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The rates of postoperative mortality and morbidity are high in patients with malignant pleural mesothelioma (MPM). Therefore, it is important to identify variables that increase the risk of postoperative complications. Pleural thickness has recently been identified as a prognostic indicator in patients with MPM. The aim of this study was to investigate clinical variables, including pleural thickness, that contribute to postoperative complications in patients with MPM.A total of 47 patients who underwent surgical excision of MPM between 2005 and 2021 were enrolled in this study. Correlations between postoperative complications within 90 days of surgery and preoperative clinical factors were investigated.A total of 27 patients underwent extrapleural pneumonectomy (EPP), and the remaining 20 underwent pleurectomy/decortication (P/D). Macroscopic complete resections were obtained in all but three patients. Of the 47 patients, 23 (49%) experienced postoperative complications of grade 3 or worse. The major complication in patients with EPP was respiratory failure (n = 6), whereas the major complication in patients with P/D was prolonged air leakage (n = 7). Univariate logistic regression analysis found a correlation between postoperative complications and age, surgical side, and pleural thickness, while multivariate logistic regression analysis found surgical side (p = 0.04, 95% Cl 1.10-21.71, OR 4.90) and pleural thickness (p = 0.03, 95% Cl 1.21-23.00, OR 5.26) to significantly influence the occurrence of postoperative complications.Pleural thickness has a significant effect on the occurrence of postoperative complications. Patients with thick pleura on the right side are at greater risk of postoperative complications.

This study aimed to demonstrate to the involved departments the goal of increasing the number of robotic-assisted thoracic surgery (RATS) cases/surgeons and acceptable surgery times.This retrospective study included 1572 patients who underwent thoracic surgery from fiscal year (FY) 2018 to FY 2021. The factors evaluated included the number of surgery cases and actual and scheduled surgery times.The total number of RATS and total surgery cases increased after the quality indicator (QI) setting (n = 363, 360, 417, and 432 in FY 2018, 2019, 2020, and 2021, respectively). In FY 2020, 93.3% of the QI target was achieved, while in FY 2021, 88% was achieved. The number of RATS lobectomy/segmentectomy increased as the FY progressed (n = 31, 47, 58, and 116 in FY 2018, 2019, 2020, and 2021, respectively). The mean surgical time by RATS starters decreased in FY 2020 and 2021 (171.4 min.; 74 cases; seven RATS starters) compared with those in FY 2018 and 2019 (198.0 min.; 57 cases; six RATS starters) (P = 0.002).The goal of increasing the number of surgery cases and RATS cases/surgeons within the given framework was achieved by setting the QI.

Multidisciplinary treatment including anatomical pulmonary and chest wall resection is recommended for lung cancer complicated by chest wall invasion. The present study aimed to investigate the survival benefit and safety of preoperative therapy followed by surgery for non-small cell lung cancer with chest wall invasion.Sixty-five patients who underwent surgical excision of lung cancer complicated with chest wall invasion between 2009 and 2020 were enrolled in this study.The median age was 65 (37-81) years old, with 59 males and 6 females. Histological types included squamous cell carcinoma (n=32) and adenocarcinoma (n=21). The median tumor diameter was 5.5 cm (2.3-12.5 cm). The clinical nodal status was N0 in 49 cases and N positive in 16 cases. Of the 65 eligible patients, 5- and 10-year overall survival (OS) rates were 58.4% and 46.0%, respectively, and 5- and 10-year progression-free survival (PFS) rates were 54.2% and 41.7%, respectively. For patients receiving preoperative therapy followed by surgery (Pre-Tx), 5- and 10-year OS survival rates were 69.2% and 62.9%, and among patients receiving up-front surgery (UFS) were 48.5% and 29.1%, respectively (p=0.03). The 5- and 10-year PFS rates for pre-Tx were 65.8% and 59.2%, respectively, and 44.7% and 26.8% for UFS, respectively (p=0.02). Cox regression analysis preoperative therapy was significantly associated with OS and PFS.We demonstrate the survival benefit of preoperative therapy followed by surgery for patients with lung cancer and chest wall invasion.

There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess the immunogenicity, immunoglobulin (Ig)-bound cryptoproteins in plasmas were profiled by mass spectrometry. The specimen set consisted of plasmas from 30 newly diagnosed NSCLC cases, pre-diagnostic plasmas from 51 NSCLC cases, and 102 control plasmas. An analysis of LUAD cell lines identified 420 cryptoproteins. Plasma Ig-bound analyses revealed 90 cryptoproteins uniquely found in cases and 14 cryptoproteins that had a fold-change >2 compared to controls. In pre-diagnostic samples, 17 Ig-bound cryptoproteins yielded an odds ratio ≥2. Eight Ig-bound cryptoproteins were elevated in both pre-diagnostic and newly diagnosed cases compared to controls. Cryptoproteins represent a class of neoantigens that induce an autoantibody response in NSCLC.

Background: Early-stage lung adenocarcinoma (LUAD) patients have substantial risk for recurrence and disease-related death. Cisplatin-based adjuvant chemotherapy remains the standard for care of LUAD patients who have undergone surgical resection with a high risk of recurrence. However, adjuvant chemotherapy is associated with increased risk of toxicity including chemotherapy-related death, with only a modest survival benefit. Therefore, there is an unmet need of biomarkers for assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. Circulating miRNAs are stably present in blood and potentially reflect different expressions in cancerous and non-cancerous tissues, making them attractive biomarkers. The purpose of this study was to identify circulating miRNAs useful for predicting recurrence in early-stage LUAD. Materials and Methods: miRNA microarray analysis was performed with pooled pretreatment plasma samples from stage I LUAD patients who developed recurrence within two years after curative surgery or remained recurrence free over a six-year follow-up period, as well as from healthy controls. miRNA biomarker candidates were assayed in two independent plasma sample sets from 85 stage I LUAD (validation set) and from 57 stage I and II LUAD (test set) patients. Results: Based on miRNA microarray data and previous reports, predictive performance of miR-23a-3p, miR-23b-3p, miR-191-5p, miR-185-5p, miR-151a-3p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p was evaluated in the validation set. Plasma levels of miR-23a-3p, miR-185-5p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p were significantly higher in those with recurrence as compared to those without. A miRNA panel comprised of miR-23a-3p, miR-320c, and miR-125b-5p was developed based on a logistic regression, with yielding an AUC of 0.776 (95% confidence interval [CI] = 0.660 to 0.893). The three-miRNA panel with fixed coefficients yielded an AUC of 0.804 (95% CI = 0.688 to 0.920) with a sensitivity of 45.8% at 95% specificity in the test set. The miRNA panel score was a significant and independent factor for predicting disease-free survival (DFS; P < 0.001, HR = 1.64, 95% CI = 1.51-4.22) and overall survival (OS; P = 0.001, HR = 1.51, 95% CI = 1.17-1.94). Conclusion: This circulating miRNA panel may serve as a noninvasive blood test for predicting DFS and OS in early-stage LUAD patients. Our findings provide rationale for further investigation to stratify early-stage LUAD patients using blood-based biomarkers to increase the ability to provide more personalized care. Citation Format: Mei-Chee Tai, Leonidas E. Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F. Fahrmann, Edwin Ostrin, Kohei Yokoi, Toyofumi F. Chen-Yoshikawa, Yoshinori Hasegawa, Samir M. Hanash, Ignacio I. Wistuba, Ayumu Taguchi. A circulating microRNA panel predicts recurrence and survival in early-stage lung adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3744.

Extended thymectomy is employed for patients with myasthenia gravis (MG) and/or thymoma with elevated serum antiacetylcholine receptor antibody (AchR) titers. However, MG symptoms occasionally worsen in post-thymectomy patients. We explored the risk factors for exacerbation of MG symptoms after surgical therapy for patients with MG and/or thymoma with an elevated AchR titer. We retrospectively analyzed 90 patients suffering from MG and/or thymoma with an elevated AchR titer who underwent thymectomy in our institute. Patients were classified into Improved, Unchanged, and Exacerbated groups by assessing their postoperative myasthenic symptoms, amount of medication, and incidence of myasthenic crisis. Risk factors for postoperative exacerbation of myasthenic symptoms were assessed by comparing the Exacerbated with the Improved and Unchanged groups. Of the 90 patients, 29 were classified into the Improved group, 47 into the Unchanged group, and 14 into the Exacerbated group. The presence of thymoma and Masaoka stage were significantly different between the Exacerbated and Improved/Unchanged groups. Although preoperative AchR titers did not significantly differ among the groups, the perioperative AchR titers in the Exacerbated group were significantly higher than those in the other groups (P = 0.003). A multiple logistic regression analysis with stepwise forward selection showed that advanced-stage thymoma was a risk factor for postoperative exacerbation of myasthenic symptoms (P = 0.007). Patients with advanced-stage thymoma have a relative risk for exacerbation of myasthenic symptoms after surgical therapy.

Extracellular vesicles (EVs) are known effectors of cell signaling and exchange implicated in cancer development and progression, as well as remodeling and immunomodulation of the tumor microenvironment. EVs are detected in various biofluids and are considered to convey signature features of the cells from which they originate. Clinical assessment of plasma-derived EV molecular contents therefore offers promise of “liquid biopsies” for detection or subtyping of cancers as well as dynamic reporting of tumor status during and after treatment. To date, there have been no comprehensive analyses aimed at interrogating the diverse repertoire of EV protein cargoes in small cell lung carcinoma (SCLC). Using plasmas from a cohort of 18 SCLC cases, 16 lung adenocarcinoma (LUAD) cases and 34 controls matched based on smoking status, age, and sex, EVs were enriched via affinity capture using magnetic beads functionalized with phosphatidyl serine binding protein TIM4 in addition to single-step density flotation ultracentrifugation to deplete abundant protein background. In-depth proteomic profiling was performed on enriched EVs via nano liquid chromatography / high-resolution ion-mobility mass spectrometry. Profiles were intersected with proteomic profiles generated from intratumor EVs dissociated from 12 SCLC patient-derived xenograft (PDX) mouse models as well as EVs isolated from cell-conditioned medias of a panel of 17 SCLC cell lines. A total of 496 proteins were quantified in TIM4pos EVs. Unsupervised hierarchical clustering and principal component analyses showed that TIM4pos EV protein cargoes differentiate SCLC from LUAD and matched controls. Differential analyses identified 117 proteins that were elevated (AUC> 0.60) in TIM4pos SCLC EVs compared to controls. Of these 117 features, 101 (86%) were also elevated (AUC> 0.60) in TIM4pos SCLC EVs compared to TIM4pos LUAD EVs. Intersection of proteins elevated in TIM4pos SCLC EVs with proteomic profiles of intratumor EVs from SCLC PDX models and conditioned media-derived EVs from SCLC cell lines yielded 67 and 92 overlapping proteins, respectively. Overlapping proteins were characterized by YAP1-associated signatures of cytoskeletal re-arrangement and epithelial-to-mesenchymal transition and included a prevalence of neuronal tubulin and actin family members, YWHA family members, and annexins. We developed and applied an optimized EV isolation and proteomics workflow to profile EV protein cargoes and establish circulating EV-associated protein signatures of SCLC with biomarker potential. Our integrated analyses identified novel EV-associated proteins for detection of SCLC that are associated with oncogenic drivers. These studies demonstrate that EVs harbor cancer cell disseminated signatures and that continued efforts to query the EV proteome towards discovery of novel SCLC biomarkers are warranted. Citation Format: Jody Vykoukal, Taketo Kato, Hiroyuki Katayama, Allison Stewart, Ehsan Irajizad, Yining Cai, Fu-Chung Hsiao, Jennifer B. Dennison, Edwin J. Ostrin, Hai T. Tran, Carl M. Gay, Lauren A. Byers, Johannes F. Fahrmann, Samir M. Hanash. Cancer cell derived extracellular vesicles convey protein signatures of small cell lung carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P078.

Simple Summary Extracellular vesicles (EVs) are extensively distributed in various biological fluids, and contain diverse bioactive molecules including proteins, nucleic acids and lipids. They are considered to provide high stability to the associated molecular cargoes because of encapsulation by the lipid bilayer, making them ideal for liquid biopsy and as a drug delivery system. Moreover, EVs can affect immunomodulatory functions, including antigen presentation and immune activation and suppression. Inhibiting the production of tumor-derived EVs can support tumor immunity, and immune cell-derived EVs can be used as an anticancer vaccine. This review summarizes the biological functions and isolation methods of EVs, and explores their diagnostic and therapeutic applications in lung cancer. Abstract Extracellular vesicles (EVs) are nano-sized lipid-bound particles containing proteins, nucleic acids and metabolites released by cells. They have been identified in body fluids including blood, saliva, sputum and pleural effusions. In tumors, EVs derived from cancer and immune cells mediate intercellular communication and exchange, and can affect immunomodulatory functions. In the context of lung cancer, emerging evidence implicates EV involvement during various stages of tumor development and progression, including angiogenesis, epithelial to mesenchymal transformation, immune system suppression, metastasis and drug resistance. Additionally, tumor-derived EVs (TDEs) have potential as a liquid biopsy source and as a means of therapeutic targeting, and there is considerable interest in developing clinical applications for EVs in these contexts. In this review, we consider the biogenesis, components, biological functions and isolation methods of EVs, and the implications for their clinical utility for diagnostic and therapeutic applications in lung cancer.

Simple Summary Small-cell lung cancer (SCLC) typically presents at an advanced stage and is associated with high mortality. When diagnosed at an early stage with localized disease, long-term survival can, however, be achieved. In this study, we report a comprehensive proteomic profiling of case plasmas collected at the time of diagnosis or preceding diagnosis of SCLC with the objective of identifying blood-based markers associated with disease pathogenesis. Our study reveals the occurrence of circulating protein features centered on signatures of oncogenic MYC and YAP1 that were elevated in plasmas of cases at and before the time-of-diagnosis of SCLC. We further report several proteins, particularly inflammatory markers, that were identified as elevated in plasma several years prior to the diagnosis of SCLC and that may indicate increased risk of disease. In summary, our study identifies several novel circulating proteins associated with SCLC development that may offer utility for early detection. Abstract Small-cell-lung cancer (SCLC) is associated with overexpression of oncogenes including Myc family genes and YAP1 and inactivation of tumor suppressor genes. We performed in-depth proteomic profiling of plasmas collected from 15 individuals with newly diagnosed early stage SCLC and from 15 individuals before the diagnosis of SCLC and compared findings with plasma proteomic profiles of 30 matched controls to determine the occurrence of signatures that reflect disease pathogenesis. A total of 272 proteins were elevated (area under the receiver operating characteristic curve (AUC) ≥ 0.60) among newly diagnosed cases compared to matched controls of which 31 proteins were also elevated (AUC ≥ 0.60) in case plasmas collected within one year prior to diagnosis. Ingenuity Pathway analyses of SCLC-associated proteins revealed enrichment of signatures of oncogenic MYC and YAP1. Intersection of proteins elevated in case plasmas with proteomic profiles of conditioned medium from 17 SCLC cell lines yielded 52 overlapping proteins characterized by YAP1-associated signatures of cytoskeletal re-arrangement and epithelial-to-mesenchymal transition. Among samples collected more than one year prior to diagnosis there was a predominance of inflammatory markers. Our integrated analyses identified novel circulating protein features in early stage SCLC associated with oncogenic drivers.

Programmed death ligand 1 (PD-L1) is reportedly expressed in various malignancies and is considered a prognostic factor. We attempted to reveal the usefulness of the PD-L1 expression as a prognostic factor in patients with thymoma.Eighty-one patients with thymoma who underwent surgical resection between 2004 and 2015 were retrospectively reviewed. The PD-L1 expression was evaluated by immunohistochemistry and stratified by the proportion of positive tumor cells. Strong membranous reactivity of the PD-L1 antibody in 1% or more of tumor cells was considered "positive." The association between the PD-L1 expression and the clinicopathologic features was investigated.The PD-L1 expression was positive in 22 patients (27%) and negative in 59 patients (73%). The PD-L1 positivity was significantly associated with type B2 and B3 thymoma (p0.001) and stage III and IV disease (p = 0.048). In addition, PD-L1 positive tumors showed a significantly higher maximum standardized uptake value than PD-L1 negative tumors (p = 0.026). The 5-year disease-free survival rate was 82% in PD-L1 positive patients and 88% in PD-L1 negative patients, showing no significant difference (p = 0.57). Furthermore, PD-L1 positivity was not an independent prognostic factor for the disease-free survival on a Cox proportional hazards analysis (p = 0.59).A strong expression of PD-L1 in thymoma was significantly associated with type B2 and B3 and higher pathologic stages. In addition, PD-L1 positivity was associated with an increased maximum standardized uptake value of the tumor. However, patients with PD-L1 positive thymomas did not show a significantly worse prognosis than patients with PD-L1 negative tumors.

Background: Differences in individual body sizes have not been well considered when analyzing the survival of patients with non-small cell lung cancer (NSCLC). We hypothesized that physique-adjusted tumor size is superior to actual tumor size in predicting the prognosis. Methods: Eight hundred and forty-two patients who underwent R0 resection of NSCLC between 2005 and 2012 were retrospectively reviewed, and overall survival (OS) was evaluated. The physique-adjusted tumor size was defined as: x-adjusted tumor size = tumor size × mean value of x/individual value of x [x = height, weight, body surface area (BSA), or body mass index (BMI)]. Tumor size category was defined as ≤2, 2–3, 3–5, 5–7, and >7 cm. The separation index (SEP), which is the weighted mean of the absolute value of estimated regression coefficients over the subgroups with respect to a reference group, was used to measure the separation of subgroups. Results: The mean values of height, weight, BSA, and BMI were 160.7 cm, 57.6 kg, 1.59 m2, and 22.2 kg/m2, respectively. The 5-year survival rates ranged from 88−59% in the non-adjusted tumor size model (SEP 1.937), from 90−57% in the height-adjusted model (SEP 2.236), from 91−52% in the weight-adjusted model (SEP 2.146), from 90−56% in the BSA-adjusted model (SEP 2.077), and from 91−51% in the BMI-adjusted model (SEP 2.169). Conclusions: The physique-adjusted tumor size can separate the survival better than the actual tumor size., ファイル公開：2019/04/01

The aim of this study was to investigate the feasibility and safety of our surgical experiences conducted in collaboration with cardiovascular surgeons at our institution. From May 2002 to December 2015, among 3595 general thoracic surgeries, 75 (2.1%) operations were carried out collaboratively with cardiovascular surgeons at Nagoya University Hospital. We investigated the surgical procedures, manipulated organs, morbidity and mortality, completeness of surgical resection, and prognosis of these 75 cases. The study cohort consisted of 56 males and 19 females, ranging in age from 18 to 79 years (median 60 years). Fifty-eight patients had a malignant disease, and 17 had a benign disease. Out of 75 collaborative surgeries, 53 (71%) were scheduled cases (cardiovascular surgeons’ support was considered to be necessary preoperatively), and 22 (29%) were emergent cases (cardiovascular surgeons’ support was considered to be necessary intraoperatively). No 30- or 90-day mortality was observed. Respiratory failure, defined as the requirement of mechanical ventilation or non-invasive positive pressure ventilation for ≥5 days, was the most common morbidity (n = 14, 18%). Forty-three patients (78%) out of 55 with thoracic neoplasms achieved microscopic complete resection. The resection status of the remaining 12 (22%) was microscopic residual tumor. Collaborative surgeries with cardiovascular surgeons at our institution were feasible. High-quality surgeries with a good balance between safety and completeness of resection are important not only for treatment, but also in terms of education for general thoracic surgeons.

OBJECTIVES The diffusing capacity of the lung for carbon monoxide (DLCO) is an indicator of lung damage. We sought to determine whether DLCO is associated with the aggressiveness of lung adenocarcinoma using histopathological indexes, such as tumour differentiation, scar grade, nuclear atypia and the mitotic index. METHODS Fifty-seven patients with low DLCO (≤80% of predicted) and 466 patients with normal DLCO (>80% of predicted) who underwent R0 resection of lung adenocarcinoma between 2005 and 2012 were retrospectively reviewed. The relationships between the DLCO status and each histopathological index as well as the overall survival were evaluated. RESULTS Low DLCO had significant relationships with moderate/poor differentiation (79% vs 57% [low DLCO vs normal DLCO]), scar grade 3/4 (37% vs 18%), nuclear atypia 3 (65% vs 30%) and the mitotic index 3 (26% vs 8%). After adjusting for the age, sex, forced expiratory volume in 1 s, smoking status and tumour size, a low DLCO still showed a significant correlation with the histopathological indexes. These histopathological indexes were all significant factors for the overall survival on log-rank tests. In a multivariable Cox regression analysis with 13 clinicopathological variables, moderate/poor differentiation and nuclear atypia Grade 3 were significant histopathological factors for the overall survival (hazard ratios: 2.16 and 1.84; 95% confidence intervals: 1.10-4.51 and 1.06-3.21; P = 0.024 and 0.029, respectively). CONCLUSIONS Our findings regarding the relationship between DLCO and the histopathological indexes of lung adenocarcinoma suggest that lung damage may be associated with carcinogenesis and progression.

There is little known about predictors of the effects of induction therapy in locally advanced lung cancer, including superior sulcus tumors. We analyzed whether intra-tumoral blood feeding could predict a pathologic complete response (pCR). Patients who underwent induction therapy followed by surgery for locally advanced lung cancer were retrospectively reviewed. The intra-tumoral blood feeding was defined by the CT value (HU, Hounsfield unit), which was calculated by subtracting the non-enhanced value from the contrast-enhanced value (divided into the early and delayed phase) at the maximum diameter of the tumor on dynamic CT. The cases were classified, according to the efficacy of induction therapy, into the pCR and residual tumor (pRT) group. There were 38 cases of T3 and 12 of T4; the induction therapy consisted of chemoradiotherapy in 39 patients, chemotherapy in 6, and radiotherapy in 5. A pCR was obtained in 15 (30%) patients. The mean CT values of the early and delayed phases in the pCR group were 14.8 and 30.7 HU, while those in the pRT were 15.3 and 32.2 HU, respectively. A logistic regression analysis revealed that a smaller tumor size (< 42 mm) was a non-significant predictor of a pCR (p = 0.09); the maximum standardized uptake value on FDG-PET and the CT values on the early and delayed phases of dynamic CT were not associated with the achievement of a pCR. In conclusion, intra-tumoral blood feeding of the locally advanced lung cancer did not predict the effects of induction therapy, whereas smaller sized tumors tended to show a better response.

Extracellular vesicles (EVs) are increasingly understood to participate directly in many essential aspects of host antitumor immune response. Tumor- and immune-cell-derived EVs function in local and systemic contexts with roles in immune processes including cancer antigen conveyance, immune cell priming and activation, as well as immune escape. Current practice of cancer immunotherapy has de facto focused on eliciting T-cell-mediated cytotoxic responses. Humoral immunity is also known to exert antitumor effects, and B cells have been demonstrated to have functions that extend beyond antibody production to include antigen presentation and activation and modulation of T cells and innate immune effectors. Evidence of B cell response against tumor-associated antigens (TAAs) is observed in early stages of tumorigenesis and in most solid tumor types. It is known that EVs convey diverse TAAs, express antigenic-peptide-loaded MHCs, and complex with circulating plasma antitumoral autoantibodies. In this review, we will consider the relationships between EVs, B cells, and other antigen-presenting cells, especially in relation to TAAs. Understanding the intersection of EVs and the cancer immunome will enable opportunities for developing tumor antigen targets, antitumor vaccines and harnessing the full potential of multiple immune system components for next-generation cancer immunotherapies.

Using a combination of mass-spectrometry and aptamer array-based proteomics, we characterized the protein features of circulating extracellular vesicles (EVs) in the context of lung (LUAD) and pancreatic ductal (PDAC) adenocarcinomas. We profiled EVs isolated from conditioned media of LUAD and PDAC cell lines to identify EV-associated protein cargoes released by these cancer cell types. Analysis of the resulting data identified LUAD and PDAC specific and pan-adenocarcinoma EV protein signatures. Bioinformatic analyses confirmed enrichment of proteins annotated to vesicle-associated processes and intracellular compartments, as well as representation of cancer hallmark functions and processes. Analysis of upstream regulator networks indicated significant enrichment of TP53, MYC, TGFB1 and KRAS-driven network effectors (p = 1.69 &times, 10&minus, 77&ndash, 2.93 &times, 49) manifest in the adenocarcinoma sEV protein cargoes. We extended these findings by profiling the proteome of EVs isolated from lung (N = 15) and pancreatic ductal (N = 6) adenocarcinoma patient plasmas obtained at time of diagnosis, along with EVs derived from matched healthy controls (N = 21). Exploration of these proteomic data revealed abundant protein features in the plasma EVs with capacity to distinguish LUAD and PDAC cases from controls, including features yielding higher performance in the plasma EV isolates relative to unfractionated plasmas.

Among the perioperative findings which included patient characteristics and imaging, surgical, and pathological findings of the tumor, the risk factors for pleural recurrence (PR) after complete resection of thymoma were explored. Fifty-three patients with Masaoka stage I to III thymoma who underwent complete resection, and five patients with stage IVa disease accompanied with pleural dissemination were analyzed. In these cohorts, the patients were divided into a non-recurrence (NR) group, PR group and stage IVa group. The maximum tumor diameter (TD) and the contact length between the tumor contour and the lung (CLTL) were measured at the maximum section of the tumor on axial computed tomography. A multivariate analysis including gender, age, TD, CLTL, tumor adhesion to the lung, Masaoka stage, and WHO histological type was performed to estimate risk factors for PR. The median follow-up period was 76.9 months. PR developed in six patients. The mean TDs were 44 mm in the NR group, 62 mm in the PR group and 73 mm in the stage IVa group, respectively. The mean CLTLs were 47, 90 and 96 mm, respectively. The CLTLs of the PR group were significantly longer than those of the NR group (p

症例は28歳女性．右下部側胸壁の膨隆を自覚し当院を受診．胸腹部CT，MRI上は胸部骨性胸郭外壁から腹腔側に連なる多房性嚢胞を認め，血管腫が疑われた．手術では先ず腫瘍胸壁部の直上を肋骨に沿って皮膚切開した．比較的薄い被膜から成る腫瘍を前鋸筋，外腹斜筋および肋間筋から剥離し，さらに創を腹壁へ延長して肋骨弓を離断し開腹すると，腹腔側腫瘍は嚢胞成分が主体で，一部胸壁腫瘍と連なるようにして腹膜外に在り，肝臓を圧迫していたため，これを腹膜と共に摘出した．病理診断は筋肉内血管腫で，胸壁と腹壁の腫瘍は起源が同一であった．皮膚の血管腫に比べ，深部軟部組織に生じる血管腫は稀であり，さらに胸腹壁に連なる巨大な血管腫は他に例を見ない．その発生機序を，胸腹壁腫瘍の発生頻度や画像所見から類推すると，下位肋間筋より発生した後に腹腔内へ進展していったものと推測された．

背景．原発性肺癌における空洞形成機序に関しては未だ議論の余地がある．今回我々はその機序，炎症併発時の対応について文献的考察を加え報告する．症例1．70歳男性．胸部単純写真にて左肺門部異常陰影を指摘．TBLBで扁平上皮癌と診断したが，その後腫瘍内に空洞を形成して吸引性肺炎を併発し，生検後7日目に左下葉切除+S1+2部分切除術を施行した．症例2．60歳男性．主訴は湿性咳嗽．胸部単純写真にて右肺門部に空洞を伴う結節影を指摘．TBLBにて扁平上皮癌の診断を得た後に血痰，発熱を認め，生検後15日目に右下葉切除術を施行した．症例3．64歳男性．健診胸部単純写真にて空洞を伴う結節影を指摘．TBBにて扁平上皮癌と診断した後に発熱，褐色膿性痰を認め，生検後26日目に左肺全摘出術を施行した．結論．本症例の空洞は気管支鏡検査後に増大したことから，癌細胞の虚血性壊死に誘導気管支のcheck valve機構の要因が絡んで形成されたものと推測された．また炎症併発時は適切な抗生剤治療の後に速やかな手術が必要と考えられた．

The prognosis of patients with malignant mesothelioma (MM) remains very poor because of highly invasive tumor characteristics and therapeutic resistance of this tumor. Recent studies have shown that MM frequently shows Hippo signaling pathway inactivation, which leads to activation of YAP1 transcriptional co-activator. Although substantial data from clinical trials and epidemiological studies showed promising results for the use of statins in many cancers, few studies have argued about the underlying tumor-suppressive mechanisms of statins. Here, we show that statins act as an inhibitor of YAP1-dependent MM cell growth via mevalonate pathway. In cell culture, statins attenuate migration and invasion of H290 malignant mesothelioma cells with homozygous deletion of NF2, which encodes Merlin, an upstream regulator of Hippo pathway. In contrast, geranylgeranyl diphosphate (GGPP), a down-stream activator of mevalonate pathway, completely rescues H290 cell growth inhibition by statins. We also found that statins accelerate YAP phosphorylation/inactivation, which results in the downregulation of Hippo-pathway targeting gene transcriptions including CTGF, CYR-61 and ANKRD1. Moreover, among 11 MM cell lines, we demonstrated that five out of the six cell lines, which showed significant cell growth inhibition with statins, harbor NF2 and/or LATS2 mutations. Finally, we found that phospho-YAP/YAP ratio was increased in statin-sensitive cells, but not in statin-resistant cells. Together, our findings suggest that mevalonate pathway plays crucial roles in YAP-dependent MM cells by Hippo pathway inactivation, and therefore represents a potential therapeutic target for MM. Citation Format: Kosuke Tanaka, Taketo Kato, Akihiro Matsushita, Hiromi Furuta, Yuko Murakami, Hirotaka Osada, Yoshitaka Sekido. Statin inhibits malignant mesothelioma cell growth by inactivating YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1046.

We report a case of a 50-year-old man with multiple glomus tumors of the chest wall and buttocks. He was admitted to our hospital because of right chest pain for 10 years. The chest pain was lancinating and gradually increasing. A computed tomography (CT) showed a mass in the right 3rd intercostal space and a mass in the right buttocks. The chest tumor was enhanced with contrast medium on chest CT. Two tumors were resected completely including the 4th rib. Histological examination showed numerous vascular space lined with sheets of epithelial cells (glomus cells), so they were diagnosed as glomus tumor. The postoperative course was well, and the pain disappeared after resection. The glomus tumor of chest wall could be diagnosed as malignant tumor, based on the criteria of the size more than 2 cm and deep location. The glomus tumors which occurred in the chest wall and buttocks were very rare. We presented the case with reference to the literature.