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Background Thymoma patients with pleural dissemination are difficult to manage, and their treatment strategy remains undefined. This study aimed to investigate the clinicopathologic features of these patients, focusing on the association between the depth of pleural invasion and prognosis. Methods Between 2003 and 2019, the study identified 120 disseminated lesions in 20 thymoma patients. Seven patients had de novo stage IVa thymoma and 13 were recurrent cases. Extrapleural pneumonectomy was performed for 8 patients and debulking surgery for 12 patients. Invasion depth of pleural tumors was classified into two groups: when the disseminated tumors invaded the pleura beneath the elastic layer, the tumor was diagnosed as Da, and when the disseminated tumors invaded the pleura beyond the elastic layer, the tumor was diagnosed as Db. Results Of 120 nodules, 31 (26%), found in eight patients with recurrent malignancies, were classified as Db. The pathologic status of the surgical margin (PSM) was positive in eight patients, seven of whom had Db nodules. The 5-year overall survival (OS) rate was 100% in the Da group and 75% in the Db group (P = 0.02). The 5-year progression-free survival (PFS) rate was 66.7% in the Da group and 25% in the Db group (P = 0.02). Cox univariate analysis showed that PFS was significantly influenced by the depth of invasion (P = 0.04) and PSM (P = 0.03). Conclusion Depth of pleural invasion may influence survival outcomes for thymoma patients with pleural dissemination. The patients in this study with Da-disseminated nodules had an increased probability of a longer OS and PFS and tended to achieve negative PSM compared with the patients with Db.

Background Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1–negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1–negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1–negative LUAD. Methods Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1–negative and 4 TTF-1–positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided. Results SRGN was markedly overexpressed at mRNA and protein levels in TTF-1–negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1–positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase–mediated impairment of methionine metabolism. Conclusions Our findings suggest that SRGN plays a pivotal role in tumor–stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1–negative LUAD.

PbTaSe$_2$ is a unique topological material, in which the number of nodal lines is expected to change at the structural transition between the lower temperature/pressure "L" phase and the higher temperature/pressure "H" phase. We report the anomalous Nernst effect attributed to the Berry curvature of nodal lines and its change with the structural transition. In the L phase, the Nernst coefficient ($S_{yx}$) shows the step-like magnetic field dependence reminiscent of the anomalous Nernst effect of nonmagnetic Dirac/Weyl semimetals. By applying hydrostatic pressure, we discovered that the amplitude of the anomalous component significantly decreases at the transition to the H phase, which might correspond to the partial annihilation of nodal line structures., Comment: 29 page, 14 figures

Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB–IIIA NSCLC. Patients with completely resected p-stage IB–IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73–1.23; P = 0.69). Although GEM-based adjuvant therapy for patients with completely resected stage IB–IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.

Background Premeditated induction chemotherapy followed by surgical resection is accepted as safe and effective. Studies on salvage surgery in patients with incompletely cured lung cancer are lacking. This study aimed to demonstrate the safety and efficacy of salvage surgery. Methods We conducted a retrospective multi‐institutional cohort study on patients who underwent salvage surgery for advanced (stage III and IV) non‐small cell lung cancer (NSCLC) between January 2005 and December 2016 at the 14 hospitals of the Chubu Lung Cancer Surgery Study Group. A total of 37 patients were assigned to the salvage surgery group; a lobectomy with mediastinal lymph node dissection was performed. The survival benefit was assessed using the Kaplan–Meier method and the Cox proportional hazard model. Results Although postoperative complications were observed in 11 patients (29.7%), surgery‐related death occurred in only one patient (mortality rate: 2.7%) resulting from respiratory failure caused by interstitial pneumonia exacerbation. Postoperative recurrence was observed in 22 patients (61.1%), the incidence of brain metastasis being high (nine patients: 40.9%). The five‐year survival rate from the first day of treatment was 60%. The survival of the postoperative pathological stage (s'‐stage) I group was significantly better (five‐year survival rate: 80.9%) than that of the other groups (p, The complication rate after salvage surgery was 29.7%. Salvage surgery for pulmonary lung cancer is safe and may result in long‐term survival, particularly in those with p‐stage I.

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.

OBJECTIVES The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort. METHODS The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients. RESULTS Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74–4.47; PRCA− NMAD: HR 1.28, 0.30–3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA− NMAD (P CONCLUSIONS Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.

Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109‐deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF‐β binding protein‐1 (LTBP1) as a CD109‐interacting protein using mass spectrometry and confirmed their interaction by co‐immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF‐β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF‐β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease., Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. We determined that CD109 deficiency significantly reduced stromal invasion and prolonged survival of the lung adenocarcinoma mouse model. Furthermore, we identified latent TGF‐β binding protein‐1 as a CD109‐interacting stromal protein, highlighting the significance of interaction between tumor cells and stroma in lung adenocarcinoma progression.

Purpose As the number of cases of early lung cancer in Japan grows, an analysis of the present status of surgical treatments for clinical stage IA lung cancer using a nationwide database with web-based data entry is warranted. Methods The operative and perioperative data from 47,921 patients who underwent surgery for clinical stage IA lung cancer in 2014 and 2015 were obtained from the National Clinical Database (NCD) of Japan. Clinicopathological characteristics, surgical procedure, mortality, and morbidity were analyzed, and thoracotomy and video-assisted thoracic surgery (VATS) were compared. Results The patients comprised 27,208 men (56.8%) and 20,713 women (43.2%); mean age, 69.3 years. Lobectomy was performed in 64.8%, segmentectomy in 15.2%, and wedge resection in 19.8%. The surgical procedures were thoracotomy in 12,194 patients (25.4%) and a minimally invasive approach (MIA) in 35,727 patients (74.6%). MIA was divided into VATS + mini-thoracotomy (n = 13,422, 28.0%) and complete VATS (n = 22,305, 46.5%). The overall postoperative mortality rate was 0.4%, being significantly lower in the MIA group than in the thoracotomy group (0.3% vs 0.8%, P Conclusions Our analysis of data from the NCD indicates that MIA has become the new standard treatment for clinical stage IA lung cancer.

Acute rejection is still a major problem in transplantation and one of the most important causes of late graft loss. Cyclosporine and tacrolimus are widely used for suppression of T cell function to avoid graft rejection, but long-term use of these compounds is associated with serious toxicities. Quercetin, a flavonoid found in fruits and vegetables, has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO) -1, an enzyme involved in heme catabolism. We hypothesized that quercetin induces HO-1 in T cells and suppresses T cell function via HO-1. In the present study, we showed that quercetin suppressed the A23187-mediated expression of interleukin (IL) -2 in T cells. Mouse splenocytes, enriched T cells, and EL4 cells, a mouse T cell line, were treated with quercetin, and then stimulated with A23187, a calcium ionophore, concanavalin A, or anti-CD3ε and anti-CD28 antibodies. Cell proliferation, expression of IL-2, calcium mobilization, apoptosis, cell cycle, and phosphorylation of extracellular signal-regulated kinase (ERK) were investigated. Quercetin induced HO-1, and this induction of HO-1 was implicated in the suppression of IL-2 production. Furthermore, the induction of HO-1 by quercetin suppressed the influx of calcium ions, a known trigger of IL-2 production. Additionally, quercetin suppressed T cell proliferation through promotion of cell cycle arrest via HO-1 induction, but quercetin did not induce apoptosis. To investigate the role of the signal transduction pathway in quercetin’s effect on cell proliferation, we evaluated the phosphorylation of ERK in T cells. Quercetin suppressed the A23187-mediated stimulation of ERK, an effect that was mediated through HO-1. These results suggested that HO-1 is involved in the suppressive effects of quercetin on T cell activation and proliferation. Our findings indicate that the quercetin may be a promising candidate for inducing HO-1 in T cells, thereby facilitating immunosuppressive effects.

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.

Background: Although multidisciplinary treatment is recommended for patients with advanced stage and recurrent thymoma, a detailed treatment strategy remains controversial. We have performed a multimodality therapy of induction chemotherapy (CAMP therapy: cisplatin, doxorubicin, and methylprednisolone) combined with surgery for those patients. We now conducted a retrospective study for investigating the results of this multimodality therapy for thymoma patients with pleural dissemination. Patients and methods: Between 2003 and 2017, 201 patients underwent surgical resection for thymomas. Twenty-six of them received induction CAMP therapy followed by surgery, and 19 of them with pleural dissemination were enrolled in this study. Those cohort were divided into 2 groups by employing surgical procedures: extrapleural pneumonectomy (EPP) group (n = 10) and resection of plural dissemination (RPD) group (n = 9). Results: The median age of all patients was 49 years. Based on the WHO classification, the histological diagnoses of those thymomas were as follows: Type B1 (n = 1), Type B2 (n = 13), and Type B3 (n = 5). Seven patients were complicated with myasthenia gravis (MG). Clinical stage of the 13 primary cases based on the Masaoka classification were stage IV, and the remaining six cases had recurrent pleural dissemination after surgery. Partial response in induction CAMP therapy was obtained in 78.9% (n = 15) of the patients. Adverse events (Grade 4) occurred in 2 patients (10.5%). Postoperative complications (Grade 4) were observed in 2 patients (10.5%). In all of the enrolled patients, the five-year overall survival rate (5Y-OS) and 5-year progression-free survival rate (5Y-PFS) were 76.7% and 55.1%, respectively. In the EPP group, 5Y-OS and 5Y-PFS were 83.3% and 83.3%, respectively, and in the RPD group, 70.0% and 29.6%, respectively. Conclusions: Multidisciplinary treatment using induction CAMP therapy and surgical resection for thymoma patients with pleural dissemination was effective and feasible. Because of the low recurrent rate of disease, young patients with good cardiopulmonary function and well-controlled MG might be good candidates for EPP., ファイル公開：2020/06/01

We assessed the utility of the tumor doubling time (TDT) for predicting the histological type of thymic epithelial tumors. We retrospectively reviewed 130 patients with thymic epithelial tumors who underwent computed tomography two or more times before surgery. The patients were divided into low-risk thymoma (types A, AB and B1), high-risk thymoma (types B2 and B3) and thymic carcinoma (thymic carcinoma and thymic neuroendocrine tumor) groups. In the 96 patients who showed tumor enlargement, the relationship between the histological type and the TDT of the tumor was investigated. The study population included 55 men and 41 women from 26 to 82 years of age. The TDT of the thymic carcinoma group (median 205 days) was significantly shorter in comparison to the low-risk thymoma (median 607 days) and high-risk thymoma (median 459 days) groups. No significant differences were observed between the low-risk thymoma and high-risk thymoma groups. When we set the cutoff time for differentiating thymic carcinoma group from thymoma at 313 days, the sensitivity and specificity were 83.8% and 82.1%, respectively. The TDT is a useful parameter for differentiating between thymoma and thymic carcinoma group.

The aim of this study was to extract predictive factors of prolonged air leak (PAL) including air flow data as objective parameter by digital drainage system (DDS). The 372 patients who underwent lung resection and had continuous log data of air flow by DDS were reviewed. PAL was defined as the air leak which was exceeding 20 ml/min and lasting 5 days or more. The 69 patients (18.5%) showed air leak and were divided into PAL group (n = 21) and non-PAL group (n = 48). The average flow per hour was calculated at 0, 12, and 24 postoperative hours (POH) and the residual ratio of flow at 12, 24, and 36 POH to that at the time after surgery was analyzed with clinical factors. Area under the receiver-operating characteristic curve (ROC-AUC) was calculated to determine optimal cut-off value of PAL predictors. ROC-AUC for flow at 36 POH was 0.88. Sensitivity and specificity were 0.91 and 0.73 when cut-off value was set at 20 mL/min at 36 POH. ROC-AUC for residual ratio at 36 POH was 0.82. Sensitivity and specificity were 0.81 and 0.79 when cut-off value of residual ratio was set at 0.20. The air flow and the residual ratio measured by DDS will be useful predictors of postoperative PAL after lung resection.

Purpose: Metastasis to the lungs arising from biliary tract carcinoma (BTC) is extremely rare, and the patient characteristics and prognosis are not well known. We aimed to identify the imaging findings of pulmonary metastases originating from BTC and the eligible indications for surgical treatment. Methods: Fifteen patients who underwent pulmonary resection for metastases originating from BTC were retrospectively analyzed. Results: The primary sites included cholangiocarcinoma (n = 12) and gallbladder carcinoma (n = 3), and all cases were histologically diagnosed as well to moderately differentiated adenocarcinomas. The median disease-free interval between resection for the primary site and the detection of pulmonary metastasis was 30 months (range 0–144 months). Nine patients had a single lesion, and six had multiple lesions. As features of pulmonary lesions on thin-section computed tomography (CT), many appeared as solid nodules with smooth margins, whereas six lesions were concomitant with spiculation or pleural indentation, three with air bronchogram or ground-glass attenuation, and one with intra-tumoral cavity, and six cases with solitary pulmonary lesion were diagnosed as primary lung cancer before metastasectomy. The 3-year survival rate in the 11 patients who underwent complete metastasectomy was 45%. A disease-free interval of more than 3 years (p = 0.03) and single lesion (p, ファイル公開：2020/11/01

OBJECTIVES The tumour, node and the metastasis (TNM) staging system for thymic epithelial tumours was adopted by the Union for International Cancer Control (UICC) in 2016. Although the T factor is defined by the invasive nature of a thymoma, tumour size is not considered. The aim of this study was to examine the clinical importance of tumour size using a nationwide retrospective database of cases treated from 1991 to 2010 compiled by the Japanese Association for Research of the Thymus. METHODS Tumour size was evaluated by the maximum diameter shown by computed tomography imaging prior to resection. Tumour size was available for 2083 thymoma patients undergoing upfront surgical treatment. The tumour size ranged from 0.6 to 19.4 cm (mean 5.1 cm, median 4.9 cm). Harrell’s C-index was adopted to determine the cut-off value of the tumour size in 0.5-cm increments. RESULTS The highest C-index value (0.7760) was obtained in terms of recurrence-free survival after the complete resection when the cut-off value was set at 5.0 cm. The 10-year recurrence-free survival rate was 93.8% in patients with a tumour ≤5.0 cm and 84.3% in patients with a tumour >5.0 cm (P CONCLUSIONS Tumour size is an important prognostic factor and should be considered when determining the treatment strategy for thymoma patients.

Introduction The Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies. Methods The clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed. Results The cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively. Conclusions This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.

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.

Purpose Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication. Methods Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used. Results Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values. Conclusions Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function.

PURPOSE To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m2, day 1) plus cisplatin (75 mg/m2, day 1) or vinorelbine (25 mg/m2, days 1 and 8) plus cisplatin (80 mg/m2, day 1) with stratification by sex, age, pathologic stage, EGFR mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients. RESULT Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had EGFR-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided P = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% v 0.3%, respectively), neutropenia (81.1% v 22.7%, respectively), and anemia (9.3% v 2.8%, respectively). One treatment-related death occurred in each arm. CONCLUSION Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.

Background We have developed a surgical navigation system that presents virtual thoracoscopic images using computed tomography (CT) image data, as if you are observing intra-thoracic cavity in synchronization with the real thoracoscopic view. Using this system, we made it possible to simultaneously visualize the 'area of lung cancer before induction therapy' and the 'optimal resection line for obtaining a safe surgical margin' as a virtual thoracoscopic view. We applied this navigation system in the clinical setting in operations for lung cancer patients with chest wall invasion after induction chemoradiotherapy. Methods The proposed surgical navigation system consisted of a three-dimensional (3D) positional tracker and a virtual thoracoscopy system. The 3D positional tracker was used to recognize the positional information of the real thoracoscope. The virtual thoracoscopy system generated virtual thoracoscopic views based on CT image data. Combined with these two technologies, patient-to-image registration was performed in two patients, and the results generated a virtual thoracoscopic view that was synchronized with the real thoracoscopic view. Results The operations were started with video-assisted thoracic surgery (VATS), and the navigation system was activated at the same time. The virtual thoracoscopic view was synchronized with the real thoracoscopic view, which also simultaneously indicated the 'area of lung cancer before induction therapy' and the 'optimal resection lines for obtaining a safe surgical margin'. We marked the optimal lines using an electric scalpel, and then performed lobectomy and chest wall resection with a sufficient surgical margin using these landmarks. Pathological examinations confirmed that the surgical margin was negative. No complications related to the navigation system were encountered during or after the procedures. Conclusions Using this proposed navigation system, we could obtain a 'CT-derived virtual intra-thoracic 3D view of the patient' that was aligned with the thoracoscopic view during surgery. The accurate identification of areas of cancer invasion before induction therapy using this system might be a useful for determining optimal surgical resection lines.

Micro-computed tomography (µCT) provides extremely high-resolution images of samples and can be employed as a non-destructive inspection tool. Using µCT, we can obtain images comparable with microscopic images. In this work, we have attempted to take high-resolution images of the human lung using µCT. Compared to clinical high-resolution computed tomography (HRCT) images of living body (in-vivo imaging), we can obtain extremely high-resolution images by µCT of ex-vivo tissues (resected lungs) as three-dimensional data. The purpose of this study was to distinguish between areas of normal lung and lung cancer by µCT images in order to study the feasibility of cancer diagnosis using this novel radiological image modality. Ten resected human lungs containing primary cancer were fixed by Heitzman’s methods to obtain high-resolution µCT images. After fixation of the lung, images of the specimens were taken by µCT between January 2016 and November 2017. The imaging conditions were tube voltage: 90 kV and tube current: 110 µA. To compare details of images gained by conventional HRCT and µCT, we measured the thickness of the alveolar walls of the normal lung area and the cancer area of which alveoli might be replaced by tumor cells, and compared their appearance by means of histopathological images. All the nodules were diagnosed as adenocarcinoma. The median whole tumor size was 18 mm (9 mm–24 mm). Each specimen was clearly divided into areas of normal alveolar wall and of thickened alveolar wall on µCT ‘visually’. Median thickness of alveolar walls of the normal lung was 0.037 mm (0.034 mm–0.048 mm), and that of the cancer area was 0.084 mm (0.074 mm–0.094 mm); there was a statistically significant difference between both thicknesses by Student’s t-test (P < 0.01). The area of thickened alveolar walls on µCT corresponded well with the area of microscopically lepidic growth patterns of adenocarcinoma. We found that µCT images could be correctly divided by alveolar walls into normal lung area and lung cancer area. Further detailed investigations with regard to µCT are needed to make comparable histological diagnoses using µCT images with conventional microscopic methods of pathological diagnoses.

Sphingolipids constitute a class of bio‐reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non–small‐cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR‐101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1‐positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

Background The aim of this study was to elucidate a curable subgroup among patients with non-small cell lung cancer (NSCLC) who developed postoperative recurrence. Patients and methods Between 1986 and 2012, among the 1408 patients who underwent complete anatomic lung resection for NSCLC at our institution, 420 developed recurrence. After excluding 14 patients with insufficient information about recurrence, 406 were included in this retrospective study. We investigated the association between several clinicopathologic factors and postrecurrence overall survival (PR-OS) and postrecurrence progression-free survival (PR-PFS). Results The 5-year PR-OS and PR-PFS rates were 14.0% and 5.9%, respectively. By multivariate analysis, female sex, longer disease-free interval, specific targeted therapy, recent recurrence, oligo-recurrence, and definitive local therapy (DLT) were found to be independent favorable prognostic factors for both PR-OS and PR-PFS. Among these 6 prognostic factors, although female sex, longer disease-free interval, and specific targeted therapy were associated with a prolonged median PR-PFS time, they were not associated with an improved 5-year PR-PFS rate. In contrast, recent recurrence, oligo-recurrence, and DLT were associated with improvement in both the median PR-PFS time and 5-year PR-PFS rate. Conclusions We found that recent recurrence, oligo-recurrence, and DLT were associated with an improved median PR-PFS time and long-term PR-PFS rate in patients with postoperative recurrence after complete resection of NSCLC. On the basis of these results, we believe that DLT should be considered first for patients with oligo-recurrence before applying noncurative treatment.

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

We aimed to determine the concordance between the clinical stage (c-stage) and pathologic stage (p-stage) for patients with small-size lung cancer. Additionally we searched for prognostic factors other than the TNM stage.We retrospectively reviewed the preoperative multidetector computed tomography (CT) and positron emission tomography/CT reports, surgical records, and pathologic reports of patients with primary lung cancer ≤ 3 cm. The Union for International Cancer Control TNM seventh edition classification of c-stage and p-stage were compared. The tumors were classified into multiple subgroups by concordance or discordance between the c-stage and p-stage. Disease-free survival (DFS) was assessed using survival analysis to assess the tumor characteristics that were predictive of prognosis.A total of 289 surgically resected primary lung cancers were evaluated. The concordance between c-stage and p-stage was 65.4%, with moderate reproducibility (kappa coefficient, 0.467). The upstaging rate from c-stage I to p-stage II-IV was 9.4%, and these patients had significantly worse DFS than those with a concordant stage I classification (P .001). The main reason for upstaging was an underestimation of metastases to the hilar lymph nodes (n = 7) or mediastinal lymph nodes (n = 11). A multivariate Cox proportional hazards model showed that the significant predictive factors for DFS were p-stage (hazard ratio, 1.342; P = .003) and maximum standardized uptake value on positron emission tomography/CT (hazard ratio, 12.162; P = .001).The concordance rate between c-stage and p-stage for small primary lung cancers had moderate reproducibility. Discordance between c-stage I and p-stage II-IV significantly affected DFS. The maximum standardized uptake value of the primary lesion was an independent prognostic factor, and combining it with c-stage might improve the prediction of therapeutic outcomes.

The Guideline Committee of the Japan Lung Cancer Society (JLCS) for Thymic Tumors published the Medical Practice Guideline for Thymic Tumors in Japanese as Chapter 3 of the Medical Practice Guidelines for Lung Cancers according to evidence-based medicine in December 2016. This medical practice guideline is the first for thymic epithelial tumors in Japan, and comprises a set of recommendations covering clinical diagnosis, treatment and pathological diagnosis. Thymic epithelial tumors include thymoma, thymic carcinoma and thymic neuroendocrine tumor. The recommendations for clinical diagnosis concern detection of the symptoms, blood and serum tests according to clinical presentation, essential imaging for differential diagnosis and staging, and the necessity and methods of definitive diagnosis. The recommendations for treatment are dependent on tumor stage and recurrence status, and the treatment modalities included surgery, radiation therapy, chemotherapy and multimodality therapy. Those for pathological diagnosis deal with the handing methods of resected specimen and essential reporting contents for pathological diagnosis. Since data from large-scale analyses or clinical studies of thymic epithelial tumor are limited due to its low prevalence, the relevant recommendations and grading were based on available reported evidence and expert opinions as well as diagnostic methods and treatments commonly used in Japan. This report summarizes the recommendations concerning each topic addressed by this JLCS guideline for thymic tumors., ファイル公開日: 2018/06/01

OBJECTIVES Little is known about the relationship between preoperative physical fitness and postoperative pneumonia after lung resection. We examined the association between preoperative 6-min walk distance (6MWD) and postoperative pneumonia. METHODS A retrospective study was conducted on patients with malignant lung tumours who were scheduled to undergo lung resection at Nagoya University Hospital from January 2014 to December 2015. Preoperative pulmonary function tests and the 6-min walk test were assessed. A logistic regression model and receiver operating characteristic curves were used to analyse clinical variables and compare the performance on 6MWD, forced expiratory volume in 1 s and diffusion capacity of the lung for carbon monoxide. RESULTS The data from a total of 321 patients including 283 with primary lung cancer and 38 with metastatic lung tumours were analysed. Pneumonia developed in 13 patients and caused longer hospital stays after surgery. The preoperative 6MWD of patients with pneumonia was significantly lower than that without pneumonia (425 vs 500 m, P = 0.002). In receiver operating characteristic analysis, 6MWD ≤ 450 m was a threshold for predicting postoperative pneumonia with 69.2% sensitivity and 71.1% specificity. A 6MWD ≤ 450 m, forced expiratory volume in 1 s

OBJECTIVES Using data obtained from a Japanese nationwide annual database with web-based data entry, we developed a risk model of mortality and morbidity after lung cancer surgery. METHODS The characteristics and operative and postoperative data from 80 095 patients who underwent lung cancer surgery were entered into the annual National Clinical Database of Japan data sets for 2014 and 2015. After excluding 1501 patients, the development data set for risk models included 38 277 patients entering in 2014 and the validation data set included 40 317 patients entering in 2015. Receiver–operating characteristic curves were generated for the outcomes of mortality and composite mortality/major morbidity. The concordance index was used to assess the discriminatory ability and validity of the model. RESULTS The 30-day mortality and overall mortality rates, including in-hospital deaths, were 0.4% and 0.8%, respectively, in 2014, and 0.4% and 0.8%, respectively, in 2015. The rate of major morbidity was 5.6% in 2014 and 5.6% in 2015. Several risk factors were significantly associated with mortality, namely, male sex, performance status, comorbidities of interstitial pneumonia and liver cirrhosis, haemodialysis and the surgical procedure pneumonectomy. The concordance index for mortality and composite mortality/major morbidity was 0.854 (P

We adopted a bilateral approach to complete robotic extended thymectomy with the excision of the pericardial fat tissue from both sides and analyzed the initial outcomes. The patient cart was docked first from the left shoulder side. After dissection of the thymus and right pericardial fat tissue, the cart was temporarily rolled out, and the bed was rotated approximately 90° clockwise. The cart was then re-docked from the right-side shoulder, and extended thymectomy was performed via the left-side approach. The outcomes were compared with four cases of unilateral approach performed for mediastinal tumor in the same term. Four patients with myasthenia gravis (two of whom had stage I thymoma) underwent extended thymectomy by the bilateral approach. The mean operative time was 288 min, and the console time was 146 min in the right side and 67 min in the left side. The resected thymus and surrounding adipose tissue were almost symmetrical, in contrast with those obtained via the unilateral approach. No remarkable events were noted. Bilateral extended thymectomy for myasthenia gravis patients was safe and reasonable based on the initial outcomes.

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.

Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT-PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E-cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors.

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.