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Li F, Ahmad M, Qayyum F, Straus CM, MacMahon H, Kindler H, Armato SG
To evaluate differences in the tumor response classifications that result from clinical measurements and to compare these response classifications with overall survival for patients with malignant pleural mesothelioma (MPM).
One hundred thirty-one computed tomography (CT) scans were collected from 41 MPM patients enrolled in a clinical trial. Primary measurements had been acquired by clinical radiologists at a single center during routine clinical workflow, and the variability of these measurements was investigated. Retrospective measurements were acquired by a single radiologist in compliance with the study protocol based on the modified response evaluation criteria in solid tumors (RECIST). Differences in response classification categories by the two measurement approaches were evaluated and compared with patient survival.
Eleven (27%) of the 41 MPM patients had primary measurements at baseline or at follow-up that deviated from the guidelines of the clinical trial protocol. Among the 41 baseline scans, no statistical difference was observed in summed tumor measurements between primary and retrospective measurements. Response classification based on primary and retrospective measurements was different in 23 (26%) of the 90 follow-up scans, and best response was the different in seven (17%) of the 41 patients. Using Harrell’s C statistic as a measure of correlation, response based on retrospective measurements correlated better with survival (C = 0.62) than did response based on primary measurements (C = 0.57).
Strict compliance with the measurement protocol yields tumor response classifications that may differ from those obtained in clinical practice. Response based on retrospective measurements correlated better with survival than did response based on primary measurements.
• Response classifications could be different between clinical primary and retrospective measurements for malignant pleural mesothelioma. • Response classifications obtained by strict compliance with the trial-specific protocol correlated better with survival than the classifications based on primary measurements. • Quality assurance and radiologist training measures should be used to ensure the integrity of image-based tumor measurements in mesothelioma clinical trials.
Zha L, Kitamura Y, Kitamura T, Liu R, Shima M, Kurumatani N, Nakaya T, Goji J, Sobue T
Occupational asbestos exposure occurs in many workplaces and is a well-known cause of mesothelioma and lung cancer. However, the association between non-occupational asbestos exposure and those diseases is not clearly described. The aim of this study was to investigate cause-specific mortality among the residents of Amagasaki, a city in Japan with many asbestos factories, and evaluate the potential excess mortality due to established and suspected asbestos-related diseases. The study population consisted of 143,929 residents in Amagasaki City before 1975 until 2002, aged ≥40 years on January 1, 2002. Follow-up was conducted from 2002 to 2015. Standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated by sex, using the mortality rate of the Japanese population as reference. A total of 38,546 deaths (including 303 from mesothelioma and 2,683 from lung cancer) were observed. The SMRs in long-term residents’ cohort were as follows: death due to all causes, 1.12 (95% CI, 1.10-1.13) in men and 1.07 (95% CI, 1.06-1.09) in women; lung cancer, 1.28 (95% CI, 1.23-1.34) in men and 1.23 (95% CI, 1.14-1.32) in women; mesothelioma, 6.75 (95% CI, 5.83-7.78) in men and 14.99 (95% CI, 12.34-18.06) in women. These SMRs were significantly higher than expected. The increased SMR of mesothelioma suggests the impact of occupational asbestos exposure among men and non-occupational asbestos exposure among women in long-term residents’ cohort. Besides, high level of excess mortality from mesothelioma persists for a while, despite the mixture of crocidolite and chrysotile no longer being used for three or four decades.
International Journal of Molecular Sciences 2019 January 3 [Link]
Turini S, Bergandi L, Gazzano E, Prato M, Aldieri E
Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)-an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.
Background: Malignant mesothelioma (MM) is a rare but deadly malignancy with about 3,000 new cases being diagnosed each year in the US. Very few studies have been performed to analyze factors associated with mesothelioma survival, especially for peritoneal presentation. The overarching aim of this study is to examine survival of the cohort of patients with malignant mesothelioma enrolled in the National Mesothelioma Virtual Bank (NMVB). Methods: 888 cases of pleural and peritoneal mesothelioma cases were selected from the NMVB database, which houses over 1400 cases that were diagnosed from 1990 to 2017. Kaplan Meier’s method was performed for survival analysis. The association between prognostic factors and survival was estimated using Cox Hazard Regression method and using R software for analysis. Results: The median overall survival (OS) rate of all MM patients, including pleural and peritoneal mesothelioma cases is 15 months (14 months for pleural and 31 months for peritoneal). Significant prognostic factors associated with improved survival of malignant mesothelioma cases in this NMVB cohort were below the age of 45, female gender, epithelioid histological subtype, stage I, peritoneal occurrence, and had treatment that consisted of combining surgical therapy with chemotherapy. Combined surgical and chemotherapy treatment was associated with improved survival of 23 months in comparison to single line therapies. Conclusions: There has not been improvement in the overall survival for patients with malignant mesothelioma over many years with current available treatment options. Our findings show that combined surgical and chemotherapy treatment in peritoneal mesothelioma is associated with improved survival compared to local therapy alone.
Hui M, Uppin SG, Bhaskar K, Kumar NN, Paramjyothi GK
Malignant mesotheliomas are histologically heterogeneous neoplasms. Definite diagnosis requires a varied panel of immunohistochemical (IHC) markers to differentiate these from histological mimics. Only a few case series have been reported in the Indian literature where mesotheliomas have been analyzed on routine histology and IHC.
To evaluate the histological features of malignant mesothelioma and to elucidate the best possible immunomarker combination useful in different scenarios.
MATERIALS AND METHODS:
A total of 24 cases of malignant mesotheliomas of different sites encountered over a 6-year period were retrospectively analyzed with regard to their histomorphology and IHC findings.
The pleura was the most common site of involvement (16 cases) followed by peritoneum (5 cases) and pericardium (3 cases). Epithelioid mesothelioma was the most common histological type (15 cases, 62.5%) followed by sarcomatoid (5 cases, 20.84%), deciduoid (2 cases, 8.34%), and 1 case each of desmoplastic and biphasic mesothelioma. Among the mesothelial markers, WT1 was positive in 17 of 20 (85%) cases and calretinin was positive in 20 of 21 (95.23%) cases. D2-40 and CK5/6 were positive in all cases where they were studied. Adenocarcinoma markers TTF-1, napsin A, and CEA had very high negative predictive value in ruling out mesothelioma.
The differential diagnosis of mesotheliomas varies with histological type and tumor location. Judicious use of various combinations of IHC markers in different situation has been highlighted in this article.
The risk of mesothelioma has been shown to be associated with exposure to asbestos fibers. Most of the existing literature focuses on occupational exposure; however, non-occupational asbestos exposure has also been identified as an important risk factor.
To estimate the association between mesothelioma and non-occupational asbestos exposure, and evaluate control recruitment and exposure measurement methods.
A systematic literature review was conducted to identify case-control (CC) and cohort studies that examined the association between mesothelioma and non-occupational exposure to asbestos, including neighborhood, domestic, and household exposure. Meta-analysis was performed to estimate a summary relative risk estimate (SRRE) and 95% confidence interval using random-effects models. Subgroup analyses were also conducted by exposure type, gender, region, and fiber type.
Twenty CC and 7 cohort studies were selected. Controls in CC studies were selected from the general population (55%), hospital records (18%), cancer registry (23%) and a combination of population and hospital records (5%). Multiple methods were used to measure neighborhood exposure (e.g., linear distance and direction of residence from an asbestos factory), domestic (e.g., whether living with an asbestos worker) and household exposure (e.g., whether involved in asbestos-containing home improvement projects). Primary meta-analyses suggested a SRRE of mesothelioma of 5.33 (95%CI: 2.53, 11.23) from neighborhood exposure, 4.31 (95%CI, 2.58, 7.20) from domestic exposure, and 2.41 (95%CI, 1.30, 4.48) from household exposure with large I2 statistics ranging from 83-99%.
Non-occupational asbestos exposure is significantly associated with an elevated risk of mesothelioma. Funnel plots indicated a potential of publication bias. Some SRREs should be interpreted with cautions because of high between-studies heterogeneity.
Expert Review of Respiratory Medicine 2018 December 30 [Link]
Ye L, Ma S, Robinson BW, Creaney J
Immunotherapy has long been considered a potential therapy for malignant mesothelioma and is currently being pursued as such. Some of the early phase clinical trials involving immunomodulators have demonstrated encouraging results and numerous clinical trials are underway to further investigate this treatment approach in various treatment settings and larger patient cohorts. Areas covered: This review summarizes the current and emerging clinical evidence for checkpoint blockade and other immunotherapeutic strategies in mesothelioma. The mesothelioma tumor immune microenvironment and mutational landscape are also discussed, including their impact on treatment strategies. We also provide an evaluation of the current evidence for neoantigen targeted personalized immunotherapy. Expert opinion: Immune checkpoint inhibitors work by unleashing the host immune response against probable neoantigens. Despite impressive activity in a small subset of patients and the potential for prolonged responses, most patients experience treatment failure. Neoantigen vaccines provide a potential complementary therapeutic strategy by increasing the immunogenic antigen load, which can lead to an increased tumor specific immune response. Further research is needed explore this treatment option in mesothelioma and technological advances are required to translate this concept into clinical practice.
Primary pericardial mesothelioma (PPM) is a rare cancer for which there is no consensus on treatment. We evaluated and summarized a large contemporary population of published PPM cases to characterize risk factors, treatment patterns, and clinical outcomes. Using Ovid and PubMed, literature published from 2000 through 2016 was searched using the terms “primary pericardial mesothelioma,” “pericardial mesothelioma,” and “malignant pericardial mesothelioma.” We identified 6 case series and 84 case reports for a total of 103 PPM cases published from 2000 through 2016. The median age at diagnosis was 55 years, and the median overall survival was 6 months. In univariate analyses of clinical characteristics including gender, asbestos exposure, tobacco use, prior radiation exposure, histologic subtype, and metastasis and/or mediastinal spread, only the presence of metastasis and/or mediastinal spread was a significant predictor of decreased survival (P = .015). Surgery did not provide a statistically significant survival benefit (P = .12). A survival benefit was noted in those who received chemotherapy (median survival, 13 months vs. 0.5 months, P = .002), specifically chemotherapy with a platinum agent with or without pemetrexed. In multivariate analysis, only the receipt of chemotherapy was associated with improved survival. PPM remains a rare and poorly understood malignancy with unclear etiology and a poor prognosis. In this retrospective systematic review, a survival benefit was seen in patients who received chemotherapy.
Sciarrillo R1, Wojtuszkiewicz A2, El Hassouni B, Funel N, Gandellini P, Lagerweij T, Buonamici S, Blijlevens M, Zeeuw van der Laan EA, Zaffaroni N, Deraco M, Kusamura S, Würdinger T, Peters GJ, Molthoff CFM, Jansen G, Kaspers GJL, Cloos J, Giovannetti E
Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.
Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.
Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.
SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.
Journal of Clinical Pharmacy and Therapeutics 2018 December 2018 [Link]
Mense ES, Smit AAJ, Crul M, Franssen EJF
WHAT IS KNOWN AND OBJECTIVE:
The use of cisplatin in the treatment of lung carcinoma is limited by nephrotoxicity. The aim of this study was to determine whether the incidence of nephrotoxicity in patients with lung carcinoma is affected by the infusion rate of cisplatin (rapid infusion of cisplatin in 1 hour compared to regular infusion in 3 hours).
This observational, retrospective study was performed on patients diagnosed with non-small-cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC) or mesothelioma receiving a cisplatin-containing chemotherapy regimen. Patients were divided into two cohorts (infusion of cisplatin in 1 hour vs 3 hours) based on the starting date of the chemotherapy regimen. The primary objectives were the difference in renal function after three cycles of chemotherapy and the incidence of nephrotoxicity. To assess nephrotoxicity, both the incidence of acute kidney injury (AKI) grade 1 and the maximum decrease in estimated glomerular filtration rate (eGFR) were determined.
A total of 230 lung carcinoma patients with a cisplatin-containing chemotherapy regimen were included. Baseline characteristics were similar for the rapid and regular infusion cohorts, except for type of lung carcinoma, chemotherapy regimen and prevalence of hypertension. There was no significant difference in renal function between rapid infusion of cisplatin and regular infusion of cisplatin (eGFR 86.1 mL/min [71.0-96.3] vs 87.9 mL/min [71.6-97.3]; P = 0.938). The incidence of AKI grade 1 was not significantly different between rapid and regular infusion of cisplatin (29.3% vs 29.8%; P = 0.932). The maximum decrease in eGFR was 14.8 mL/min in the rapid infusion cohort and 17.7 mL/min in the regular infusion cohort (P = 0.364).
WHAT IS NEW AND CONCLUSION:
The incidence of nephrotoxicity after repeated infusion of cisplatin was not affected by the infusion rate of cisplatin. Therefore, a 1-hour infusion of cisplatin is a safe and feasible method, which may potentially shorten duration of hospital admittance and enable treating patients in the outpatient setting.