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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.

Background : Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods : The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results : MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/ c -myc and PI3K/AKT/mTOR signaling. Conclusions : Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

Background: The aim of this study was to assess the efficacy and safety of amrubicin for previously treated malignant pleural mesothelioma., Methods: The eligibility criteria were: previously treated unresectable malignant pleural mesothelioma; performance status 0-1; age ≤ 75; adequate hematological, hepatic, and renal function. The patients were injected with 35 mg/m 2 amrubicin on days one, two, and three every 3-4 weeks. The planned number of patients was 32., Results: The study was terminated due to delay in enrollment and 10 patients were subsequently enrolled (nine males and one female; median age 67 [range 49-73]), of which four had epithelioid tumors, three had sarcomatoid tumors and three had biphasic tumors, respectively. According to the International Mesothelioma Interest Group (IMIG), one, four, and four patients had stage II, III, and IV, respectively, and one had postoperative recurrence. There was one (10%) partial response, four (40%) had stable disease, and five (50%) patients exhibited disease progression. The overall response and disease control rates were 10% (95% CI: 0.3-44.5%) and 60% (95% CI: 26.2-87.8%), respectively. The median progression-free survival time was 1.6 months. The median overall survival time was 6.6 months, and the one-, two-, and three-year survival rates were 23%, 23%, and 0%, respectively. The observed grade 3 or 4 toxicities included neutropenia in six (60%) patients; leukopenia in five (50%) patients; and febrile neutropenia, thrombocytopenia, anemia, and pneumonia in one (10%) patient each., Conclusions: There was not enough data to evaluate the efficacy because the study was terminated early. However, amrubicin showed limited activity and acceptable toxicities when used in previously treated malignant pleural mesothelioma patients., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile., Methods: In this single-center, real-world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next-generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off-label therapy custom-tailored to the individual patient., Results: In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD-L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender-specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease., Conclusions: Our observations suggest that a molecular-guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Studies of bevacizumab and pembrolizumab in the treatment of malignant pleural mesothelioma suggest anticancer efficacy; clinical trial populations are not reflective of real-world patients. We aimed to determine the proportion of real-world patients who would be eligible for trials, identify patients who participated in clinical trials, and examine treatment and outcome data., Patients and Methods: Consecutive patients with unresectable malignant pleural mesothelioma seen at our center from January 2012 to July 2018 were assessed with regards to their eligibility for Mesothelioma Avastin Cisplatin Study (MAPS) and KEYNOTE-028 clinical trials. Prognostic information, treatment use, and overall survival (OS) data were also collected., Results: A total of 133 patients were included: 50% and 37%, respectively, did not meet trial eligibility for MAPS or KEYNOTE-028, most commonly owing to age ≥75 (23%), Eastern Cooperative Oncology Group performance status of ≥2 (21%), concomitant medication (21%), or comorbidity (12%). MAPS eligibility did not correlate with use of bevacizumab (P = .30) or improved OS (P = .87). Eligibility for KEYNOTE-028 correlated with pembrolizumab use (P < .001), but not improved OS (P = .21). Patients who received an investigational anticancer therapy on any clinical trial had improved OS: 32.4 (95% CI, 23.9-40.9) months versus 20.5 (95% CI, 15.8-25.3) months (P = .01)., Conclusion: Only ≤63% of our patients were eligible for these trials, highlighting the differences between real-world patients and the highly select trial population. Our patients who participated in clinical trials had superior OS, further emphasizing the selection bias in the trial population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: It has been proven that ALK-rearranged non-small cell lung cancer (NSCLC) is sensitive to ALK inhibitors while the chemotherapy resistance is unavoidable. In this study, safety and antitumor activity of the novel ALK inhibitor (ALKi) CT-707 were evaluated in Chinese patients with advanced ALK-rearranged NSCLC., Methods: This single-center, open-label phase I study recruited adult patients with ALK-rearrangement (confirmed by fluorescence in situ hybridization and/or immunohistochemistry) of locally advanced/metastatic malignancies including NSCLC. This study consisted of two parts: dose escalation and dose expansion. CT-707 was administered orally once a day for 21 days., Results: A total of 13 patients who were treated with CT-707 from 450 to 600 mg (in the dose increasing phase) were enrolled in this trial (two patients were previously treated with crizotinib). There were 12 patients diagnosed with lung adenocarcinoma and one patient with malignant pleural mesothelioma. After treatment, grade 3 diarrhea (600 mg once a day) was found as dose-limiting toxicity (DLT).The most common adverse events included diarrhea (92%), elevated aspartate aminotransferase (61%), elevated alanine aminotransferase (54%), hair loss (38%), and vomiting (31%). The overall response rate was 77% (10/13). Among all patients, four of the five patients who did not receive any treatment, one of the two patients who had received treatments with crizotinib, and five of the six patients who received standard chemotherapy achieved partial response (PR). One patient reached a complete remission (CR)., Conclusions: This study indicated that CT-707 is clinically effective as a new antitumor drug for Chinese lung adenocarcinoma patients with ALK rearrangement. It is safe and reliable and the dose-expansion phase recruitment has started., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors., Materials and Methods: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzyme-linked immunosorbent assay and compared with clinicopathologic parameters., Results: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028)., Conclusion: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Objectives: Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC)., Patients and Methods: GEM (1000 mg/m 2 ) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS)., Results: In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients., Conclusions: The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit., Competing Interests: Declaration of Competing Interest All the authors declare no competing interests. None of the authors have received funding for this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the pleural cavity, while the remaining cases initiate in the peritoneal cavity, in the pericardial cavity or on the tunica vaginalis. Usually, mesotheliomas grow in a diffuse pattern and tend to enclose and compress the organs in the various body cavities. Mesothelioma incidence is increasing worldwide and still today, the prognosis is very poor, with a reported median survival of approximately one year from presentation. Thus, the development of alternative and more effective therapies is currently an urgent requirement. The aim of this review article was to describe recent findings about the anti-cancer activity of curcumin and some of its derivatives on mesotheliomas. The potential clinical implications of these findings are discussed.

The distributions of light and tissue oxygenation (S t O 2 ) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment-averaged fluence rate was similar among sites, ranging from a median of 40-61 mW cm -2 during periods of light exposure to a detector. S t O 2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median S t O 2 >90%; interquartile ranges ~85-95%). PDT effect on S t O 2 was characterized as the S t O 2 ratio (post-PDT S t O 2 /pre-PDT S t O 2 ). High S t O 2 pre-PDT was significantly associated with oxygen depletion (S t O 2 ratio < 1), although the extent of oxygen depletion was mild (median S t O 2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment-averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre-PDT S t O 2 , which may suggest the presence of a treatment effect., (© 2020 American Society for Photobiology.)

Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM., Competing Interests: Competing interests: KH has honoraria from AstraZeneca, Ono Pharmaceuticals, BMS, MSD, Eli Lilly Japan, Nihon Kayaku, Taiho Pharmaceuticals and Chugai Pharmaceuticals, as well as unrelated research funding from AstraZeneca, BMS, and Eli Lilly Japan. NF has received consultancy fees from Boehringer Ingelheim, Ono, Bristol-Myers Squibb, Kyorin, and Kissei, and honoraria or research funding from Ono, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly Japan, and MSD related to this manuscript, as well as unrelated research funding from Hisamitsu, Chugai, Taiho, Novartis and GSK., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment., Materials and Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients., Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes., Conclusions: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with dismal prognosis, largely due to poor response rates to and rapid relapse after first-line pemetrexed (MTA)/cisplatin chemotherapy. A better understanding of the molecular mechanisms underlying chemotherapy sensitivity and duration represents a significant but still unmet clinical need. In this study, we reported on a kinome CRISPR/Cas9 knockout screen that identified several G 2 -M checkpoint kinases, including WEE1, whose loss of function sensitizes MPM cells to standard chemotherapy. We further showed that deregulation of the G 2 -M checkpoint contributes to chemotherapy resistance, and that WEE1 inhibition synergizes with cisplatin/MTA, leading to enhanced MPM cell death in vitro and potent antitumor effects in vivo Mechanistically, WEE1 blockage overrides chemotherapy-induced G 2 -M cell-cycle arrest and promotes premature mitotic entry, which causes DNA damage accumulation and ultimately apoptosis. Our results suggest a new therapeutic combination for MPM, and support the application of CRISPR/Cas9-based functional genomics in identifying novel therapeutic targets to potentiate existing cancer therapies., (©2019 American Association for Cancer Research.)

V-domain Ig-containing suppressor of T-cell activation (VISTA) is an immune checkpoint gene that inhibits anti-tumor immune responses. Since most malignant pleural mesotheliomas do not respond to anti-programmed cell death(-ligand)1 (PD-(L)1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) therapy and given the recent finding of The Cancer Genome Atlas Study that pleural mesothelioma displays the highest expression of VISTA among all cancers studied, we examined VISTA expression in a large pleural mesothelioma cohort. VISTA and PD-L1 immunohistochemistry were performed on tissue microarray of immunotherapy-naive pleural mesotheliomas (254 epithelioid, 24 biphasic and 41 sarcomatoid) and ten whole-tissue sections of benign pleura (VISTA only). Percentages of tumor and inflammatory cells with positive staining were assessed. Optimal prognostic cutoff percentages were determined using maximally selected rank statistics. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. All benign mesothelium expressed VISTA. Eighty-five percent of 319 and 38% of 304 mesotheliomas expressed VISTA and PD-L1 (88% and 33% of epithelioid, 90% and 43% of biphasic, and 42% and 75% of sarcomatoid), respectively. Median VISTA score was significantly higher in epithelioid (50%) (vs. biphasic [20%] and sarcomatoid [0]) (p < 0.001), while median PD-L1 score was significantly higher in sarcomatoid tumors (20%) (vs. biphasic and epithelioid [both 0%]) (p < 0.001). VISTA and PD-L1 were expressed in inflammatory cells in 94% (n = 317) and 24% (n = 303) of mesothelioma, respectively. Optimal prognostic cutoffs for VISTA and PD-L1 were 40% and 30%, respectively. On multivariable analysis, VISTA and PD-L1 expression in mesothelioma were associated with better and worse overall survival (p = 0.001 and p = 0.002), respectively, independent of histology. In a large cohort of mesothelioma, we report frequent expression of VISTA and infrequent expression of PD-L1 with favorable and unfavorable survival correlations, respectively. These findings may explain poor responses to anti-PD-(L)1 immunotherapy and suggest VISTA as a potential novel target in pleural mesothelioma.

Korean herbal medicine treatment (KHMT) involves treating with a combination of natural products, which have been used for thousands of years. Recently, it has been reported to be effective and safe in cancer patients. This case report demonstrates the efficacy of KHMT in a 49-year-old man with malignant pleural mesothelioma (MPM), a rare and highly aggressive cancer. The patient showed recurrent pleural effusion and was diagnosed with epithelioid MPM at cT3NxM0 stage III in December 2017. The multidisciplinary care team recommended multimodal treatment based on an extrapleural pneumonectomy, but he refused this because the treatment was aggressive and the effectiveness was unclear. He decided to undergo pemetrexed plus cisplatin chemotherapy if his condition worsened. He visited the Korean Medicine Cancer Center for alternative treatment options. A KHMT regimen, consisting of twice-daily Gunchil-dan and thrice-daily Bangam-tang, was initiated in December 2017. Since commencement of KHMT, computed tomography and X-ray imaging scans have shown no significant interval changes and progression. At 21 months into treatment (September 2019), no significant adverse events have occurred. Given that the median overall survival of patients with MPM is approximately 1 year, the ongoing progression-free survival of this patient for 21 months is relatively long. This case, therefore, suggests that KHMT is a potential treatment option for MPM patients.

Introduction: Cytoreductive surgery with hyperthermic intraoperative chemotherapy (HITHOC) is a therapeutic option for treatment of malignant pleural mesothelioma. Anesthetic management might be challenging., Patients and Methods: A descriptive analysis of a case series is presented. Seven patients with malignant pleural mesothelioma diagnostic undergoing HITHOC surgery were studied. Combined general and epidural anesthesia were administered. An intensive hemodynamic monitorization was implemented. Data regarding perioperative course was analyzed., Results: Between May 2015 and October 2018 7patients underwent HITHOC procedure. Blood transfusions were administered in all patients, and 5of the 7patients required vasoactive drug administration. Extubation at the end of the procedure was able in 6of the 7patients. The median length of stay in ICU was 4 days, and 29 days for the whole hospitalary stay. No significant postoperative pain was observed., Conclusions: HITHOC surgery is a complex procedure in which several hemodynamic changes occur. An intensive intraoperative monitorization was useful for controlling complications., (Copyright © 2019 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland., Methods: Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression., Results: Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71-10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35-6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97-4.67) for MSLN+/PD-L1- patients., Conclusions: Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Malignant pleural mesothelioma (MPM) is closely linked to asbestos exposure and is an extremely aggressive tumor with poor prognosis., Objective: Our study aimed to elucidate hub genes and potential drugs in MPM by integrated bioinformatics analysis., Methods: GSE42977 was download from the Gene Expression Omnibus (GEO) database; the differentially expressed genes (DEGs) with adj.p value <0.05 and |logFC| ≥2 were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by DAVID database. The STRING database was used to construct a protein-protein interaction network, and modules analysis and hub genes acquisition were performed by Cytoscape. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to assess the impact of hub genes on the prognosis of MPM patients. The Drug-Gene Interaction database (DGIdb) was used to select the related drugs., Results: A total of 169 upregulated and 70 downregulated DEGs were identified. These DEGs are enriched in the pathway of extracellular matrix-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and PPAR signaling pathway. Finally, 10 hub genes (CDC20, CDK1, UBE2C, TOP2A, CCNB2, NUSAP1, KIF20A, AURKA, CEP55, and ASPM) were identified, which are considered to be closely related to the poor prognosis of MPM. In addition, 119 related drugs that may have a therapeutic effect on MPM were filtered out., Conclusion: These discovered genes and small-molecule drugs provide some new ideas for further research on MPM., (© 2020 The Author(s)Published by S. Karger AG, Basel.)