations. CONCLUSIONS: These observations support with quantitative data the conclusion that chrysotile causes mesothelioma and encourage exposure-response analyses of mesothelioma in other cohorts exposed to chrysotile.

Body composition and nutritional status in malignant pleural mesothelioma: implications for activity levels and quality of life.

BACKGROUND/OBJECTIVES: Malignant pleural mesothelioma (MPM) is an incurable cancer and optimizing daily physical activity and quality of life are key goals of patient management. Little is known about the prevalence of pre-sarcopenia and malnutrition in MPM or their associations with patient outcomes. This study aimed to determine the prevalence of pre-sarcopenia and malnutrition in MPM and investigate if activity levels and quality of life differed according to body composition and nutritional status. SUBJECTS/METHODS: Patients with a diagnosis of MPM were recruited. Pre-sarcopenia was defined as low appendicular skeletal muscle mass (≤ 7.26 kg/m2 for men and ≤ 5.45 kg/m2 for women), measured by dual energy X-ray absorptiometry. Malnutrition was defined as a rating of B or C on the Patient-Generated Subjective Global Assessment. Outcome measures included objective activity levels (Actigraph GT3X) and health-related quality of life (HRQoL; Functional Assessment of Cancer Therapy General). RESULTS: Sixty-one people participated (79% male, median age 69 [IQR 62-74] years and median BMI 25.8 [IQR 24.3-28.4] kg/m2). Fifty-four percent were pre-sarcopenic and 38% were malnourished. Percent of time spent in light activity/day was lower in participants with pre-sarcopenia compared with non-sarcopenic participants (median 25.4 [IQR 19.8-32.1]% vs. 32.3 [27.1-35.6]%; p = 0.008). Participants with malnutrition had poorer HRQoL than well-nourished participants (mean 69.0 (16.3) vs. 84.4 (13.3); p < 0.001). CONCLUSION: Participants with MPM had high rates of pre-sarcopenia and malnutrition. Pre-sarcopenia was associated with poorer activity levels, whilst malnutrition was associated with poorer quality of life. Interventions that aim to address reduced muscle mass and weight loss, should be tested in MPM to assess their impact on patient outcomes.

Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification.

INTRODUCTION: The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group. METHODS: Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models. RESULTS: Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015). CONCLUSIONS: Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.

Real-life feasibility of home-based pulmonary rehabilitation in chemotherapy-treated patients with thoracic cancers: a pilot study.

BACKGROUND: Patients with advanced lung cancer (LC) or malignant pleural mesothelioma (MPM) exhibit limitation of exercise capacities and alteration of quality of life (QoL) induced by cancer and its treatment. Few studies assessed pulmonary rehabilitation (PR) in these chemotherapy-treated patients, and none evaluated a home-based PR program. METHODS: In this prospective uncontrolled observational pilot study, patients treated by chemotherapy for LC or MPM were screened for a home-based PR program combining exercise training with global cares including therapeutic education and psychosocial management. Feasibility and safety were evaluated by attendance and adherence to PR program. Various exercise tolerance tests, including 6-min walk test (6MWT) and 6-min stepper test (6MST), were performed before and after PR associated with, QoL and psychological assessment (VSRQ and HAD, respectively). RESULTS: 243 patients were considered eligible but only 71 (60.6 ± 8.8 years) started a PR and 47 completed the program. Refusals to participate were mostly related to lack of motivation whereas withdrawals to PR were related to cancer-related medical issues. No adverse event related to PR was observed. Baseline 6MWT distance was associated with performance status (r = - 0.45, p = 0.001) and mMRC dyspnea scale (r = - 0.49, p < 0.001) but not with lung cancer stage. Post-PR reassessment showed 6MWT stability and 6MST improvement in patients who completed the program. Daily physical activity (p = 0.007) and anxiety (p = 0.02) scores were significantly improved. CONCLUSIONS: Home-based PR was feasible and safe in patients with advanced LC or MPM. Exercise capacities stability in patients who completed the PR program suggests that PR might be beneficial. Further studies are warranted to confirm and to improve the potential value of PR in these patients.

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.

Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.

[Update on epidemiology, pathophysiology, diagnosis and treatment of malignant pleural mesothelioma]. / Actualización sobre la epidemiología, fisiopatología, diagnóstico y tratamiento del mesotelioma maligno pleural.

Malignant pleural mesothelioma is an occupational tumor caused by asbestos exposure. In Mexico, as asbestos usage is not prohibited, an increase in the number of cases is expected. Asbestos exposure is ubiquitous due to the great amount of products in which it is present. Its carcinogenicity is caused as the inhaled asbestos fibers cannot be eliminated by macrophages and, thus, they travel to the pleura through lymphatic pathways, producing a persistent inflammatory response. Diagnosis approach includes occupational history, along with clinical signs and symptoms, and paraclinical studies, such as pleural fluid cytology, chest x-rays, computed tomography, magnetic resonance imaging, and biopsy with immunohistochemistry. The main differential diagnosis is lung adenocarcinoma. Regarding the treatment of this tumor, it mainly comprises palliative care, even though chemotherapy, radiotherapy, and, in selected cases, surgical treatments have been used. There is an urgent need for general physicians and specialists to identify asbestos exposure, in order to make a timely diagnosis. Research is necessary to develop screening and prompt diagnostic tools, along with an epidemiological surveillance program for the workers and the general population exposed to asbestos.

El mesotelioma maligno pleural es un tumor ocupacional ocasionado por la exposición a cualquier tipo de fibra de asbesto. Y dado que en México el uso del asbesto no está prohibido, se espera que la incidencia de este tumor siga aumentando. La exposición al asbesto es ubicua, debido a la gran diversidad de productos en los que se encuentra. Su carcinogenicidad está dada porque las fibras de asbesto inhaladas no pueden ser eliminadas por los macrófagos y viajan hacia la pleura por vía linfática, donde producen una reacción inflamatoria persistente. Para su diagnóstico se precisa de una historia clínica laboral, además de que hay que orientarse con base en el cuadro clínico y los estudios paraclínicos, como la citología de líquido pleural, radiografía de tórax, tomografía axial computarizada, resonancia magnética y biopsia con inmunohistoquímica. El principal diagnóstico diferencial es el adenocarcinoma de pulmón. El tratamiento es principalmente paliativo, aunque se ha utilizado quimioterapia, radioterapia y, en seleccionados casos, cirugía. Para lograr un diagnóstico oportuno y certero es de vital importancia identificar las exposiciones al asbesto. Por otra parte, es necesaria la investigación para desarrollar pruebas de diagnóstico temprano y tamizaje, además de un programa de vigilancia epidemiológica para los trabajadores y la población general expuesta al asbesto.

Symptom burden in mesothelioma patients admitted to home palliative care.

CONTEXT: Mesothelioma is a very aggressive cancer that is brought on by asbestos exposure. Because there is a long latency period between exposure to asbestos and symptoms of disease, most patients with mesothelioma present with advanced disease and survive an average of 8-12 months. Thus, best supportive care should be considered critical to optimally manage these patients. AIM: The aim of this study was to examine the epidemiological characteristics and symptom burden of mesothelioma patients when admitted to home palliative care. METHODS: The charts of a consecutive sample of patients admitted to the home palliative care program with a diagnosis of mesothelioma in an endemic industrialized area were reviewed. The estimated survival time was about two months from admission. Epidemiological characteristics were collected. Karnofsky status, characteristics of pain and analgesic treatment at time of admission were recorded. ESAS (Edmonton Symptom Assessment System) and other clinical problems reported in the charts at admission time were also recorded. RESULTS: Of the 674 charts reviewed, 56 patients (8.3%) had a diagnosis of mesothelioma. About three quarters of those had pain, with 18 and 2 patients with moderate and severe pain, respectively, despite receiving medium to high doses of opioids. The principal pain site was the chest. Pain was significantly associated with opioid consumption (p < .0005) and dyspnea (p = .049). Symptom burden was relevant, with a global ESAS of about 40. Pain, weakness, poor appetite, poor well-being, and dyspnea were the most frequent symptoms with the highest intensity; cough and pleural effusion were more frequently present as clinical problems. CONCLUSION: This study shows that mesothelioma is a devastating cancer with a relevant symptom burden, and that patients were referred to palliative care late in the course of their disease, suggesting that earlier integration of palliative care should be considered to relieve suffering in all disease stages - not only at the end of life.

The role of the HGF/Met axis in mesothelioma.

Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.

UK asbestos imports and mortality due to idiopathic pulmonary fibrosis.

BACKGROUND: Previous studies have demonstrated that the rising mortality due to mesothelioma and asbestosis can be predicted from historic asbestos usage. Mortality due to idiopathic pulmonary fibrosis (IPF) is also rising, without any apparent explanation. AIMS: To compare mortality due to these conditions and examine the relationship between mortality and national asbestos imports. METHODS: Mortality data for IPF and asbestosis in England and Wales were available from the Office for National Statistics. Data for mesothelioma deaths in England and Wales and historic UK asbestos import data were available from the Health & Safety Executive. The numbers of annual deaths due to each condition were plotted separately by gender, against UK asbestos imports 48 years earlier. Linear regression models were constructed. RESULTS: For mesothelioma and IPF, there was a significant linear relationship between the number of male and female deaths each year and historic UK asbestos imports. For asbestosis mortality, a similar relationship was found for male but not female deaths. The annual numbers of deaths due to asbestosis in both sexes were lower than for IPF and mesothelioma. CONCLUSIONS: The strength of the association between IPF mortality and historic asbestos imports was similar to that seen in an established asbestos-related disease, i.e. mesothelioma. This finding could in part be explained by diagnostic difficulties in separating asbestosis from IPF and highlights the need for a more accurate method of assessing lifetime occupational asbestos exposure.

Which is the Role of Pneumonectomy in the Era of Parenchymal-Sparing Procedures? Early/Long-Term Survival and Functional Results of a Single-Center Experience.

AIM: Despite the increasing adoption of parenchymal-sparing procedures, pneumonectomy is still necessary in several pleural and pulmonary (benign or malignant) diseases. We reviewed clinical data of a large cohort of patients treated by pneumonectomy with the aim of better define its impact on early and long-term results. METHODS: Clinical and pathological characteristics of all consecutive patients treated by pneumonectomy between January 2005 and May 2012 were retrospectively reviewed. Thirty- and 90-day mortality, as well as long-term survival was assessed. Factors associated to long-term survival were analyzed by univariate and multivariate analyses. Evaluation of quality of life was carried out by a standard questionnaire (SF-12) administrated by phone to patients surviving beyond 1 year. RESULTS: A total of 398 patients (293 men; mean age 61 ± 10.9 years) were operated on in the study period. Indication was malignancy in 380 patients (350 primary lung cancers). Thirty-day mortality was 9 % (right: 12.6 % vs. left: 6.3 %, p = 0.013), significantly correlating with age (p = 0.021), comorbidities (p = 0.034), PS > 1 (p = 0.018), preoperative dyspnea (p = 0.0013), and FEV1 (p = 0.0071). Overall 1-, 3-, 5-, and 7-year survival rates were 76.6, 46.6, 34.4, and 29.2 %. In case of primary lung cancer, these figures were 76.8, 46.4, 34.5, and 29.7 %. At univariate analysis, a less favorable survival was associated to PS > 1 (p = 0.0078), right side (p = 0.044), occurrence of postoperative complications (p = 0.00079), and T3-4 status (p = 0.013). At multivariate analysis, PS > 1, right side, and occurrence of postoperative complications were identified as independent worse prognostic factors. SF12 physical score was 39.1 ± 9.0 and was correlated to the presence of preoperative symptoms (p = 0.013). Mental score was 50.68 ± 9.63 and was correlated to preoperative FEV1/FVC ratio (p = 0.023) and side of disease (p = 0.023). CONCLUSION: In current practice, pneumonectomy is still performed for malignancy, sometimes after induction treatment. High postoperative morbidity and mortality are observed; however, at a farer interval time point, long-term survival with preserved quality of life can be observed.

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies.

Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.