Impact of Operation on Disease Progression and Survival of Patients With Pleural Mesothelioma.

BACKGROUND: The effects of surgery on the survival of patients with pleural mesothelioma remain poorly understood. We compared the therapeutic outcomes of patients receiving neoadjuvant chemotherapy, followed by surgery or refusing surgery, for pleural mesothelioma. METHODS: This retrospective study included consecutive patients who were eligible for curative-intent surgery after 3 cycles of neoadjuvant chemotherapy with platinum plus pemetrexed at our hospital during January 2011 to December 2021. Patients were divided into 2 groups. The surgery group comprised patients who underwent curative-intent surgery for pleural mesothelioma. The refusal-of-surgery group comprised patients who were medically eligible for surgery but refused to consent to surgery. Overall survival and progression-free survival were calculated using the Kaplan-Meier method with the generalized Wilcoxon test. RESULTS: Of the 296 eligible patients for the study, 272 underwent surgery and 24 refused surgery. During the surgery, 204 patients (75.0%), 43 (15.8%), and 25 (9.2%) underwent pleurectomy/decortication, extrapleural pneumonectomy, and exploratory thoracotomy, respectively. The median follow-up length was 28.4 months. The median overall survival periods were 40.7 months (95% CI, 32.2-45.6 months) for surgery and 23.6 months (95% CI, 15.2-43.0 months) for refusal of surgery (P = .03). The median progression-free survival periods were 20.2 months (95% CI, 17.0-22.5 months) for surgery and 12.9 months (95% CI, 8.3-16.8 months) for refusal of surgery (P < .001). CONCLUSIONS: Overall survival and progression-free survival were significantly better in surgery than in refusal of surgery. Surgery may improve the survival outcomes of patients with pleural mesothelioma.

Prognosis prediction of patients with malignant pleural mesothelioma using conditional variational autoencoder on 3D PET images and clinical data.

BACKGROUND: Deep learning (DL) has been widely used for diagnosis and prognosis prediction of numerous frequently occurring diseases. Generally, DL models require large datasets to perform accurate and reliable prognosis prediction and avoid overlearning. However, prognosis prediction of rare diseases is still limited owing to the small number of cases, resulting in small datasets. PURPOSE: This paper proposes a multimodal DL method to predict the prognosis of patients with malignant pleural mesothelioma (MPM) with a small number of 3D positron emission tomography-computed tomography (PET/CT) images and clinical data. METHODS: A 3D convolutional conditional variational autoencoder (3D-CCVAE), which adds a 3D-convolutional layer and conditional VAE to process 3D images, was used for dimensionality reduction of PET images. We developed a two-step model that performs dimensionality reduction using the 3D-CCVAE, which is resistant to overlearning. In the first step, clinical data were input to condition the model and perform dimensionality reduction of PET images, resulting in more efficient dimension reduction. In the second step, a subset of the dimensionally reduced features and clinical data were combined to predict 1-year survival of patients using the random forest classifier. To demonstrate the usefulness of the 3D-CCVAE, we created a model without the conditional mechanism (3D-CVAE), one without the variational mechanism (3D-CCAE), and one without an autoencoder (without AE), and compared their prediction results. We used PET images and clinical data of 520 patients with histologically proven MPM. The data were randomly split in a 2:1 ratio (train : test) and three-fold cross-validation was performed. The models were trained on the training set and evaluated based on the test set results. The area under the receiver operating characteristic curve (AUC) for all models was calculated using their 1-year survival predictions, and the results were compared. RESULTS: We obtained AUC values of 0.76 (95% confidence interval [CI], 0.72-0.80) for the 3D-CCVAE model, 0.72 (95% CI, 0.68-0.77) for the 3D-CVAE model, 0.70 (95% CI, 0.66-0.75) for the 3D-CCAE model, and 0.69 (95% CI 0.65-0.74) for the without AE model. The 3D-CCVAE model performed better than the other models (3D-CVAE, p = 0.039; 3D-CCAE, p = 0.0032; and without AE, p = 0.0011). CONCLUSIONS: This study demonstrates the usefulness of the 3D-CCVAE in multimodal DL models learned using a small number of datasets. Additionally, it shows that dimensionality reduction via AE can be used to learn a DL model without increasing the overlearning risk. Moreover, the VAE mechanism can overcome the uncertainty of the model parameters that commonly occurs for small datasets, thereby eliminating the risk of overlearning. Additionally, more efficient dimensionality reduction of PET images can be performed by providing clinical data as conditions and ignoring clinical data-related features.

Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Clinical Efficacy and Safety of Nivolumab in Malignant Non-Pleural Mesothelioma: A Multicenter, Open-Label, Single-Arm, Japanese Phase II Trial (Viola) Protocol.

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.

Malignant Peritoneal Mesothelioma Features Shown by FDG-PET/CT.

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 18 F-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.

Long-term outcomes and risk factors of residual thoracic spaces after pleurectomy/decortication for mesothelioma.

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.

The utility of 68F-FDG PET/CT for evaluation of tumor response to immune checkpoint inhibitor therapy and prognosis prediction in patients with non-small-cell lung cancer.

OBJECTIVE: To compare three fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (EORTC criteria and PERCIST) and computed tomography (CT) (RECIST1.1) for response evaluation and prognosis prediction in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI) monotherapy. SUBJECTS AND METHODS: Forty NSCLC patients underwent 18F-FDG PET/CT scans at baseline and after 4 to 8 cycles of nivolumab or pembrolizumab. Therapeutic response was evaluated according to EORTC criteria, PERCIST, and RECIST1.1,then concordance among those was assessed using Cohen's κ coefficient. Progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. RESULTS: The 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: P<0.0001 and P<0.0001, respectively, PERCIST: P<0.0001 and P=0.0001, respectively, RECIST1.1: P<0.0001 and P<0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatment 18F-FDGPET/CT scans was significantly associated with progression. Highest SUVmax (P<0.0001), total MTV (P=0.0062), total TLG (P<0.0001), highest SULpeak (P<0.0001), and total TLGL (P<0.0001) on post-ICI treatment 18F-FDG PET/CT scans were also were significantly associated with progression. Moreover, the change rate of highest SUVmax (P<0.0001), total metabolic tumor volume (MTV) (P<0.0001), total lesion glycolysis(TLG) (P<0.0001), highest SULpeak (P<0.0001), total TLGL (P<0.0001), size (P=0.0012), EORTC (P<0.0001), PERCIST (P<0.0001), and RECIST 1.1 (P<0.0001) on two PET/CT scans were significantly associated with progression. A multivariate analysis confirmed the change rate of total MTV (P=0.034), and total TLGL (P=0.0027), EORTC (P=0.018), PERCIST (P=0.045), and RECIST1.1 (P=0.0037) as independent negative PFS predictors. CONCLUSION: Both 18F-FDG PET (EORTC criteria and PERCIST) and CT (RECIST1.1) after 4 to 8ICI monotherapy cycles are accurate for evaluation of tumor response and predicting prognosis in NSCLC patients.

Radiation Pneumonitis After Volumetric Modulated Arc Therapy for Non-small Cell Lung Cancer.

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.

Deep learning with deep convolutional neural network using FDG-PET/CT for malignant pleural mesothelioma diagnosis.

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.

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.

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.

Response to Immune Checkpoint Inhibitor Therapy in Patients with Unresectable Recurrent Malignant Pleural Mesothelioma Shown by FDG-PET and CT.

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 < 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.

Usefulness of Quantitative Bone Single-Photon Emission Computed Tomography/Computed Tomography for Evaluating the Treatment Response of Bone Metastasis in a Lung Cancer Patient.

We report a case of bone metastasis arising from lung cancer, including quantitative values obtained with bone single-photon emission computed tomography/computed tomography (SPECT/CT), which were useful to evaluate the treatment response. The first bone SPECT/CT during pembrolizumab therapy for lung cancer recurrence showed intense 99mTc-HMDP uptake of the right femur head and mild uptake of the left ribs. After the palliative radiotherapy for the right femur head metastasis and chemotherapy, the second bone SPECT/CT showed a decrease in focal uptake of the right femur hip and increasing uptake of the left ribs. There was also new uptake appearance in the sternum, right rib, spine (Th2, Th9, Th12, L4, S1), and bilateral pelvic bone (left ilium, acetabular cartridge, femur, right ilium and ischium). The change of maximum standardized uptake values (SUVmax) for the right femur head and left third and eighth rib bony metastases were -72.6% (from 22.96 to 6.28), +407.7% (from 2.97 to 15.08), and +229.2% (from 2.60 to 8.56), respectively. The change of whole-lesion metabolic bone volume and total bone uptake was +235.4% (from 22.75 to 76.3 cm3) and +219.1% (from 205.0 to 654.09), respectively. Two quantitative bone SPECT/CT images clearly showed the good response of femur head metastasis due to radiotherapy, and progression of other bone metastases regardless of chemotherapy.

Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

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.

Complications and Predictive Factors for Air Leak > 10 Days with Neoadjuvant Chemotherapy Followed by Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

BACKGROUND: A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D). OBJECTIVE: The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Bevacizumab plus cisplatin/pemetrexed then bevacizumab alone for unresectable malignant pleural mesothelioma: A Japanese safety study.

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.

Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment.

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.

Comparison of modified Response Evaluation Criteria in Solid Tumors, European Organization for Research and Treatment of Cancer criteria, and PET Response Criteria in Solid Tumors for evaluation of tumor response to chemotherapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.

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.

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-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß 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-1ß 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-1ß, 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-1ß/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).