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Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P

Background Evaluation of tumor markers may facilitate follow-up of malignant pleural mesothelioma (MPM). We aimed was to evaluate the value of tumor markers for monitoring and predicting recurrence in patients with MPM. Methods In total, 152 patients who underwent curative-intent surgery after induction chemotherapy for MPM between July 2004 and December 2017 were retrospectively reviewed. Preoperative and postoperative (≤3 months after surgery) levels of soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (Cyfra21-1), and tissue polypeptide antigen (TPA) and rates of recurrence and non-recurrence were evaluated. Factors associated with recurrence-free survival (RFS) were assessed using the Kaplan-Meier method and Cox proportional hazards model. Results Of the 152 patients, the positive rates of preoperative SMRP, Cyfra21-1, and TPA, levels were 26.7%, 8.6%, 9.6%, respectively; the respective postoperative levels were 4.0%, 6.3%, and 6.5%; the respective levels in patients with recurrence were 39.3%, 31.4%, 28.6%; the respective levels in patients with no recurrence were 3.7%, 0.0%, 3.8%. Nearly half (45.2%) of the patients with recurrence exhibited an increase in one or more tumor marker levels. Multivariate analysis revealed that the preoperative positive rates of one or more of the three tumor markers (hazard ratio: 1.8, 95% confidence interval: 1.1-2.8; P=0.02) were independent significant predictors of recurrence. Conclusions The positive rates of SMRP, Cyfra21-1, and TPA in recurrence-free patients were extremely low, with high specificity. Preoperative levels of SMRP, Cyfra21-1, and TPA, which identified patients with a high risk for recurrence, could improve management of patients with MPM.

Background and purpose Disruption of the endothelial glycocalyx is causally related to microvascular endothelial dysfunction, a characteristic of sepsis-induced acute respiratory distress syndrome (ARDS). Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries, but the underlying mechanism remains elusive. Here, we investigated the structural basis and molecular mechanisms of rhTM effects on vascular endothelial injury in a model of sepsis. Experimental approach LPS (20 mg·kg-1 ) was intraperitoneally injected into 10-week-old male C57BL6 mice, and saline or rhTM was intraperitoneally injected 3 and 24 h after LPS injection. Using serum and/or lung tissue, histological, ultrastructural, and microarray analyses were performed. Key results Survival rate of rhTM-treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum concentrations of IL-6 and high-mobility group box 1 were lower in the rhTM-treated group than in the control. Injury to the endothelial glycocalyx in pulmonary capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed up-regulation of gene sets corresponding to cell proliferation/differentiation and anti-inflammation, such as the TGF-β pathway, and negative regulation of IL-6, upon rhTM treatment. Gene expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule 1 (components of the endothelial glycocalyx) was significantly preserved by rhTM treatment, and their protein expression levels were maintained in endothelial cells. Conclusion and implications Our findings show that rhTM treatment affected inflammation, cell proliferation/differentiation, and glycocalyx synthesis in serum and lung tissue, subsequently attenuating ARDS caused by endothelial injury.

OBJECTIVES Impact of pleurectomy/decortication (P/D) on quality of life (QOL) is not widely reported. We investigated QOL and lung function after P/D. METHODS A single-centre, retrospective cohort study was performed among patients who underwent P/D for malignant mesothelioma between June 2014 and June 2018 at Hyogo College of Medicine. Data at 4 points before and 3, 6 and 12 months on QOL and lung function were evaluated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function tests. RESULTS Forty-five out of 65 patients completed SF-36. Physical function and role physical decreased from 78 to 65 and 69 to 41 and did not recover. Body pain decreased from 74 to 52. It increased to 62 at 12 months but was lower than before. General health perceptions, vitality and social function decreased from 56 to 49, 50 to 47 and 63 to 50, respectively, but returned to baseline. Role emotional decreased from 75 to 54, then once increased to 63, but decreased again to 58. Mental health tended to improve from 58 to 70. Thirty-eight patients out of 45 completed pulmonary function tests. Forced vital capacity and forced expiratory volume in 1 s decreased from 98% to 61% and 93% to 67% and did not increase. Right-sided surgery or complications was the risk factors of poor lung function but no significant risk factors in QOL. CONCLUSIONS This study suggests that P/D had an impact on QOL. Despite the lack of recovery in lung function QOL in mental aspects tended to improve, suggesting that pulmonary function tests alone are limited in assessing QOL.

We compared less invasive surgery with conventional surgery for malignant pleural mesothelioma (MPM). We retrospectively reviewed consecutive patients with MPM who received surgery at Hyogo College of Medicine between July 2004 and April 2016. Patients underwent multimodal treatment comprising chemotherapy (neoadjuvant and/or adjuvant) and surgery with or without 54 Gy hemithoracic radiotherapy. Patients were grouped into 3 groups according to the surgery intended: Conventional extrapleural pneumonectomy was intended in Group 1 (until August 2009); less invasive extrapleural pneumonectomy was intended in Group 2 (after September 2009); pleurectomy/decortication was intended in Group 3 (after September 2012). We included 152 patients (median age 64 [37-71] years; 131 men, 21 women), mostly with epithelioid subtypes (91.4%). Of them, 149 (98.0%) underwent neoadjuvant chemotherapy and 117 (77.0%) underwent surgery (60 had extrapleural pneumonectomy and 57 had pleurectomy/decortication). Macroscopic complete resection was achieved in 94.9% (111/117), and the mortality rates at 30 and 90 days were 1.7% (2/117) and 3.4% (4/117), respectively. The overall median survival time and progression-free survival for all 152 patients were 34.9 and 17.4 months. The overall median survival time for Groups 1, 2, and 3 were 18.5, 41.9, and 43.4 months, respectively. The progression-free survival for Groups 1, 2, and 3 were 12.0, 24.5, and 21.8 months, respectively. Compared with conventional surgical techniques, less invasive surgery for MPM yielded lower surgical risks and comparable or improved survival.

The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group. Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models. Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1)

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.

Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.

Pleural biopsy through video-assisted thoracic surgery (VATS pleural biopsy) is the most reliable diagnostic procedure for malignant pleural mesothelioma (MPM). However, definitive diagnosis of MPM is occasionally difficult to establish. This study aims to investigate clinicopathological features of MPM patients who failed diagnosis by the first VATS pleural biopsy. Four hundred consecutive patients with suspected MPM who received VATS pleural biopsy between March 2004 and July 2017 were enrolled in this retrospective study. Patients, whose histological diagnoses were not definitive in the first VATS pleural biopsy, were followed up as atypical mesothelial proliferation (AMP) or non-specific pleuritis (NSP). Re-examination was performed in cases strongly suspected of having MPM. Of the 400 patients, 267 (66.8%) were pathologically diagnosed with MPM, 25 with metastatic carcinoma and 6 with benign pleural disease by the first VATS pleural biopsy. Of the remaining 102 patients diagnosed with AMP or NSP, 10 patients (9.8%) were subsequently diagnosed with MPM. Analysis of the clinical course revealed that only insufficient tissue for diagnosis was obtained via VATS pleural biopsy in all cases and that it was caused by very early stage without visible tumour in 4 patients, intrathoracic inflammation in 4 and desmoplastic MPM in 2. In our review, 9.8% of patients diagnosed with AMP or NSP in first VATS pleural biopsy were subsequently diagnosed with MPM due to insufficient tissue for diagnosis. Definitive diagnosis via VATS pleural biopsy is sometimes challenging in following situation; very early stage, intrathoracic inflammation and desmoplastic MPM.

Background/aim We performed multimodality therapy comprising preoperative chemotherapy, extrapleural pneumonectomy (EPP), and radiation therapy for patients with malignant pleural mesothelioma (MPM). Although multimodality therapy resulted in good prognosis, further improvement is required. Therefore, herein, we analysed the prognostic factors using surgical specimens and searched for suitable molecular targets to improve the prognosis after multidisciplinary treatment. Patients and methods Forty-six patients with MPM underwent multimodality therapy. Paraffin-embedded surgical samples were used for immunohistochemistry to evaluate the expression of phosphorylated (p-) AKT, extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and S6 ribosomal protein (S6RP). Results On univariate and multivariate analyses, significant differences were observed according to the histological type, pathological stage, and p-mTOR expression rate. Conclusion The prognosis of MPM is affected by p-mTOR expression, suggesting that molecular-targeted treatment might be used during multimodal therapy for MPM.

Background Most patients with malignant pleural mesothelioma experience recurrence after treatment. However no clinical studies have evaluated postrecurrence survival after pleurectomy/decortication for malignant pleural mesothelioma. This study aimed to clarify postrecurrence survival, treatment, prognostic factors, and recurrence pattern after pleurectomy/decortication. Methods We conducted a retrospective cohort study of 90 patients who underwent neoadjuvant chemotherapy followed by pleurectomy/decortication at our hospital between September 2012 and December 2017. Survival and recurrence were calculated using the Kaplan-Meier method with the log-rank test. Clinical factors related to postrecurrence survival were assessed using multivariate analysis with the Cox proportional hazards model. Results Of 90 patients, 57 (63.3%) developed recurrence. The 1- and 3-year recurrence-free survival rates were 69.7% and 34.0%, respectively (median recurrence-free survival time, 19.0 months). With regard to initial recurrence, 39 patients (68.4%) developed local recurrence, 6 (10.5%) developed distant recurrence, and 12 (21.1%) developed both local and distant recurrences. The 1-year postrecurrence survival rate was 59.5% (median post-recurrence survival time, 14.4 months). Forty-three patients (75.4%) underwent a postrecurrence treatment. Multivariate analysis revealed that postrecurrence treatment (hazard ratio, 0.2; 95% confidence interval, 0.07-0.55; P = .002), performance status 0 to 1 (hazard ratio, 0.24; 95% confidence interval, 0.08-0.76; P = .01), and disease-free interval more than 12 months (hazard ratio, 0.4; 95% confidence interval, 0.16-0.99; P = .04) were the independent, favorable, and significant prognostic factors of postrecurrence survival. Conclusions Postrecurrence survival after pleurectomy/decortication is acceptable, and postrecurrence treatment, performance status, and disease-free interval are important prognostic factors of postrecurrence survival.

Background: Programmed death 1 (PD-1) blockade with Nivolumab are effective in patients with malignant pleural mesothelioma (MPM), however; successful predictive biomarker has not been available. Unlike invasive test with tumor biopsy, peripheral blood is safe and easily obtainable source of biomarkers. We have previously reported that T cell receptor (TCR) diversity of CD8+PD-1+ T cells were effective to predict response to anti-PD-1 antibody treatment in non-small cell lung cancer (NSCLC) patients (AACR2019: Abstract nr 2230). In this study, Next generation sequence(NGS)-based TCR α and β repertoires were examined with peripheral CD8+PD-1+ T cells isolated from 11 patients with MPM and treatment responses were evaluated 2 months after anti-PD-1 antibody treatment. Methods: Peripheral blood mononuclear cells were collected from 11 MPM patients enrolled in this study before administration of anti-PD-1 antibody (Nivolumab). NGS-based TCR α and β repertoire analysis were performed with CD8+PD-1+ T cells isolated with FACS sorting by Repertoire Genesis Inc. TCR diversity was statistically evaluated by Shannon, Simpson and Diversity Evenness 50 (DE50) indices. CT scan was performed during week 8 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Three of 11 (27.3%) MPM patients responded to anti-PD-1 treatment. There were good correlation of all diversity indices between TCRα and TCRβ. TCRβ diversity was significantly higher among responders than non-responders based on DE50 (0.0019 ± 0.00032 vs 0.0011 ± 0.00042, P < 0.05). Also, responders exhibited a clear trend to have higher TCR diversity of CD8+PD-1+ T cells in terms of Shannon, normalized Shannon and Simpson indices. Conclusion: Like NSCLC patients, PD-1 blockade was more effective in MPM patients who had higher levels of TCR diversity in peripheral CD8+PD-1+ T cells. This result suggested the TCR diversity of peripheral CD8+PD-1+ T cells has potential to predict response to immune checkpoint inhibitors in various tumor patient. Further clinical study would be needed to verify effectiveness of this biomarker. Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Ryo Takahashi, Takashi Yokoi, Hiroshi Kodama, Yoshie Inao, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Aki Kobayashi, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Koichiro Yamakado, Takashi Kijima, Seiki Hasegawa. Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4478.

Objectives Definitive diagnosis of the T-component is sometimes challenging in malignant pleural mesothelioma (MPM). Pleural thickness has been reported to be a prognostic factor for MPM and is a potential T-component. Methods We conducted a historical cohort study of patients who underwent neoadjuvant chemotherapy (NAC) and curative-intent surgery as a multimodal treatment for MPM from January 2007 to June 2016. The maximum measurement of pleural thickness among 3 levels and the sum at each level determined using axial computed tomography imaging before and after NAC were termed as "max" and "sum," respectively. We assessed the association between pleural thickness and the primary and secondary end points of overall survival and recurrence-free survival. Survival was analyzed using the Kaplan–Meier curve, log rank test, and multivariate Cox regression model. Results We enrolled 105 patients. We excluded 1 because of missing data; thus, the sample size was 104. The median follow-up period was 29.1 months with recurrence in 78 patients (70.3%) and death in 67 (60.4%). Max and sum ranged from pre (before NAC) values of 0 to 35 (median, 6.05) and 0 to 97 (median, 12.9) to post (after NAC) values of 0 to 30.8 (median, 4.25) and 0 to 67.0 (median, 9.25), respectively. Post values max and sum were associated with overall survival and recurrence-free survival. Post sum values were associated with recurrence (adjusted hazard ratio, 2.59; 95% confidence interval, 1.42-3.83) and death (adjusted hazard ratio, 2.13; 95% confidence interval, 1.16-4.52), respectively. Conclusions Pleural thickness after NAC was an independent prognostic factor in patients who underwent multimodal treatment.

Background: Circulating tumour cells (CTCs) are a potential surrogate for distant metastasis and are considered a useful clinical prognostic marker for metastatic colorectal cancer (mCRC). This prospective study evaluated the preoperative CTC count as a prognostic factor for pulmonary metastasectomy in mCRC patients. Methods: Seventy-nine mCRC patients who underwent curative-intent pulmonary metastasectomy were included. Preoperatively, 7.5 mL of peripheral blood from each patient was quantitatively evaluated for CTCs with the CellSearch ® system. The clinical significance of CTC count was evaluated according to Kaplan-Meier analyses and log-rank test. Multivariate analyses of the perioperative variables were performed. Results: The distribution of CTC counts were as follows; 0 in 66 patients (83.5%), 1 in eight patients (10.1%), 2 in three patients (3.8%), and 3 and 6 in one patient (1.3%). The patients with multiple CTCs (CTC count ≥2) had significant shorter disease-free survival (DFS) (P=0.005, median DFS; 19.8 vs . 8.6 months) and overall survival (OS) (P=0.035, median DFS; not reached vs . 37.8 months), respectively. Multivariate analysis showed the patients with multiple CTCs had elevated risk of recurrence [hazard ratio (HR), 3.28; 95% confidence interval (CI), 1.24–8.67; P=0.017]. Conclusions: The detected rate of CTCs was quite low in mCRC patients who underwent pulmonary metastasectomy. The patient with multiple CTCs had shorter DFS in this study. The larger prospective clinical study is needed to establish the meaning of CTC in mCRC candidate for pulmonary metastasectomy.

Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers, including malignant melanoma, non-small cell lung cancer (NSCLC), renal cell cancer, and head and neck squamous cell carcinoma. Immune checkpoint inhibitors (ICIs) are only effective in around 20% of patients, which saw a demand for the development of biomarkers that predict a therapeutic response before administering treatment. As the biomarkers intratumoral PD-L1 expression and tumor mutation burden (TMB) both require tumor tissue biopsy, there is now a demand for safer and less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. CT scan was performed during week 12 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P < 0.05, P < 0.05, P < 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P < 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. Conclusion: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy. In the future, we intend to analyze TMB and neoepitopes using surgical specimens of these patients and determine the efficacy of this biomarker for cancers other than NSCLC. Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Seiki Hasegawa. Diversity of peripheral CD8+PD-1+ T cells is a novel predictive biomarker for response to anti-PD-1 antibody treatment in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2230.

e20067 Background: It is difficult to predict prognosis for malignant pleural mesothelioma (MPM). The association of thoracic asymmetry and survival in patients with MPM was reported by Cho et al. in at the 18th World Conference on Lung Cancer. Here we investigated the survival impact of thoracic cavity reduction during neoadjuvant chemotherapy (NAC). Methods: The subjects were patients with resectable epithelioid MPM who underwent NAC with platinum and pemetrexed followed by surgery at the Hyogo College of Medicine from Jan 2009 to Aug 2018. The length of the ant-post and med-lat extent of both hemithoraces at the level of carina was measured before and after NAC. Asymmetric ratio (ASR) was defined as the product of the ant-post and med-lat extent of affected side divided by those of healthy side. Results: One hundred thirty-three patients were enrolled: median age 66 (16-79) years, M/F 112/21, R/L 70/63, extrapleural pneumonectomy 40 and pleurectomy/decortication 93. Significantly poor prognosis was associated with ≥ 10mm reduction of the med-lat extent of affected side during NAC and ≥ 10% reduction of the product of the ant-post and med-lat extent of affected side during NAC (p = 0.0021). ASR ≤ 0.9 before or after NAC was not associated with significantly poor survival. Conclusions: This study revealed that thoracic cavity reduction during NAC was associated with significantly poor prognosis of MPM.

8548 Background: Since any surgery for malignant pleural mesothelioma (MPM) are cytoreductive, effective chemotherapy is a prerequisite for surgery. In this context, we give neo-adjuvant chemotherapy (NAC) to all surgical candidates. Methods: Hyogo College of Medicine MPM Surgery Program mandates all surgical candidates to receive NAC, and only patients with stable disease (SD) or better response proceeds to surgery. The program comprised NAC followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation until 2012, and NAC followed by pleurectomy/decortication (P/D) and postoperative chemotherapy thereafter. Eligibility criteria are histologically confirmed non-sarcomatoid MPM, clinically resectable stage (T1-3N0-1M0), performance status 0–1, and no major comorbidity. Results: From December 2006 to December 2018, 225 patients were enrolled. Of 225, 24 patients (10.7%, Group A) did not proceed to surgery because of progressive disease (n=23) or serious adverse events (n=2). Of the remaining 201 patients with partial response (n=38, 16.9%) or stable disease (n=163, 72.4%), 19 refused surgery (Group B), 16 received exploratory thoracotomy (Group C), and 165 completed surgery (Group D, EPP58, P/D107). Surgical mortality rates at 30 and 90 days were 1.1% (n=2) and 2.8% (n=5), and surgical morbidity (≧grade 3) was 26.0% (n=47). Median survival time and survival rates of each group were shown in the table. Briefly, 2-yr survival competed among Group B,C and D, whereas 5-yr survival rapidly dropped in Group B and C. Conclusions: Approximately 90% of MPM patients with surgical intent successfully underwent either of EPP or P/D after effective chemotherapy with acceptable surgical mortality and morbidity. Comparison of patients who refused or accepted surgery suggested that surgery contributed to long-term survival. [Table: see text]

e24326Background: The prognosis of malignant pleural mesothelioma (MPM) is very poor; a new drug for MPM is need. The percentage of p16 loss in MPM patients is high. We hypothesized that CDK4/6 is ...

Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM. Methods We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model. Results Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1] component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone. Conclusions Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.

e20082Background: The retinoblastoma (Rb) protein binds E2F transcription factors in the G1 phase to inhibit the activity of the Rb protein, thereby blocks the cell from initiating DNA replication....

Purpose Surgical treatment of lung cancer in patients receiving hemodialysis carries a high risk because of poor cardiac function and a fragile electrolyte balance. Because the number of patients receiving hemodialysis has increased, the proportion of such patients with lung cancer is expected to rise. However, few studies have examined the results of surgery for lung cancer in hemodialysis patients, especially by video-assisted thoracoscopic surgery (VATS). Methods We conducted a retrospective analysis of 5 hemodialysis patients who underwent VATS for lung cancer. Results All patients were men, and the mean age was 70.4 years. The operative procedure was lobectomy in 4 patients and segmentectomy in 1. During the perioperative period, none required urgent hemodialysis. There were no critical complications and in-hospital deaths. Three of the 5 patients are currently alive and recurrence-free. One patient died of recurrence at 4 month after surgery, and the other patient died at 17 months after surgery without cancer recurrence. Conclusions VATS appears to be a safe procedure for hemodialysis patients with lung cancer, and the long-term outcome is satisfactory.

Tracheal stenosis after intubation is a fairly common complication, and treatment of such cases can be difficult. A 52-year-old woman was admitted to our hospital because of severe dyspnea. Seven years previously, she had suffered tracheal stenosis after tracheal intubation and had undergone tracheal resection and placement of a self-expandable metal stent. In this case, tracheal restenosis had occurred and we successfully treated the patient by insertion of a silicone T-tube after tracheotomy. Use of a T-tube is safe and effective for relief of tracheal restenosis after self-expandable metal stent placement.

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy for which no targeted therapy exists. The mitogen-activated protein kinase (MAPK) pathway plays critical roles in the regulation of tumorigenesis in multiple solid tumors, including MPM. Trametinib, a selective MEK inhibitor, have a survival benefit in patients with V600 BRAF-mutant metastatic melanoma. The effect of trametinib on MPM cells has not been well studied. Hyaluronan (HA) is one of the major components of the extracellular matrix. MPM is in most cases associated with elevated amounts of HA, which has increased the malignant properties of MPM cells. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has antitumor effects in various malignant tumors, but its effect on MPM cells has not been well studied. Purpose: We evaluated the effects of trametinib, 4-MU and their combination on MPM cells in vitro and in vivo. Experimental Design: The effects of trametinib, 4-MU, and their combination on MPM cells were evaluated using cell viability assay, western blot analysis, and mouse xenograft model. Results: Trametinib exhibited an antiproliferative activity in all four MPM cell lines, NCI-H226, NCI-H2452, NCI-H2052, and MSTO-211H, with IC50 values ranging from 0.15 μM to 12.7 μM. Trametinib blocked the phosphorylation of ERK until 72 hours and decreased the expression of CD44 in a dose-dependent manner. In addition, the expression of CD44 was inhibited (48-72 hours) after the suppression of ERK phosphorylation by trametinib. 4-MU exhibited an antiproliferative activity in MPM cells. 4-MU inhibited ERK phosphorylation but not CD44 expression. In mouse xenograft model, trametinib and 4-MU suppressed tumor growth (trametinib vs. control, P < 0.0001; 4-MU vs. control, P < 0.01), and their combination suppressed more strongly (combination vs. trametinib, P < 0.01; combination vs. 4-MU, P < 0.0001; combination vs. control, P < 0.0001). Conclusions: Trametinib and 4-MU exhibited antitumor activities in MPM cell lines. Furthermore, their combination exhibited more potent antitumor activities. These results suggests that Trametinib and 4-MU are promising therapeutic agents in MPM, and these combination therapies may be effective for the treatment of MPM. Citation Format: Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Hiroshi Date, Seiki Hasegawa. Antitumor effect of Trametinib, a selective MEK inhibitor, in combination with 4-methylumbelliferone, a hyaluronic acid synthesis inhibitor, in Malignant pleural mesothelioma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2581. doi:10.1158/1538-7445.AM2015-2581

e18543 Background: The mTOR signal pathways are activated in a broad range of malignancies. Methods: A multimodality therapy consisting of induction chemotherapy , extrapleural pneumonectomy (EPP) ...

e18542 Background: Cisplatin plus pemtrexte is first line chemotherapy for Malignant Pleural Mesothelioma (MPM). In multimodality include extrapleural pneumonectomy (EPP), chemotherapy is essential...

Introducion: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy and there is no approved targeted therapy. The MAPK pathway plays critical roles in the regulation of cell proliferation, growth, differentiation, and survival in multiple solid tumors, including MPM. Trametinib, a selective MEK inhibitor, have a survival benefit in patients with V600 BRAF-mutant metastatic melanoma. FDA approved Trametinib for these patients in May 2013. The effect of Trametinib in MPM cells has not been well studied. Purpose: We examined the effects of Trametinib in MPM cells in vitro. Methods: To examine the effect of Trametinib on the proliferation of MPM cells, we performed cell proliferation assay using four MPM cell lines, NCI-H2452, NCI-H226, NCI-H2052 and MSTO-211H. To examine the effect of Trametinib on intracellular signaling, we performed Western blot analysis in NCI-H226 cell line. Results: Trametinib exhibited potent antiproliferative activity in all four MPM cell lines with IC50 values ranging from 0.5 μM to 44 μM. Trametinib blocked the phosphorylation of ERK until 72 hours and decreased the expression of CD44 in a dose-dependent manner. In addition, the expression of CD44 was inhibited (48-72 hours) after the suppression of ERK phosphorylation by Trametinib. Conclusions: Our results suggest that Trametinib is a promising therapeutic agent for MPM. Citation Format: Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Hiroshi Date, Seiki Hasegawa. Antitumor activity of Trametinib, a MEK1/2 inhibitor, in malignant pleural mesothelioma cells in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 742. doi:10.1158/1538-7445.AM2014-742

7585 Background: Malignant Pleural Mesothelioma (MPM) is a rare disease with poor prognosis. The combination chemotherapy with cisplatin and pemetrexed is the first line of MPM. The AKT/mTOR (Mamma...

BACKGROUND Glypican-3 (GPC3) is an onco-fetal antigen which is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we completed a phase I clinical trial of HLA-A2-restricted GPC3144-152 (FVGEFFTDV) and A24-restricted GPC3298-306 (EYILSLEEL) peptide vaccine in 33 patients with advanced HCC. This clinical trial of GPC3-derived peptide vaccine showed the vaccination to be safe, and indicates many immunological responses. To develop more efficient immunotherapy, we investigated large scale expansion of GPC3 peptide specific CTLs for adoptive immunotherapy. PURPOSE In this study, we investigated the efficiency of new method to induce expansion of GPC3 peptide specific CTLs. METHODS Treatment of human peripheral blood mononuclear cells (PBMCs) with zoledronate is a method that enables large-scale γδ T cell expansion. To induce expansion of GPC3 peptide specific CTLs and γδ T cells, the PBMCs of patients vaccinated with GPC3 peptide were cultured with GPC3 peptide and zoledronate for 14 days. We used CD8+ and CD8− cells that isolated from cultured cells using CD8 microbeads at day 14 as a effector cells. GPC3 peptide specificity and cytotoxic activity of CTLs were analysed by Dextramer assay, cytotoxicity assay and IFN-γ ELISPOT assay. We used human liver cancer cell line SK-Hep-1 (GPC3−, HLA-A*02:01/24:02) and a human GPC3 gene transfectant, SK-Hep-1 [[Unsupported Character - ⁄]] hGPC3 (GPC3+, HLA-A*02:01/24:02) as target cells. T2 (HLA-A*02:01, TAP−) was pulsed with GPC3 peptide or HIV peptide at room temperature for 1h. To evaluate antitumor activity in vivo, we inoculated SK-Hep-1/hGPC3 and SK-Hep-1/vec cells at the right flank of NOD/SCID mice. We injected the CD8+, CD8− or all cells as effector cells intravenously. RESULTS The expansion of Lymphocytes from a few PBMCs of vaccinated patients with advanced HCC using zoledronate yields cell numbers sufficient for adoptive transfer. The rate of increase of GPC3 specific CTLs was approximate 490 to 170,000-fold, whereas the rate of increase of total cell number was approximate 13 to 1,000-fold. These CD8+ cells including CTLs showed GPC3 specific cytotoxicity against SK-Hep-1/hGPC3 and T2 pulsed with GPC3 peptide, but not against SK-Hep-1/vec and T2 pulsed with HIV peptide, whereas CD8− cells including γδ T cells showed cytotoxicity against SK-Hep-1/hGPC3 and SK-Hep-1/vec while did not show GPC3 specificity. Furthermore, adoptive cell transfer of CD8+ cells, CD8− cells and total cells after expansion significantly inhibited tumor growth in NOD/SCID mouse model. CONCLUSION This study indicates that zoledronate is useful to large-scale expand antigen-specific CTLs and γδ T cells for adoptive immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3508. doi:1538-7445.AM2012-3508