Treatment Of Malignant Pleural Mesothelioma Research Articles

New Developments in Malignant Pleural Mesothelioma Treatment

New Developments in Malignant Pleural Mesothelioma Treatment

Nivolumab in pre-treated malignant pleural mesothelioma: real-world data from the Dutch expanded access program.

BackgroundRandomized phase III trials are ongoing to investigate the efficacy of nivolumab in malignant pleural mesothelioma (MPM), but real-world data are still scarce. In this real-world study, we investigated the clinical outcomes of nivolumab treatment in pre-treated MPM patients.MethodsData from 107 nivolumab treated MPM patients within the Dutch expanded access program were retrospectively analyzed. Treatment was independent of programmed death ligand 1 (PD-L1) expression on tumor samples. Univariable and multivariable analyses were performed to evaluate the relationship between clinically important factors, baseline peripheral blood parameters and survival. The landmark method was used to compare the outcome of patients according to their radiological response.ResultsIn the full cohort, the median progression-free survival (mPFS) was 2.3 months (95% CI: 1.6–2.9) and the median overall survival (mOS) was 6.7 months (95% CI: 6.2–10.0). After 12 weeks, the disease control rate (DCR) was 37% and the objective response rate (ORR) was 10%. PD-L1 status was determined in 33 patients (30%) and PD-L1 positivity (≥1%) was associated with an improved ORR (36% vs. 9%, P value 0.05), but not with PFS or OS. Low albumin was associated with worse OS (P value 0.002). Median OS was significantly longer for patients who had partial response to treatment (P value 0.0002).ConclusionsIn this real-world analysis, ORR and mOS were lower compared to those obtained in phase II trials. However, exceptional survival rates were observed in patients who had a radiological response. Although we cannot determine whether prognostic or predictive, PD-L1 expression and albumin were associated with greater response rate and may represent useful biomarkers for nivolumab treatment in MPM.

Extracellular Vesicles-Based Drug Delivery Systems: A New Challenge and the Exemplum of Malignant Pleural Mesothelioma.

Research for the most selective drug delivery to tumors represents a fascinating key target in science. Alongside the artificial delivery systems identified in the last decades (e.g., liposomes), a family of natural extracellular vesicles (EVs) has gained increasing focus for their potential use in delivering anticancer compounds. EVs are released by all cell types to mediate cell-to-cell communication both at the paracrine and the systemic levels, suggesting a role for them as an ideal nano-delivery system. Malignant pleural mesothelioma (MPM) stands out among currently untreatable tumors, also due to the difficulties in achieving an early diagnosis. Thus, early diagnosis and treatment of MPM are both unmet clinical needs. This review looks at indirect and direct evidence that EVs may represent both a new tool for allowing an early diagnosis of MPM and a potential new delivery system for more efficient therapeutic strategies. Since MPM is a relatively rare malignant tumor and preclinical MPM models developed to date are very few and not reliable, this review will report data obtained in other tumor types, suggesting the potential use of EVs in mesothelioma patients as well.

Maintaining Equipoise With Maintenance Therapy in Mesothelioma

Dudek et al 1 Dudek A.Z. Wang X. Gu L. et al. Randomized study of maintenance pemetrexed versus observation for treatment of malignant pleural mesothelioma: CALGB 30901. Clin Lung Cancer. 2020; (https://doi.org/10.1016/j.cllc.2020.06.025, accessed August 5, 2020) Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar have presented the results of the “Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB [Cancer and Leukemia Group B] 30901” in the current issue of Clinical Lung Cancer. The goal of the study was to determine whether continuation maintenance therapy with pemetrexed would improve the progression-free survival (PFS) of patients with malignant pleural mesothelioma whose tumors had not progressed during frontline treatment with pemetrexed and a platinum agent. The study was closed because of slow accrual, likely owing to the widespread acceptance of maintenance pemetrexed for mesothelioma in the United States and competing clinical trials. Of the 49 patients who had been randomized to pemetrexed or observation and analyzed, no improvement was seen in PFS or overall survival (OS).

Progress in the Understanding of the Immune Microenvironment and Immunotherapy in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a remarkably aggressive thoracic malignancy with a limited survival of only 5-12 months. However, MPM still remains unresponsive to conventional standards of treatment, including pleurectomy and decortication, extrapleural pneumonectomy for resectable disease with or without chemotherapy, and/or radiation therapy. The mechanism of carcinogenesis has not been fully elucidated, although approximately 80% of cases can still be linked to asbestos exposure. The tumor immune microenvironment (TME) has been proven to play an important role in MPM pathogenesis and treatment outcomes. Several molecular pathways have been implicated in the MPM tumor microenvironment, such as angiogenesis, apoptosis, cell cycle regulation, and stromal processes. Immunotherapy has already shown promising results in other thoracic solid tumors, such as non-small-cell lung cancer (NSCLC). However, immunotherapy has shown less convincing results in MPM than in melanoma and NSCLC. A multicenter, randomized trial (DETERMINE) proved that immune checkpoint inhibition using tremelimumab, an anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, failed to improve median overall survival. Therefore, it is important to explore the relationship between the characteristics of the tumor microenvironment and immunotherapy. Here, we review the heterogeneity of the TME and the progress in the understanding of the immune microenvironment and immunotherapy in MPM to explore the mechanisms of resistance to immunotherapy.

FDG PET versus CT radiomics to predict outcome in malignant pleural mesothelioma patients

BackgroundCareful selection of malignant pleural mesothelioma (MPM) patients for curative treatment is of highest importance, as the multimodal treatment regimen is challenging for patients and harbors a high risk of substantial toxicity. Radiomics—a quantitative method for image analysis—has shown its prognostic ability in different tumor entities and could therefore play an important role in optimizing patient selection for radical cancer treatment. So far, radiomics as a prognostic tool in MPM was not investigated.Materials and methodsThis study is based on 72 MPM patients treated with surgery in a curative intent at our institution between 2009 and 2017. Pre-treatment Fluorine-18 fluorodeoxyglucose (FDG) PET and CT scans were used for radiomics outcome modeling. After extraction of 1404 CT and 1410 FDG PET features from each image, a preselection by principal component analysis was performed to include only robust, non-redundant features for the cox regression to predict the progression-free survival (PFS) and the overall survival (OS). Results were validated on a separate cohort. Additionally, SUVmax and SUVmean, and volume were tested for their prognostic ability for PFS and OS.ResultsFor the PFS a concordance index (c-index) of 0.67 (95% CI 0.52–0.82) and 0.66 (95% CI 0.57–0.78) for the training cohort (n = 36) and internal validation cohort (n = 36), respectively, were obtained for the PET radiomics model. The PFS advantage of the low-risk group translated also into an OS advantage. On CT images, no radiomics model could be trained. SUV max and SUV mean were also not prognostic in terms of PFS and OS.ConclusionWe were able to build a successful FDG PET radiomics model for the prediction of PFS in MPM. Radiomics could serve as a tool to aid clinical decision support systems for treatment of MPM in future.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos‐related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin‐1 receptor (IL‐1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro‐inflammatory cytokine IL‐1β and the IL‐1R in MPM cells. Stimulation by IL‐1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor‐associated macrophages (TAMs) as the major source of IL‐1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos‐activated inflammasome in TAMs induced the production of IL‐1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL‐1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL‐1β/IL‐1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Volumetric PET Response Assessment Outperforms Conventional Criteria in Patients Receiving High-Dose Pembrolizumab for Malignant Mesothelioma.

Fixed-dose pembrolizumab (200 mg absolute, day 1, every 3 wk) for the treatment of malignant pleural mesothelioma did not result in survival benefit in the phase 3 PROMISE-meso trial compared with second-line chemotherapy. Because of lack of validated imaging response criteria, responder subgroups with potential survival benefit have not yet been identified. Here, we administered high-dose pembrolizumab (10 mg/kg, day 1, every 2 wk) considering the KEYNOTE-028 trial and assessed the prognostic value of PET metabolic response in patients with chemotherapy-resistant malignant mesothelioma of the pleura or peritoneum. Methods: Data from 27 patients with baseline and follow-up 18F-FDG PET/CT imaging were retrospectively analyzed. RECIST, version 1.1; modified RECIST; and PERCIST using both tumor lesion metabolic activity in a 1 cm3 spheric region of interest of up to 5 target lesions (PERCISTSULpeak) and metabolic tumor volume PERCIST (PERCISTMTV) were applied separately to categorize responders in CT and PET imaging studies. Progression-free survival (PFS) and overall survival (OS) were compared between responders and nonresponders using Kaplan-Meier and log-rank analyses. Programmed cell death protein 1 ligand expression status was assessed, and its association with outcome was investigated. Results: Twenty-seven patients had 18F-FDG PET/CT imaging at baseline and after at least 4 cycles pembrolizumab. Median PFS and OS were 3.4 and 15.1 mo, respectively. Response rates were 7%, 7%, 30%, and 30% based on RECIST, modified RECIST, PERCISTSULpeak, and PERCISTMTV response criteria, respectively. Response according to PERCISTMTV predicted prolonged OS or PFS (P < 0.01), whereas all other imaging criteria and programmed cell death protein 1 ligand expression did not. Conclusion:18F-FDG PET metabolic volume response predicts survival in patients with malignant mesothelioma receiving high-dose pembrolizumab. These results should prompt inclusion of PET response assessment in future phase 3 clinical trials.

Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a treatment recalcitrant tumor with a poor overall survival (OS). Current approved treatment consists of first line chemotherapy that only modestly increases OS, illustrating the desperate need for other treatment options in MPM. Unfortunately, clinical studies that investigate the effectivity of checkpoint inhibitor (CI) treatment failed to improve clinical outcome over current applied therapies. In general, MPM is characterized as an immunological cold tumor with low T-cell infiltration, which could explain the disappointing results of clinical trials investigating CI treatment in MPM. Currently, many other therapeutic approaches, such as cellular therapies and cancer vaccines are investigated that could induce a tumor-specific immune response and increase of the number of tumor-infiltrating lymphocytes. In this review we will discuss these novel treatment approaches for MPM.

Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma

ObjectivesCytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury. MethodsWe conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 μmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days. ResultsAcute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models. ConclusionsAcute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.

Efficacy and safety of nivolumab for malignant mesothelioma in the real world.

9052 Background: Until recently, the standard treatment for advanced malignant pleural mesothelioma (MPM) was only cisplatin plus pemetrexed. Nivolumab, an anti-programmed death-1 monoclonal antibody, shows efficacy against pretreated MPM and has been approved in Japan, but the data regarding the efficacy and safety of nivolumab in MPM are limited to those from a small number of patients of the MERIT study. Therefore, it is important to accumulate real-world data on the efficacy and safety of nivolumab for MPM. Methods: We retrospectively analyzed all patients with MPM who received nivolumab at Hyogo College of Medicine Hospital from August 2018 to December 2018. Results: A total of 77 patients (61 males and 16 females) were included. There were 62, 10, and 5 patients with performance statuses of 0–1, 2, and 3, respectively. There were 63, 8, and 6 patients with epithelioid, sarcomatoid, and bi-phasic histologies, respectively. Nivolumab was administered as second-, third-, and ≥fourth-line treatment to 48, 15, and 11 patients, respectively. In 66 patients who were examined for efficacy, the response rate (RR) was 24.2% and the disease control rate (DCR) was 63.6%. By the histology type, the RR and DCR were 15.1% and 62.3% for the epithelioid type, 62.5% and 87.5% for the sarcomatoid type, and 20.0% and 40.0% for the bi-phasic type, respectively. The median progression-free survival (mPFS) was 4.1 months and the median overall survival (mOS) was 13.3 months. Analyzing the efficacy based on the neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood, the RRswere 14.7% in the NLR≥3.5 group and 25.8% in the NLR &lt; 3.5 group. The mPFS and mOS in the NLR≥3.5 group were 3.1 months and 11.4 months, respectively,whereas those in the NLR &lt; 3.5 group were 5.6 months and not reached, respectively. There were no significant differences in the RR, PFS, and OS between the groups, but a trend of better RRs and longer survivals wasobserved in the NLR &lt; 3.5 group than in the NLR≥3.5 group. Regarding adverse events, fatigue (grades 1−2) was observed in 8, hypothyroidism (grade 1–2) in 11, renal dysfunction (grade 1–3) in 6, loss of appetite (grade 1–2) in 2, pneumonitis (grade 3) in 1, rash (grade 1) in 2, and hypopituitarism (grade 3) in 1 patient(s). Conclusions: This retrospective study revealed the effectiveness and safety of nivolumab for MPM in the real-world setting.Nivolumab can be used as a standard second-line treatment for MPM. Furthermore, it has been suggested that the NLR may be a predictive marker of the effect of nivolumab for MPM, as pointed out in other carcinomas.

Statin treatment improves response to anti-PD1 agents in patients with malignant pleural mesothelioma and non-small cell lung cancer.

3074 Background: After progression to standard chemotherapy, only a small proportion of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) patients (pts) benefit from anti-programmed cell death (PD-1) treatment. Combination strategies might improve response. In pre-clinical models, statins showed vaccine adjuvant activities and synergized with anti-PD1 agents. In this multi-center study, we evaluated the impact of baseline statin treatment in MPM and NSCLC pts. Methods: We separately examined MPM and NSCLC pts treated with anti-PD1 monotherapy after progression to standard chemotherapy at two European academic institutions. As control cohort, MPM pts treated with first-line chemotherapy were also examined. Pts receiving statins at start of treatment were compared with those who did not. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 287 patients were examined. Twenty-seven out of 80 (34%) MPM and 36 out of 130 (20%) NSCLC pts received statins at start of anti-PD1 treatment. The most common statins were simvastatin, atorvastatin and rosuvastatin. In MPM pts, statin use was associated with improved ORR (22% versus 5%, P = 0.05), longer PFS (median 6.7 versus 2.4 months, hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.23–0.77, P &lt; 0.01), and longer OS (median not reached versus 6.0 months, HR 0.43, 95% CI 0.21–0.85, P = 0.01). In NSCLC pts, statin use was associated with improved ORR (40% versus 22%, P = 0.04), longer PFS (median 7.8 versus 3.6 months, HR 0.59, 95% CI 0.37–0.97.2, P = 0.03) but similar OS (median 13.1 versus 10.1 months, HR 0.79, 95% CI 0.49–1.28, P = 0.30). At multivariate analyses, after adjusting for ECOG performance status (PS) and histological subtype, the impact of statins remained significant for ORR, PFS and OS in MPM and for PFS in NSCLC. Conversely, no association between statin use and outcomes was found in 77 MPM pts treated with first-line chemotherapy. Conclusions: This study shows that statin use at start of anti-PD1 treatment improves response to anti-PD1 agents in MPM and NSCLC pts who progressed to standard chemotherapy in routine clinical practice. This association could not be found in MPM pts treated with first-line chemotherapy, thus suggesting a synergy between statins and anti-PD1 agents. Prospective studies are needed to confirm whether the combination of statin and anti-PD1 therapy could improve outcome in pts with poorly immunogenic thoracic malignancies.

Metformin-loaded chitosomes for treatment of malignant pleural mesothelioma – A rare thoracic cancer

The purpose of this study was to design and evaluate chitosan dispersed lipid vesicles (chitosomes) as potential delivery carriers for repurposing metformin (Met) against malignant pleural mesothelioma. Chitosomes were prepared by directly hydrating the thin lipid film using chitosan solution as hydration medium, instead of using it as a coating agent. Developed chitosomes demonstrated spherical morphology, positive surface charge (~30 mV) and ~60% encapsulation efficiency. The calorimetric studies and X-ray diffraction pattern of Met-loaded chitosomes confirmed the successful encapsulation of Met inside the chitosome vesicles. Optimized chitosome formulation showed ~70% drug release in 72 h, displaying prolonged and controlled release of drug. Results demonstrated that Met encapsulated chitosomes possessed enhanced cellular internalization and improved cytotoxic potential. Our findings also supported inhibitory activity of chitosomes against metastatic property of pleural mesothelioma cells. The in-vitro tumor simulation studies further established anti-tumor activity of Met encapsulated chitosomes as supported by reduction in tumor volume and presence of minimal viable cells in tumor mass. The obtained results establish the effectiveness of chitosomes as delivery carrier for Met as treatment alternative for malignant pleural mesothelioma.

Phase II study of amrubicin for previously treated patients with malignant pleural mesothelioma.

e21095 Background: Malignant pleural mesothelioma (MPM) is a rare disease with few effective treatments and poor prognosis. Although pemetrexed (PEM) and cisplatin for the first-line treatment, and nivolumab for the second-line are considered as the standard treatment for patients with unresectable disease, these effects are still limited. There are no other effective agents for second-line treatment, although PEM-based regimens, vinorelbine, gemcitabine are recommended by some guidelines. Novel therapeutic strategies for the treatment of MPM are urgently required. Amrubicin (AMR) is a chemically synthesized anthracycline-based anticancer drug that inhibits cell growth by stabilizing the cleavable complex via topoisomerase II. The same anthracycline; adriamycin was one of the key drugs for MPM prior to the appearance of PEM, but its efficacy against MPM has not been revealed. Thus, we planned a phase II study of AMR therapy for previously treated MPM. Methods: Eligibility criteria were previously treated patients with unresectable MPM, performance status 0-2, age≦75, and adequate hematological, hepatic and renal function. Patients were treated with injections of AMR 35 mg/m2 on days 1, 2, and 3. The treatments were repeated every 3-4 weeks. The primary endpoint was the response rate (RR), the secondary endpoints were safety, progression-free survival time (PFS), overall survival time (OS). Results: Although the number of target cases was 32 cases, case registration was delayed and evaluation was performed with 10 cases enrolled. Patients' characteristics were as follows: male/female = 9/1; performance status 0/1/2 = 0/10/0; median age (range) = 67 (49-73); histology epithelial/sarcomatoid/mixed = 4/3/3; stage (IMIG) I/II/III/IV/postoperative recurrence = 0/1/4/4/1. RR was 10.0% (1/10), median PFS was 1.6 months and median OS was 6.6 months. Disease control rate was 50.0% (5/10). Adverse events of Grade 3 or 4 were neutropenia 60.0% (6/10), thrombocytopenia 10.0% (1/10), anemia 10.0% (1/10), febrile neutropenia 10.0% (1/10), and pneumonia 10.0% (1/10). Conclusions: This study demonstrated that AMR therapy for previously treated MPM was tolerable. The efficacy was limited, but may be effective in some cases. Clinical trial information: UMIN000006381 .

Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.

Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

Background: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. Objectives: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. Methods: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. Results: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. Conclusions: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

Targeted Phototherapy for Malignant Pleural Mesothelioma: Near-Infrared Photoimmunotherapy Targeting Podoplanin.

Malignant pleural mesothelioma (MPM) has extremely limited treatment despite a poor prognosis. Moreover, molecular targeted therapy for MPM has not yet been implemented; thus, a new targeted therapy is highly desirable. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer therapy that combines the specificity of antibodies for targeting tumors with toxicity induced by the photoabsorber after exposure to NIR-light. In this study, we developed a new phototherapy targeting podoplanin (PDPN) for MPM with the use of both NIR-PIT and an anti-PDPN antibody, NZ-1. An antibody–photosensitizer conjugate consisting of NZ-1 and phthalocyanine dye was synthesized. In vitro NIR-PIT-induced cytotoxicity was measured with both dead cell staining and luciferase activity on various MPM cell lines. In vivo NIR-PIT was examined in both the flank tumor and orthotopic mouse model with in vivo real-time imaging. In vitro NIR-PIT-induced cytotoxicity was NIR-light dose dependent. In vivo NIR-PIT led to significant reduction in both tumor volume and luciferase activity in a flank model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). The PDPN-targeted NIR-PIT resulted in a significant antitumor effect in an MPM orthotopic mouse model (p < 0.05, NIR-PIT group versus NZ-1-IR700 group). This study suggests that PDPN-targeted NIR-PIT could be a new promising treatment for MPM.

Extended pleurectomy and decortication with resection and reconstruction of pericardium and hemidiaphragm for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumor of the visceral and parietal pleura that is most commonly associated with occupational exposure to asbestos. Since tumor biology is both aggressive and highly heterogeneous at histopathological and molecular level, prediction of prognosis and treatment effect remains challenging. Up to date, the best outcome in primary treatment is achieved by a multimodality approach that includes chemotherapy, followed by macroscopic complete resection (MCR). However, due to the morbidity associated with radical surgery and the limited life expectancy, a deliberate allocation to MCR is crucial. While MCR can be accomplished by extrapleural pneumonectomy (EPP) or extended pleurectomy and decortication (EPD), the current preferential treatment is EPD due to its lower morbidity and mortality. The present article describes the surgical perspective of MPM treatment starting off with correct allocation to MCR by applying a multimodality prognostic score (MMPS), followed by a step-wise description of the EPD with resection and reconstruction of pericardium and hemidiaphragm. We highlight the importance of repeated intraoperative biopsies and frozen section of the chest wall, the diaphragm and the pericardium to allow an accurate intraoperative staging and to adapt the surgical procedure in case of multifocal infiltration. Additionally, the prevention of possible pitfalls associated with EPD such as esophageal obstruction by the reconstructed hemidiaphragm or prolonged hospital stay due to persisting air leak are going to be discussed.

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells.

Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.