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.

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.

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.

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.

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.

Quantitative 67Ga-citrate SPECT/CT for evaluating disease activity in patients with interstitial lung disease.

OBJECTIVE: To determine whether results of a standardized uptake value (SUV)-based semi-quantitative analytic method for gallium-67 (67Ga)-citrate single photon emission tomography/computed tomography (SPECT/CT) reflects disease activity in patients with interstitial lung disease. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Semi-quantitative values obtained with 67Ga-citrate SPECT/CT showed a moderate correlation with KL-6 and moderate diagnostic performance for predicting disease activity of interstitial lung disease. It is rather unlikely that quantitative 67Ga-citrate SPECT/CT will have a role into the algorithm of interstitial lung disease.

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).

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

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.

Initial evaluation of nivolumab in patients with post-operative recurrence of malignant pleural mesothelioma.

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.

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest.

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.

Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review.

Chemoradiotherapy is important for treating malignancies. However, radiation-induced toxicities develop as chemoradiotherapy-related complications. Various agents reduce or prevent toxicities, but there are no standard treatments. Polaprezinc (PZ), a chelating compound used for gastric ulcers, has antioxidant and free radical scavenging effects. Although few studies have evaluated PZ and radiation-induced normal tissue damage, several clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis and taste alterations during and after radiotherapy. Moreover, preclinical data support the clinical data, indicating good potential of testing PZ in future trials. However, as there are only few well-documented review articles on PZ use in cancer treatment, we conducted this literature review. PZ reduced several radiation-induced toxicities and improved the quality of life.

Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma.

BACKGROUND/AIMS: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. METHODS: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. RESULTS: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. CONCLUSION: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

Suppression of heme oxygenase-1 activity reduces airway hyperresponsiveness and inflammation in a mouse model of asthma.

OBJECTIVE: Carbon monoxide (CO) levels in expired gas are higher in patients with bronchial asthma than in healthy individuals. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes the degradation of heme to yield biliverdin, CO and free iron. Thus, HO-1 is implicated in the pathogenesis of bronchial asthma. However, whether HO-1 expression and activity in lung tissue are related to allergic airway inflammation remains unclear. We investigated whether expression of HO-1 is related to allergic airway inflammation in lungs and whether HO-1 could influence airway hyperresponsiveness and eosinophilia in mice sensitized to ovalbumin (OVA). METHODS: C57BL/6 mice immunized with OVA were challenged thrice with an aerosol of OVA every second day for 8 days. HO-1-positive cells were identified by immunostaining in lung tissue, and zinc protoporphyrin (Zn-PP), a competitive inhibitor of HO-1, was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 23 (day before inhalation of OVA) and immediately before inhalation on the subsequent 4 days (total five doses). Mice were analyzed for effects of HO-1 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue. Ethical approval was obtained from the concerned institutional review board. RESULTS: Number of HO-1-positive cells increased in the subepithelium of the bronchi after OVA challenge, and HO-1 localized to alveolar macrophages. Zn-PP clearly inhibited AHR, pulmonary eosinophilia and IL-5 and IL-13 expression in the lung tissue. CONCLUSION: Expression of HO-1 is induced in lung tissue during attacks of allergic bronchial asthma, and its activity likely amplifies and prolongs allergic airway inflammation.

Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM).

PURPOSE: To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM). METHODS: We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM. A semiautomated system was used to capture CTCs with an antibody against the epithelial cell adhesion molecule. RESULTS: Of 136 eligible patients, 32 were finally diagnosed with nonmalignant diseases (NM), and 104 had MPM. CTCs were detected in 32.7 % (34 of 104) of MPM patients but in only 9.4 % (3 of 32) of NM patients (P = 0.011). The CTC count was significantly higher in MPM patients than in NM patients (P = 0.007), and a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between MPM and NM, with an area under ROC curve of 0.623 (95 % confidence interval, 0.523-0.723; P = 0.036). Among MPM patients, CTCs were more frequently detected in patients with epithelioid subtype (39.7 %, 31 of 78) than in those with nonepithelioid subtypes (11.5 %, 3 of 26; P = 0.016). Positive CTCs (CTC count ≥ 1) were a significant factor to predict a poor prognosis among epithelioid patients (median overall survival, 22.3 months for positive CTCs vs. 12.6 months for negative CTCs; P = 0.004) and not in nonepithelioid patients (P = 0.649). A multivariate analysis showed that positive CTCs were a significant and independent factor to predict a poor prognosis (hazard ratio, 2.904; 95 % confidence interval, 1.530-5.511; P = 0.001) for epithelioid MPM patients. CONCLUSIONS: CTC was a promising marker in diagnosis and prediction of prognosis in MPM, especially in epithelioid MPM.

Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.

OBJECTIVES: Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST (imPERCIST), shown by [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and modified RECIST (mRECIST), shown by CT, were compared for response evaluation and prognosis prediction. RESULTS: imPERCIST indicated nine progressive metabolic disease (PMD), eight stable metabolic disease (SMD), four partial metabolic response (PMR), and five complete metabolic response (CMR) cases. mRECIST showed nine with progressive disease (PD), nine stable disease (SD), seven partial response (PR), and one complete response (CR). Although high concordance was noted (κ = 0.827), imPERCIST correctly judged a greater percentage with CMR (15.4%). Following a median 10.0 months, 15 patients showed progression and eight died from MPM. With both, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients without progression (CMR/PMR/SMD, CR/PR/SD, respectively) as compared to PMD/PD patients (imPERCIST p < 0.0001 and p = 0.015, respectively; mRECIST p < 0.0001 and p = 0.015, respectively). METHODS: Twenty-six patients (23 males, 3 females; median 73.5 years) with histologically proven MPM and no curative surgery received nivolumab plus ipilimumab combination therapy. FDG-PET/CT and diagnostic CT scanning at the baseline, and after 2-4 cycles (2 in three, 3 in 17, 4 in six patients) were performed. Therapeutic response findings evaluated using imPERCIST and mRECIST were compared. PFS and OS analyses were done using log-rank and Cox methods. CONCLUSION: For unresectable MPM patient examinations, FDG-PET and CT provide accurate findings for evaluating tumor response and also prognosis prediction following first-line nivolumab plus ipilimumab immunotherapy (approximately three cycles).

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.