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Treatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery.Treatment comprised 360 mg nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 6 weeks, both administered intravenously. Both were discontinued for progressive disease or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), post-treatment survival, progression-free survival (PFS), and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Survival analysis was estimated using a Kaplan-Meier plot. Feasibility analysis was performed using the National Cancer Institute Common Terminology Criteria for AEs version 5.0.Forty-one patients received nivolumab with ipilimumab for recurrent MPM after primary curative-intent surgery (median follow-up, 10.4 months; median treatment, 5.1 months). Overall, 18 patients exhibited partial response, 13 exhibited stable disease, and 10 had documented progressive disease. ORR and DCR were 43.9 and 75.6%, respectively. The 12-month post-treatment survival rate and PFS rate were 74.2 and 40.0%, respectively (median survival, not calculated; median PFS, 7.3 months). Further, 47 AEs were reported in 29 patients (70.7%), including grade 3-4 AEs in 14 patients (34.1%). Grade 4 hepatobiliary disorders were observed in 2 patients and grade 4 neutropenia was observed in 1.Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Background: There is no authorized treatment for malignant non-pleural mesothelioma (MNPM) worldwide. In contrast to malignant pleural mesothelioma, MNPM has not been investigated, and no treatment has been established due to its rarity. Objectives: This multicenter, open-label, single-arm, Japanese phase II trial aims at evaluating the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in advanced or metastatic MNPM treatment. Methods: This phase II trial commenced in October 2020. Twenty-three patients with advanced or metastatic MNPM who meet the inclusion and exclusion criteria were enrolled from five institutions within 2 years. Regardless of prior therapy, 240 mg of nivolumab will be administered intravenously to MNPM patients every 2 weeks to investigate its efficacy and safety until disease progression or unacceptable toxicities are detected, or the patient’s condition meets the withdrawal criteria. Results: The primary endpoint is the objective response rate by central assessment following the Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints include disease control rate, overall survival, progression-free survival, adverse events, and treatment-related adverse events. Conclusions: This is the first prospective investigator-initiated trial to evaluate the effect of nivolumab monotherapy for MNPM.

Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494

Supplementary materials and methods, as well as supplementary figures S1-S7.

Background/aim To evaluate the incidence and grade of radiation pneumonitis after volumetric modulated arc therapy (VMAT) performed for the treatment of non-small cell cancer (NSCLC). Patients and methods Fifty consecutive non-surgical candidates with NSCLC underwent VMAT. Thirty-five patients had stage-III tumors and 15 had recurrent tumors. The prescribed radiation dose for the gross tumor and the elective nodal area was 69 Gy in 30 fractions and 51 Gy in 30 fractions, respectively. Results Radiation pneumonitis developed in 38 patients (76%, 38/50), and grade ≥2 radiation pneumonitis developed in 11 patients (22%, 11/50). The percentage of lung volume that received a dose in excess of 5 Gy (V5), V10, V20, V30, and the mean lung dose (MLD) in the bilateral and ipsilateral lung were significantly associated with the development of grade ≥2 radiation pneumonitis. Conclusion The incidence and degree of radiation pneumonitis are acceptable following treatment of NSCLC with VMAT.

OBJECTIVES The residual thoracic spaces (RTS) after pleurectomy/decortication (P/D) remain unexplored to date. Hence, this study aims to examine the details and risk factors of RTS during the 3 post-P/D months. METHODS We retrospectively examined patients who underwent neoadjuvant chemotherapy, followed by P/D for malignant pleural mesothelioma from September 2012 to December 2020. The RTS group included cases of residual thoracic cavity unaccompanied by pleural effusion on 3 postoperative months computed tomography. We determined risk factors for RTS using univariable and multivariable analyses. RESULTS Of 170 patients examined, 58 (34.1%) were in the RTS group and 112 (65.9%) in the non-RTS group. In the RTS group, 43 patients recovered from RTS during the follow-up period; 4 patients developed chronic fistular empyema, while 2 required fenestration and 2 were thoracoscopic debridement. Besides, 11 patients exhibited RTS continuously. The univariable analysis revealed that compared with the non-RTS group, the RTS group reported a significantly longer postoperative air leak (>7 days; P < 0.01) and right P/D (P = 0.04). The multivariable analysis demonstrated that longer postoperative air leak (>7 days) remained a risk factor for RTS (odds ratio 2.5, 95% confidence interval: 1.3–4.9, P < 0.01). CONCLUSIONS RTS was a postoperative event that frequently observed in patients undergoing P/D. Overall, the current study findings suggest longer postoperative air leak (>7 days) as a significant risk factor for RTS.

Background/Aim: Malignant peritoneal meso-thelioma (MPeM) has no specific imaging findings that can distinguish it from other peritoneal tumors and the accuracy of peritoneal cytology is low, therefore definitive diagnosis is usually performed by histology. This study investigated whether 18F-fluorodeoxyglucose positron emission tomography/ computed tomography representing glucose metabolism is a useful modality for identifying biopsy sites using the tumor viability of MPeM. Patients and Methods: Sixty MPeM patients underwent pre-biopsy FDG-PET/CT examination. The findings were retrospectively evaluated, and histopathological subtype differences were investigated. Results: The diffuse MPeM type was found in 45 (75.0%) and the localized type in 15 (25.0%) cases. The most frequent site of occurrence was the peritoneum (91.7%), followed by the omentum (51.7%). FDG-avid results were noted in 55 patients (91.7%), while 5 (8.3%) showed no FDG uptake with a variety of maximum standardize uptake value (SUVmax) values (range=0-16.77, mean=7.32±4.05). In the 53 epithelial cases, mean SUVmax (7.09±4.07, range=0-16.77) was slightly lower compared to the 4 biphasic (8.30±4.70, range=2.35-13.36) and 3 sarcomatoid (10.08±2.64, range=8.21-13.10) cases, without any significant difference (p=0.12). Diffuse and focal disease patterns showed similar percentages in the three types. Six cases (10.0%) had nodal metastases and 6 (10.0%) extra-abdominal metastases. Compared to the biphasic and sarcomatoid groups, nodal metastases were more common in the epithelial group, while extra-abdominal metastases were more often seen in the biphasic and sarcomatoid groups. Ascites was seen in 53 (83.3%), pleural effusion in 43 (71.7%), and pleural plaque in 31 (51.7%) cases. Conclusion: Through reviewing and elucidation of the FDG-PET/CT features of MPeM, it was shown that FDG-PET/CT is an extremely useful modality for identifying biopsy sites of MPeM.

Objectives This study analyzed an artificial intelligence (AI) deep learning method with a three-dimensional deep convolutional neural network (3D DCNN) in regard to diagnostic accuracy to differentiate malignant pleural mesothelioma (MPM) from benign pleural disease using FDG-PET/CT results. Results For protocol A, the area under the ROC curve (AUC)/sensitivity/specificity/accuracy values were 0.825/77.9% (81/104)/76.4% (55/72)/77.3% (136/176), while those for protocol B were 0.854/80.8% (84/104)/77.8% (56/72)/79.5% (140/176), for protocol C were 0.881/85.6% (89/104)/75.0% (54/72)/81.3% (143/176), and for protocol D were 0.896/88.5% (92/104)/73.6% (53/72)/82.4% (145/176). Protocol D showed significantly better diagnostic performance as compared to A, B, and C in ROC analysis (p = 0.031, p = 0.0020, p = 0.041, respectively). Materials and methods Eight hundred seventy-five consecutive patients with histologically proven or suspected MPM, shown by history, physical examination findings, and chest CT results, who underwent FDG-PET/CT examinations between 2007 and 2017 were investigated in a retrospective manner. There were 525 patients (314 MPM, 211 benign pleural disease) in the deep learning training set, 174 (102 MPM, 72 benign pleural disease) in the validation set, and 176 (104 MPM, 72 benign pleural disease) in the test set. Using AI with PET/CT alone (protocol A), human visual reading (protocol B), a quantitative method that incorporated maximum standardized uptake value (SUVmax) (protocol C), and a combination of PET/CT, SUVmax, gender, and age (protocol D), obtained data were subjected to ROC curve analyses. Conclusions Deep learning with 3D DCNN in combination with FDG-PET/CT imaging results as well as clinical features comprise a novel potential tool shows flexibility for differential diagnosis of MPM.

A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D). The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D. Data on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak > 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses. Of 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien–Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3–12.7; p = 0.02) remained the only variable predicted for AL10. Recent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.

Background: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. Methods: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. Results: patients’ median age was 65 years (range 50–79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. Conclusions: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Aims Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis and limited treatment options. Cisplatin plus pemetrexed is the only approved first‐line treatment for patients with unresectable MPM. Recently, promising outcomes were observed with first‐line bevacizumab combined with cisplatin/pemetrexed, leading to the recommendation of this regimen as a first‐line treatment option for patients with MPM. Bevacizumab plus cisplatin/pemetrexed has been shown to be safe and effective in non–small cell lung cancer, however, there are no efficacy or safety data in Japanese patients with MPM treated with this regimen. We conducted a multicenter study to evaluate tolerability and safety for Japanese patients with chemotherapy‐naïve, unresectable MPM. Methods Eligible patients (n = 7) received bevacizumab plus cisplatin/pemetrexed (up to six cycles), then single‐agent bevacizumab until disease progression or onset of unacceptable adverse events (AEs), according to the 3+3 design analogy. Results One patient (14.3%) reported an AE (gastric ulcer) meeting tolerability criteria. All patients experienced gastrointestinal disorders, including nausea (grade 1/2 only, n = 6, 85.7%) and constipation (grade 1/2 only, n = 5, 71.4%). Five patients (71.4%) had grade 3 hypertension. Two patients discontinued treatment due to gastric ulcer (n = 1) and proteinuria (n = 1). At data cut‐off, four patients had stable disease, two had partial response and one had non‐complete response/non‐progressive disease due to the absence of target lesions. Conclusions Bevacizumab plus cisplatin/pemetrexed then bevacizumab was well tolerated in Japanese patients with MPM., The addition of bevacizumab to standard cisplatin/pemetrexed showed survival benefit in mesothelioma patients, leading to its recommendation as a first‐line treatment option. Until now, there have been no tolerability or safety data for the triplet combination in Japanese mesothelioma patients. We evaluated this triplet combination for Japanese mesothelioma patients in a clinical trial according to the 3+3 design analogy and demonstrated its safety and tolerability.

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)., In the present study, we clarified the role of tumor‐associated macrophages (TAMs) in the reinforcement of malignant potential of malignant pleural mesothelioma (MPM) cells. High mobility group box 1 (HMGB1) released from MPM cells (signal 1) induces pro‐interleukin (IL)‐1β production through interactions with Toll‐like receptor 4 (TLR4) in TAMs. In TAMs, phagocytosed asbestos constitutively activates the inflammasome (signal 2), which causes maturation and secretion of IL‐1β. Secreted IL‐1β interacts with the IL‐1 receptor on MPM cells via a paracrine mechanism. Finally, MPM cells acquire a cancer stem cell (CSC)‐like phenotype.

A superior vena cava (SVC) aneurysm is a rare disease that can be confused with upper mediastinal tumor. A 57-year-old female visited our hospital regarding an abnormal shadow in her mediastinum on a chest X-ray. Upon closer examinations, which included three-dimensional computed tomography, we diagnosed it as a SVC aneurysm. Since her SVC aneurysm was regarded as fusiform type at low risk of rupture and thrombosis, she has been managed conservatively and is free from any complications to date. Thus, it is important to keep SVC aneurysms in mind during routine examinations.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW–II–41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.

To compare three fluorine-18-fluorodeoxyglucose positron emission tomography (Forty NSCLC patients underwentThe number of complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) were 8/10/4/18 for EORTC criteria and 9/9/4/18 for PERCIST. Using RECIST1.1, those of CR/PR/SD/PD were 4/10/12/14. Although there was high concordance between PERCIST and EORTC (92.5% of patients; κ=0.924), that between PERCIST and RECIST1.1 was substantial (65.0%; κ=0.560) and that between EORTC and RECIST1.1 (65.0%; κ=0.574). After a median 23.2 months (range 7.2 to 51.8 months), 32 patients had documented progression and 24 patients died from NSCLC. According to both PET and CT, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and OS than PMD or PD patients (EORTC: P0.0001 and P0.0001, respectively, PERCIST: P0.0001 and P=0.0001, respectively, RECIST1.1: P0.0001 and P0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatmentBoth

Background/aim Nivolumab is an immune checkpoint inhibitor for advanced non-small cell lung cancer (NSCLC). We investigated the safety and efficacy of nivolumab by analyzing the response factor, adverse effects (AE), and the post-treatment condition of pretreated advanced or recurrent NSCLC patients. Patients and methods Nivolumab (3 mg/kg) was administered to 79 pre-treated NSCLC patients from December 2015 to January 2018. Nivolumab efficacy and AE were assessed using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria, respectively. Results Progression-free survival (PFS) was significantly prolonged in cases where the therapeutic effect of the pretreatment was a partial response (p=0.0004). Five cases (6.3%) experienced grade 3-4 AEs. PFS was significantly prolonged in the skin rash group versus the non-skin rash group, and in patients where nivolumab treatment was discontinued. Conclusions Long-term survival was observed in patients with skin rash. Therapeutic effect of nivolumab immediately following its administration appears to be favorable for survival.

To determine whether results of a standardized uptake value (SUV)-based semi-quantitative analytic method for gallium-67 (Gallium-67-citrate SPECT/CT was used to evaluate disease activity in 24 patients with interstitial pneumoniaon clinical grounds at a single institution from June 2018 to August 2020. SUV in a given volume of interest over the bilateral pulmonary parenchyma was calculated using a dosimetry software package. Correlations of maximum SUV (SUVmax) and mean SUV (SUVmean) with clinical factors, including KL-6, lactate dehydrogenase (LDH), and C-reactive protein (CRP), were evaluated in all 24, as well as in 15 patients with spirometry results using Pearson's rank correlation test.The mean bilateral pulmonary SUVmax value showed a moderately significant correlation with KL-6 (Pearson's correlation coefficient r=0.51, P=0.012) and LDH (r=0.51, P=0.010), a weak non-significant correlation with DLCO% (r=-0.26, P=0.34), and no correlation with CRP (r=-0.01, P=0.94), FVC% (r=0.11, P=0.71), or FEV1.0% (r=0.14, P=0.62). Eleven patients with high KL-6 (≥1000U/mL) were defined as having disease activity. Maximum SUV sensitivity, specificity, and accuracy for predicting interstitial lung disease activity were 72.7%, 76.9%, and 75.0%, respectively, with a best cut-off value of 3.78.Semi-quantitative values obtained with

Background: To compare three FDG-PET criteria (EORTC, PERCIST, imPERCIST) with CT criteria (combined modified RECIST and RECIST 1.1) for response evaluation and prognosis prediction in patients with recurrent MPM treated with ICI monotherapy. Methods: Thirty MPM patients underwent FDG-PET/CT and contrast-enhanced CT at the baseline and during nivolumab therapy (median 10 cycles). Therapeutic response was evaluated according to EORTC, PERCIST, imPERCIST, and CT criteria. PFS and OS were examined using log-rank and Cox methods. Results: CMR/PMR/SMD/PMD numbered 5/3/4/18 for EORTC, 5/1/7/17 for PERCIST, and 5/3/9/13 for imPERCIST. With CT, CR/PR/SD/PD numbered 0/6/10/14. There was high concordance between EORTC and PERCIST (κ = 0.911), and PERCIST and imPERCIST (κ = 0.826), while that between EORTC and imPERCIST (κ = 0.746) was substantial, and between CT and the three PET criteria moderate (κ = 0.516–0.544). After median 14.9 months, 26 patients showed progression and nine died. According to both PET and CT findings, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and somewhat longer OS than PMD and PD patients (EORTC p = 0.0004 and p = 0.055, respectively, PERCIST p = 0.0003 and p = 0.052, imPERCIST p &lt, 0.0001 and p = 0.089, CT criteria p = 0.0015 and p = 0.056). Conclusions: Both FDG-PET and CT criteria are accurate for response evaluation of ICI therapy and prediction of MPM prognosis. In comparison with CT, all three FDG-PET/CT criteria judged a greater percentage of patients (16.7%) as CMR, while two (EORTC, PERCIST) judged a greater percentage (10–13.3%) as PMD. For predicting PFS, the three FDG-PET criteria were superior to the CT criteria, and imPERCIST demonstrated the highest rate of accurate prediction.

Integrated positron emission tomography/computed tomography (PET/CT) with 2-[18F]fluoro-2-deoxyd-glucose (18F-FDG) has emerged as a powerful tool for combined metabolic and anatomic evaluations in clinical oncologic imaging. 18F-FDG PET/CT is also a useful tool to manage patients with malignant pleural mesothelioma, including diagnosis, initial staging, and treatment response assessment. However, a further improvement about PET is desirable.

Summary Background Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. Methods The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0–1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov , NCT02628067 . Findings Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4–15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0–16·6]). Median overall survival was 10·0 months (95% CI 7·6–13·4) and median progression-free survival was 2·1 months (2·1–3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3–4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. Interpretation Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. Funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.

Lung cancer remains one of the most common cancers, and the mortality rate is still high. Radiotherapy plays an important role in radical treatment for locally advanced non-small cell lung cancer. Treatment outcomes in lung cancer have improved over the last few decades. Several treatment regimens have been shown to be effective and safe. Further, modern technological approaches of radiotherapy have been developed along with advanced imaging and immunotherapy in order to improve outcomes and minimize radiation-induced toxicity. This chapter summarizes the historical results of the key clinical studies that were conducted in the past with the focus on various regimens of chemoradiotherapy used. In addition, we discuss future perspectives of definitive radiotherapy for locally advanced non-small cell lung cancer.

A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D).The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D.Data on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses.Of 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien-Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3-12.7; p = 0.02) remained the only variable predicted for AL10.Recent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.

Objective To compare modified RECIST (mRECIST), EORTC criteria, and PERCIST for response evaluation and prognosis prediction in advanced malignant pleural mesothelioma (MPM) patients treated with chemotherapy. Methods Patients with MPM and not curative surgery candidates (n = 75) underwent standard chemotherapy with cisplatin and pemetrexed. CT and [F]fluorodeoxyglucose PET/CT scans were performed at baseline and after three chemotherapy cycles. Chemotherapeutic response was evaluated according to mRECIST, EORTC, and PERCIST, then concordance among those was assessed using Cohen's κ coefficient. PFS and OS were examined using log-rank and Cox methods. Results With EORTC, 27 patients had PMD, 23 SMD, 17 PMR, and eight CMR, while with PERCIST those were 28, 22, 11, and 14, respectively. Using mRECIST, 28 had PD, 29 SD, 18 PR, and 0 CR. Although there was high concordance between EORTC and PERCIST (82.7% of patients; κ = 0.83), that between mRECIST and EORTC (38.7%; κ = 0.27) and mRECIST and PERCIST (36.0%; κ = 0.26) was low. According to both EORTC and PERCIST, patients with no progression (CMR/PMR/SMD) showed significantly longer PFS and OS than PMD patients (EORTC: P = 0.0024 and P = 0.039, respectively, PERCIST: P = 0.0012 and P = 0.024, respectively), while according to mRECIST, those who achieved no progression (PR/SD) showed significantly longer PFS than PD patients (P = 0.011), but not significantly longer OS (P = 0.11). Conclusion EORTC and PERCIST are more accurate than mRECIST for evaluation of tumor response to chemotherapy and predicting prognosis in unresectable MPM patients.

Background Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting. Methods This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan–Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1–14 months), and median of 8 cycles (range: 2–32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed. Conclusion Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.

Pulmonary pleomorphic carcinoma (PPC) has a poor prognosis due to the poor results of treatment with systemic chemotherapy. We report the case of a 73-year-old woman with PPC who showed a favorable response to nivolumab. As first-line treatment for postoperative recurrence, she received carboplatin and nanoparticle albumin-bound paclitaxel. However, 12 months later, a new metastatic lymph node appeared. Nivolumab was administered as second-line treatment, and the patient showed a favorable prolonged response. The effects of treatment of PPC with nivolumab seem promising. The results of a future prospective study are expected to identify indicators for the treatment of PPC.

Mesothelioma of peritoneal origin has wider variation in treatment outcomes than mesothelioma of pleural origin, likely because peritoneal mesothelioma comprises borderline malignant variants and aggressive malignant peritoneal mesothelioma (MPeM). This study retrospectively evaluates the efficacy of first-line systemic pemetrexed and cisplatin chemotherapy in MPeM.Twenty-four patients with histologically proven MPeM were treated with pemetrexed plus cisplatin as a first-line systemic chemotherapy. The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Twenty-two patients underwentTwo complete responses and 9 partial responses were achieved. Overall response rate and disease control rate were 45.8% and 91.7%, respectively. Median progression-free survival and median overall survival were 11.0 months and 15.8 months, respectively. Wet- type MPeM had significantly longer survival (40.9 months median) than other clinical types (15.5 months) (P = 0.045). The baseline maximum standardized uptake value in 22 patients was 8.93 (range, 2.5-16.77).Systemic pemetrexed plus cisplatin is active for MPeM. Disparity with the outcome of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50%.

Efficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT.Histologically confirmed MPM patients (N=82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders.After three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0days (95% confidence interval [CI]: 545.9-910.1) and cumulative median TTP was 365.0days (95% CI: 296.9-433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29%) were classified as metabolic non-responders. The median TTP for metabolic responders was 13.7 months, while it was 10.0 months for non-responders(p0.001). Metabolic responders had a trend toward longer OS, although the difference did not reach statistical significance (metabolic responders:33.9 months; non-responders: 21.6 months; p0.05).Several mRECIST-confirmed SD MPM patients may be classified as metabolic non-responders on18F-FDGPET/CT. Metabolic response is significantly correlated with the median TTP, suggesting it should be included in the evaluation of the response to chemotherapy in MPM patients classified as mRECIST SD, to identify non-responders.

Purpose To investigate the relationships between pretreatment volume-based quantitative 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) parameters and overall survival (OS) in patients with malignant pleural mesothelioma (MPM). Materials and methods We retrospectively reviewed data from 201 MPM patients, of whom 38 underwent surgical resection, and calculated the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), including primary tumors and nodal or distant metastatic lesions, on pretreatment 18 F-FDG PET/CT. Relationships between clinicopathological factors (age, sex, performance status, European Organization for Research and Treatment of Cancer [EORTC] score, histological subtype, TNM stage, and treatment strategy), volume-based quantitative PET/CT parameters, and OS were evaluated using a Cox proportional hazards model and log-rank test. Results The median follow-up was 15 months (range, 1–96 months; median, 17 months). In a univariate analysis of all patients, older age (p Conclusions Pretreatment volume-based quantitative 18 F-FDG PET/CT parameters, especially TLG, could serve as potential surrogate markers for MPM prognosis.

Introduction: The surgical arm of the Mesothelioma and Radical Surgery (MARS) trial involved a multimodal approach, with combined therapy consisting of chemotherapy, complete gross resection, and radiation therapy. However, the MARS trial did not compare surgery with chemotherapy, and the survival and quality of life outcomes of this trial's surgical arm were inferior to those of the non-surgical arm. Methods for achieving complete gross resection (macroscopic complete response [MCR]) include extrapleural pneumonectomy (EPP), wherein the pleura, lung, diaphragm, and pericardium are removed en bloc, and pleurectomy/decortication (P/D), wherein the affected lung is preserved. Nonetheless, the most effective therapy remains unclear.Areas covered: Here, surgery post-neoadjuvant chemotherapy for malignant pleural mesothelioma with either EPP or P/D has been discussed, along with trimodal and bimodal therapies.Expert opinion: With the development of post-P/D radiation therapy, it is currently possible to truly compare EPP with P/D. Moreover, R0 resection cannot be achieved with either EPP or P/D; thus, both must incorporate debulking, although the two procedures are largely incompatible. Therefore, there is a need to rebuild the status of surgery as a multimodal therapy.

// Kazuhiro Kitajima 1 , Masaki Hashimoto 2 , Takayuki Katsuura 1 , Nobuyuki Kondo 2 , Toshiyuki Minami 3 , Kozo Kuribayashi 3 , Seiki Hasegawa 2 , Takashi Kijima 3 and Koichiro Yamakado 4 1 Division of Nuclear Medicine and PET Center, Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan 2 Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan 3 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan 4 Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Correspondence to: Kazuhiro Kitajima, email: ka-kitajima@hyo-med.ac.jp Keywords: mesothelioma; positron emission tomography; computed tomography; recurrence Received: September 18, 2019 Accepted: October 19, 2019 Published: November 26, 2019 ABSTRACT Objectives To assess the diagnostic accuracy of fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) findings for recurrent malignant pleural mesothelioma (MPM) after a radical surgery procedure and their impact on clinical management in comparison with contrast-enhanced CT. Results Treatment failure was confirmed in 40 patients. The patient-based area under the receiver-operating characteristic (ROC) curves (AUC)/sensitivity/specificity/accuracy were 0.915/90.0%/80.0%/88.0% for FDG-PET/CT, and 0.805/75.0%/90.0%/78.0% for contrast-enhanced CT, respectively. AUC and sensitivity values were significantly different between the modalities (both p=0.041). Patient-based AUC values for diagnosing locoregional recurrence (ipsilateral hemithoracic recurrence) and distant metastasis, including peritoneal dissemination and lung, bone, muscle, and liver metastasis, were also significantly different (p=0.023 and p=0.035, respectively). The findings of FDG-PET/CT resulted in a change of management for 14 of the 50 patients (28%) by initiating new treatment. Of six patients judged as not having recurrence by contrast-enhanced CT but truly having recurrence based on FDG-PET/CT findings, 4 patients received new treatment due toFDG-PET/CT. Methods Fifty patients who underwent radical surgery for MPM received FDG-PET/CT and contrast-enhanced neck/chest/abdomen/pelvis CT examinations for surveillance or suspected recurrence within a 2-week period. Diagnostic ability was determined on a patient and lesion-site basis by 2 experienced examiners, and the modalities were compared using ROC analysis and McNemar test results. Lesion status was determined on the basis of histopathology, radiological imaging and clinical follow-up for longer than 6 months. Conclusion FDG-PET/CT findings were shown to be more accurate for assessing MPM recurrence and more often led to therapy change than contrast-enhanced CT.

A republication, with permission, of 'Air Pollution in the Asia‐Pacific Region. A Joint Asian Pacific Society of Respirology/American Thoracic Society Perspective'. Am. J. Respir. Crit. Care Med. 2019; 199: 693–700. doi: 10.1164/rccm.201804‐0673PP

Background Nintedanib targets VEGF receptors 1-3, PDGF receptors alpha and beta, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma. Methods This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged >= 18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100. Findings Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5.3 months (IQR 2.8-7.3) in the nintedanib group and 5.1 months (2.7-7.8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6.8 months [95% CI 6.1-7.0]) and the placebo group (7.0 months [6.7-7.2]; HR 1.01 [95% CI 0.79-1.30], p=0.91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]). Interpretation The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Talc pleurodesis has been reported to increase fluorodeoxyglucose (FDG) uptake in the high attenuation areas of pleural thickening, making it difficult to distinguish between benign granulomatous inflammatory processes and malignancies, which may therefore interfere with the post-chemotherapy disease evaluation on FDG-positron emission tomography/computed tomography (PET/CT). We present two cases of malignant pleural mesothelioma treated with talc pleurodesis and neoadjuvant chemotherapy (NAC) before pleurectomy/decortication in which post-NAC FDG-PET/CT showed intense FDG uptakes in the high attenuation areas of pleural thickening with false positive result, whereas post-NAC 11C-choline PET/CT showed mild choline uptake of pleural talc deposit, which did not interfere with the post-chemotherapy disease evaluation. Thus we suggest choline-PET/CT may show little choline uptake to granulomatous inflammation and evaluate treatment response in malignant pleural mesothelioma patients treated with talc pleurodesis and NAC.

Integrated positron emission tomography/computed tomography (PET/CT) using 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) has emerged as a powerful tool for combined metabolic and anatomic evaluation in clinical oncologic imaging. This review discusses the utility of (18)F-FDG PET/CT as a tool for managing patients with lung cancer. We discuss different patient management stages, including diagnosis, initial staging, therapy planning, early treatment response assessment, re-staging, and prognosis.

Introduction This study aimed to assess prognostic factors to better understand malignant pleural mesothelioma (MPM) and to develop a new classification protocol beyond the standard tumor node metastasis (TNM) staging system. Materials and Methods We retrospectively reviewed the data of 188 patients with MPM who had not undergone surgical resection. For each patient, we calculated the maximum standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis (TLG) on pretreatment 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography. Using the Cox proportional hazards model, we evaluated the relationships among potential MPM predictors, including age, gender, performance status, histologic type, stage, possible serum markers, and volume-based positron emission tomography parameters, as well as overall survival. Results The median survival was 461 days, and the 1- and 2-year overall survival rates were 60.70% and 31.10%, respectively. Univariate and multivariate analyses revealed that the significant independent predictors of poor survival outcomes were the non-epithelioid histologic type, elevated serum lactate dehydrogenase levels, a neutrophil-to-lymphocyte ratio of ≥ 5.0, and a TLG of ≥ 525 g. We then used these results to develop a prognostic risk classification system. From the resulting survival curve, we found a significant difference among the 3 risk groups of independent variables. Moreover, there were significant differences between all pairs of 2 separated risk groups. Conclusions Pathologic subtypes, serum lactate dehydrogenase, neutrophil-to-lymphocyte ratio, and TLG in 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography were independent and significant prognostic factors of MPM. Using this model, we created a new risk classification system that supplants the standard TNM staging protocol.

Background/Aim: A strategy for improving survival of malignant pleural mesothelioma (MPM) patients is earlier diagnosis paired with earlier stage implementation of therapeutic interventions. This study aimed to determine the clinical signs of early-stage MPM to aid an earlier diagnosis and earlier-stage intervention. Materials and Methods: Out of the 72 cases in our institution, 40 cases with 18F-FDG-PET/CT-negative MPM were retrospectively identified between 2007 and 2015. Overall survival rates were determined and compared with pathological features, histology, and treatment. Results: The biphasic histological type of early-stage MPM was characterized by poor prognosis (p=0.0006). Additionally, the cytology-negative group (Class III and below) showed significantly shorter survival times (p=0.0290). There was no significant difference in survival between patients who received pleurectomy and those who received chemotherapy only (p=0.6991). Bimodal therapy resulted in a longer survival rate than trimodal therapy. Conclusion: In early-stage PET-negative MPM cases, biphasic histology and pleural effusion of Class III and below correlated with a poor prognosis. Surgical treatment using pleurectomy/decortication resulted in higher patient survival outcomes than therapy with extrapleural pneumonectomy.