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Purpose: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe., Methods: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis., Results: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38)., Conclusion: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe., (© 2024. The Author(s).)

Background: The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC., Patients and Methods: From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT., Results: A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference ( p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively ( p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group., Conclusions: Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group., (© 2024 Ayako Shiono et al., published by Sciendo.)

Objectives: The objective of this study was to clarify the clinicopathological features and prognostic factors of resected lung adenosquamous carcinoma (ASC) using a nationwide multi-institutional database., Methods: We retrospectively reviewed the records of 15,542 patients who underwent complete R0 resection for ASC (n = 326), adenocarcinoma (AC, n = 11,820), or squamous cell carcinoma (SC, n = 3396) from a Japanese lung cancer registry in 2010. To reduce the selection bias, an inverse probability of treatment weighting (IPTW) method using a propensity score was implemented., Results: The ASC group showed worse recurrence-free and overall survival (RFS and OS) than both the AC and SC groups (5-year OS: 57.5% in ASC, 83.9% in AC [< 0.001], and 62.3% in SC [P = .086]). In multivariate analyses, prognostic factors that affected OS for ASC included male, p-stage II-III, and postoperative complications within 30 days (grade ≥ 3 in the Clavien-Dindo classification). The sensitizing EGFR mutation was detected in 28 (21.5%) of 130 screened patients with ASC, but it did not affect either RFS, OS, or postrecurrence survival. Although more patients in the ASC group received adjuvant chemotherapy compared to the AC and SC groups, both multivariate and IPTW-adjusted analyses did not show positive impact of adjuvant chemotherapy on RFS and OS in ASC., Conclusions: In this nationwide registry study, lung ASC was more aggressive than both AC and SC. No apparent survival impact of conventional adjuvant chemotherapy prompted us to investigate novel adjuvant strategies to optimize survival outcomes., Competing Interests: Disclosure All of the authors declare that there are no conflicts of interest. We certify that this submission is our original work and is not under review by any other publication., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Claudin-1 (CLDN1) is highly expressed in human lung adenocarcinoma-derived A549 cells and is involved in the augmentation of chemoresistance. However, the mechanism of chemoresistance is not fully understood. In the tumor microenvironment, cancer cells are exposed to stress conditions such as hypoxia and malnutrition. Here, we investigated the effect of CLDN1 expression on amino acid (AA) flux and chemoresistance using A549 cells. The expression of L-type AA transporters, LAT1 and LAT3, was decreased by CLDN1 silencing in A549 spheroids. A reduction in extracellular AA concentration increased the expression of these AA transporters in two-dimensional (2D) cultured cells. The paracellular AA flux except for Ser, Thr, Tyr, Ala, and Gly was enhanced by CLDN1 silencing. These results suggest that CLDN1 forms a paracellular barrier to some AAs, leading to the elevation of LAT1/3 expression in spheroids. The production of reactive oxygen species in the mitochondria and cytosol was decreased by CLDN1 silencing in spheroids, resulting in downregulation of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidant genes. CLDN1 silencing enhanced the cytotoxicity of anticancer drugs including doxorubicin and cisplatin, which was blocked by sulforaphane, an inducer of Nrf2 signaling. Similarly, the anticancer-induced toxicity was enhanced by Nrf2 silencing. In 2D cultured cells, the anticancer-induced toxicity was attenuated by AA deficiency and sulforaphane. We suggest that CLDN1 forms an AA barrier in spheroids, leading to the augmentation of Nrf2-dependent chemoresistance in A549 cells., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The current study was designed to analyze the impact of the COVID-19 pandemic on general thoracic surgeries in Japan., Methods: Changes in surgeries for lung cancer and metastatic lung tumors were evaluated based on National Clinical Database data regarding cancer screening., Results: In 2021, surgeries for primary lung cancer increased by 3.4% compared to 2020, which, given the increase from 2014 to 2019, indicates an overall 11.1% decrease. In contrast, surgeries for metastatic lung tumors in 2021 decreased by 5.8% compared to 2020, which, given the increase from 2014 to 2020, indicates an overall 9.2% decrease. Half of the primary diseases for metastatic lung tumor were cases of colorectal cancer. Low anterior resection procedures in 2020 decreased by 5.5% compared to 2019. Lung and colon cancer screening examinees in 2021 were increased compared to 2020; however, they still showed respective decreases of 11% and 9.0% compared to 2019., Conclusions: Surgeries for primary lung cancer still decreased substantially during the COVID-19 pandemic. The continued stagnation of screening was responsible for this decrease. Surgeries for metastatic lung tumors decreased profoundly, and the decrease in screening for primary tumors was responsible for this reduction. Our findings emphasize the significance of maintaining cancer screening efforts, even during a pandemic., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Pulmonary lymphangitis carcinomatosis is generally characterized by resistance to chemotherapy and is associated with a poor prognosis. Herein, we present a case of pulmonary lymphangitic carcinomatosis from recurrent breast cancer that responded well to trastuzumab deruxtecan(T-DXd). The patient was a 40-year-old woman with hormone receptor-positive, HER2-positive breast cancer. At the age of 31, she had undergone a left mastectomy with axillary lymph node dissection. She received adjuvant chemotherapy(5-fluorouracil-epirubicin-cyclophosphamide, docetaxel, and trastuzumab)followed by endocrine therapy(tamoxifen and LH-RHa). Three years after the surgery, pulmonary and bone metastases were detected and she was treated with trastuzumab, pertuzumab, and capecitabine. Liver metastases were detected, and she was treated with trastuzumab emtansine. Nine years after surgery, the patient developed dyspnea and was diagnosed with lymphangitis carcinomatosis. After initiating T-DXd, dyspnea rapidly improved, and ground glass opacity on CT scan disappeared. She responded well to the treatment, with prolonged, stable disease for 1 year and 2 months. Thus, T-DXd may be effective against pulmonary lymphangitis carcinomatosis, which is generally characterized by resistance to chemotherapy.

Background: Intensity-modulated radiation therapy (IMRT) has been increasingly used as a new radiation modality for unresectable non-small cell lung cancer (NSCLC). The risk factors for radiation pneumonitis (RP) during consolidation durvalumab following concurrent chemoradiotherapy (CCRT) using IMRT have not been thoroughly investigated., Methods: This retrospective study analyzed medical record data from consecutive patients diagnosed with NSCLC who underwent CCRT and consolidation durvalumab at our institution between April 2018 and September 2022. Since we adopted IMRT for the treatment of NSCLC in April 2020, these patients were categorized into two groups: those treated with IMRT after April 2020 and those treated with three-dimensional conformal radiotherapy (3D-CRT) before April 2020., Results: A total of 31 patients underwent IMRT (the IMRT group), while 25 patients underwent 3D-CRT (the 3D-CRT group). In both groups, the total dose was 60 Gy in 30 fractions. The cumulative incidence of ≥ grade 2 RP at 12 months was significantly lower in the IMRT group than in the 3D-CRT group (27.0% vs. 64.0%, hazard ratio [HR]: 0.338, 95% confidence interval [CI]: 0.144-0.793, p = 0.013). In the multivariable analysis, V20 (≥ 25.6%, HR: 2.706, 95% CI: 1.168-6.269, p = 0.020) and radiotherapy technique (IMRT, HR: 0.414, 95% CI: 0.172-0.994, p = 0.048) were identified as significant risk factors for ≥ grade 2 RP., Conclusions: IMRT is associated with a lower rate of ≥ grade 2 RP in patients with NSCLC who received CCRT followed by durvalumab., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Small-cell lung cancer (SCLC), which accounts for about 15 % of all lung cancers, progresses more rapidly than other histologic types and is rarely detected at an operable early stage. Therefore, chemotherapy, radiation therapy, or their combination are the primary treatments for this type of lung cancer. However, the tendency to acquire resistance to anticancer drugs is a severe problem. Recently, we found that an intercellular adhesion molecule, claudin (CLDN) 1, known to be involved in the migration and invasion of lung cancer cells, is involved in the acquisition of anticancer drug resistance. In the present study, we investigated the effect of CLDN1 on the anticancer-drug sensitivity of SCLC SBC-3 cells. Since epithelial-mesenchymal transition (EMT), which is involved in cancer cell migration and invasion, is well known for its involvement in anticancer-drug sensitivity via inhibition of apoptosis, we also examined EMT involvement in decreased anticancer-drug sensitivity by CLDN1. Sensitivity to doxorubicin (DOX) in SBC-3 cells was significantly decreased by CLDN1 overexpression. CLDN1 overexpression resulted in increased TGF-β1 levels, enhanced EMT induction, and increased migratory potency of SBC-3 cells. The decreased sensitivity of SBC-3 cells to anticancer drugs upon TGF-β1 treatment suggested that activation of the TGF-β1/EMT signaling pathway by CLDN1 causes the decreased sensitivity to anticancer drugs and increased migratory potency. Furthermore, treatments with antiallergic agents tranilast and zoledronic acid, known EMT inhibitors, significantly mitigated the decreased sensitivity of CLDN1-overexpressing SBC-3 cells to DOX. These results suggest that EMT inhibitors might effectively overcome reduced sensitivity to anticancer drugs in CLDN1-overexpressing SCLC cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The efficacy of adjuvant chemotherapy (ACT) in elderly patients with completely resected p-stage II-IIIA non-small-cell lung cancer (NSCLC) remains unclear because all previous randomized controlled trials on ACT have been conducted among patients aged <75 years. Thus, this study aimed to evaluate the effectiveness of ACT in elderly patients with completely resected NSCLC., Patients: We extracted the nationwide data of 812 patients aged ≥75 years who underwent lobectomy with mediastinal nodal dissection in 2010 and were diagnosed with p-stage II-IIIA NSCLC, from nationwide registry data accumulated in 2016., Methods: We classified the 812 patients into 2 groups based on the ACT administration status and analyzed the differences in their postoperative overall survival (OS)., Results: Overall, 295 patients received ACT (36.3%; group A), whereas 517 patients did not (63.70%; group N). Group A showed significantly better OS as a whole (hazard ratio [HR]: 0.650 [95% confidence interval {CI}: 0.526-0.804]), in the p-stage II subset (HR: 0.688 [95% CI: 0.513-0.925]), and p-stage IIIA subset (HR: 0.547 [95% CI: 0.402-0.743]) than group N. Even after propensity score matching, group A showed significantly better OS as a whole (HR: 0.626 [95% CI: 0.495-0.792]), in the p-stage II subset (HR: 0.690 [95% CI: 0.493-0.964]), and p-stage IIIA subset (HR: 0.554 [95% CI: 0.398-0.772]) than group N., Conclusion: ACT is recommended even in elderly patients with completely resected p-stage II-IIIA NSCLC. Hence, physicians should not avoid ACT in patients with completely resected NSCLC based solely on age., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The efficacy of tegafur-uracil as adjuvant chemotherapy for patients with completely resected stage I non-small-cell lung cancer is proven; however, its efficacy for elderly patients remains unclear. Herein, we evaluated the effectiveness of adjuvant chemotherapy for elderly patients with completely resected stage I non-small-cell lung cancer based on real-world Japanese data using propensity score matching., Methods: This retrospective study extracted data from a nationwide registry study, performed in 2016, on patients ≥75 years who underwent lobectomy with mediastinal nodal dissection for non-small-cell lung cancer in 2010 and were diagnosed with p-stage IA (>2 cm) or stage IB non-small-cell lung cancer. We classified the 1294 patients into two groups-Group A, postoperative adjuvant chemotherapy (n = 295, 22.8%) and Group N, no adjuvant chemotherapy (n = 999, 77.2%)-and analyzed differences in postoperative overall survival between groups., Results: Group A showed no advantage in overall survival over Group N as a whole (hazard ratio: 0.824 [95% confidence interval: 0.631-1.076]), in p-stage IA (hazard ratio: 0.617 [95% confidence interval: 0.330-1.156]) and in p-stage IB (hazard ratio: 0.806 [95% confidence interval: 0.597-1.088]) subsets. Even after propensity score matching, Group A showed no significant advantage in overall survival over Group N as a whole (hazard ratio: 0.975 [95% confidence interval: 0.688-1.381]), in p-stage IA (hazard ratio: 1.390 [95% confidence interval: 0.539-3.586]) and in p-stage IB (hazard ratio: 0.922 [95% confidence interval: 0.633-1.343])., Conclusions: adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer showed no benefit for recommendation for elderly patients; considering the risk of adverse events, we do not recommend adjuvant chemotherapy for elderly patients., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

It has been reported that the recurrent nerve may not be recognized during mediastinal lymph node dissection in surgery for right upper lobe lung cancer associated with the right aortic arch. In the present case, a 66-year-old man underwent thoracoscopic right upper lobectomy for right upper lobe lung cancer associated with the right aortic arch. The gap between the superior vena cava and descending aortic arch was narrow, and the vagus nerve ran between the superior vena cava and the aorta. The recurrent laryngeal nerve was able to confirm. The vagus nerve ran the hilum of lung back side from arch of azygos vein on the peripheral side. The morphology of the right aortic arch varies from case to case, and if the vagus nerve and recurrent nerve are difficult to identify, the nerve may be hidden by the superior vena cava. If the nerve cannot be recognized, the space between the superior vena cava and the aorta should be dissected and confirmed. In addition, taping the vagus nerve and observing it from the caudal to the cephalic side may be useful for the recurrent nerve that turns to the mediastinum. In this case, magnification of the thoracoscope is extremely useful.

Purpose: To investigate the incidence of postoperative cerebral infarction after curative lobectomy, its association with the type of lobectomy, and how postoperative new-onset arrhythmia contributes to postoperative cerebral infarction., Methods: The subjects of this analysis were 77,060 patients who underwent curative lobectomy for lung cancer between 2016 and 2018 according to the National Clinical Database. Incidences of postoperative cerebral infarction and postoperative new-onset arrhythmia were analyzed. Moreover, mediation analysis was performed to evaluate the causal pathway between postoperative new-onset arrhythmia and postoperative cerebral infarction., Results: Postoperative cerebral infarction occurred in 110 (0.7%) patients after left upper lobectomy and in 85 (0.7%) patients after left lower lobectomy. Left upper lobectomy and left lower lobectomy were associated with a higher likelihood of postoperative cerebral infarction than right lower lobectomy. Left upper lobectomy was the strongest independent predictor of postoperative new-onset arrhythmia. However, in the mediation analysis, the odds ratio for cerebral infarction did not change after the addition of the factor of postoperative new-onset arrhythmia., Conclusion: Cerebral infarction occurred significantly more often not only after left upper lobectomy, but also after left lower lobectomy. Postoperative new-onset arrhythmia was less likely to be related to cerebral infarction after left upper lobectomy., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background and Objectives: Anaplastic lymphoma kinase (ALK) rearrangement is a representative driver mutation in lung cancer. However, the biology of early-stage ALK-rearranged lung cancer remains unclear. We aimed to assess the clinicopathological features, prognostic implications, and influence of ALK rearrangement on the postoperative course in surgically resected lung cancer., Methods: We retrospectively analyzed data from the Japanese Joint Committee of Lung Cancer Registry database. Of the 12 730 patients with lung adenocarcinoma, 794 (6.2%) were tested for ALK rearrangement and were included., Results: ALK rearrangements were detected in 76 patients (10%). The 5-year overall survival (OS) rate was significantly higher in the ALK rearrangement-positive group than in the ALK rearrangement-negative group (p = 0.030). Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved OS (hazard ratio, 0.521; 95% confidence interval, 0.298-0.911; p = 0.022). Regarding the postrecurrence state, there was no difference in the initial recurrence sites between both groups. Administration of ALK-tyrosine kinase inhibitors (TKIs) improved postrecurrence survival in any treatment lines., Conclusion: In one of the largest national surveys, ALK rearrangement was associated with improved long-term outcomes in surgically resected patients. ALK-TKIs may be an important treatment strategy for ALK rearrangement-positive lung adenocarcinoma in the postrecurrence state., (© 2023 Wiley Periodicals LLC.)

The patient is a 72-year-old man. He was diagnosed as a duplication of left upper lobe lung adenocarcinoma cStage ⅣB and transverse colon cancer cStage Ⅳc. Because he had symptoms of atelectasis and esophageal stricture due to the progression of lung cancer, we decided to precede immunochemotherapy(CBDCA plus PEM plus pembrolizumab)for lung cancer. After the start of treatment, both lung and colorectal cancer were shrinking, but after the 3 courses of treatment, he developed intestinal obstruction due to transverse colon cancer. Because generalized peritonitis due to perforation of the colon by endoscopic stenting for the obstruction and then emergency surgery was performed. The resected transverse colon lesion was diagnosed as pathologically complete response. Lung cancer was also diagnosed as clinically complete response. Since his ADL decreased postoperatively, he is under observation without reintroduction of immunochemotherapy. Fourteen months have passed since the last administration, and no progression has been observed in either lung nor colon cancers. Pembrolizumab is considered to be successful in the patient with dMMR colorectal cancer lacking MLH1 and PMS2.

Background: The recurrence rate of non-small cell lung cancer (NSCLC) is as high as 30%, even in the cancer with pathological stage I disease. Therefore, identifying factors predictive of high-risk pathological recurrence is important. However, few studies have examined the genetic status of these tumors and its relationship to prognosis., Materials and Methods: A cohort of 328 cases of primary lung cancer that underwent complete resection at Tokyo Medical and Dental University (TMDU) was screened for 440 cancer-associated genes using panel testing. Further analyses included 92 cases of pathological stage I NSCLC who did not receive adjuvant chemotherapy. Ridge regression was performed to identify association studies mutational status and postoperative recurrence. These data were then validated using clinical and genetic data from 56 patients in The Cancer Genome Atlas (TCGA)., Results: Mutations in TP53, RAS signaling genes KRAS and HRAS, and EGFR were recurrently detected. Ridge regression analysis relevant to recurrence, as well as survival analysis, performed using data from the TMDU cohort revealed significantly shorter relapse-free survival (RFS) for patients with RAS signaling or TP53 gene mutations than for those without (log-rank test, p = 0.00090). This statistical trend was also suggested in the TCGA cohort (log-rank test, p = 0.10)., Conclusion: Mutations in RAS signaling genes and/or TP53 could be useful for the prediction of shorter RFS of patients with stage I NSCLC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy., Methods: This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors., Results: Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence., Conclusion: Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4/ILT3) is an up-and-coming molecule that promotes immune evasion. We have previously reported that LILRB4 facilitates myeloid-derived suppressor cells (MDSCs)-mediated tumor metastasis in mice. This study aimed to investigate the impact of the LILRB4 expression levels on tumor-infiltrating cells on the prognosis of non-small cell lung cancer (NSCLC) patients., Methods: We immunohistochemically evaluated the LILRB4 expression levels of completely resected 239 NSCLC specimens. Whether the blocking of LILRB4 on human PBMC-derived CD33 + MDSCs inhibited the migration ability of lung cancer cells was also examined using transwell migration assay., Results: The LILRB4 high group, in which patients with a high LILRB4 expression level on tumor-infiltrating cells, showed a shorter overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.0017) compared to the LILRB4 low group. Multivariate analyses revealed that a high LILRB4 expression was an independent factor for postoperative recurrence, poor OS and RFS. Even in the cohort background aligned by propensity score matching, OS (p = 0.023) and RFS (p = 0.0046) in the LILRB4 high group were shorter than in the LILRB4 low group. Some of the LILRB4 positive cells were positive for MDSC markers, CD33 and CD14. Transwell migration assay demonstrated that blocking LILRB4 significantly inhibited the migration of human lung cancer cells cocultured with CD33 + MDSCs., Conclusion: Together, signals through LILRB4 on tumor-infiltrating cells, including MDSCs, play an essential role in promoting tumor evasion and cancer progression, impacting the recurrence and poor prognosis of patients with resected NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Immune checkpoint inhibitors (ICIs) have become the standard treatment for many types of cancer and have improved patient prognosis. However, ICIs upregulate the immune system against tumors, leading to immune-related adverse events (irAEs). Kidney irAEs are less common, and most of them are acute tubulointerstitial nephritis (ATIN). However, there has been a recent increase in recognition of glomerular disease related to ICI therapies. We report the case of a 65-year-old man with lung adenocarcinoma who was treated with pembrolizumab (a monoclonal antibody targeting programmed cell death protein-1 [PD-1]). Pembrolizumab was discontinued after seven cycles due to the development of destructive thyroiditis. Within three months of discontinuing the pembrolizumab treatment, the patient developed rapid progressive glomerulonephritis (RPGN), liver dysfunction, and dysgeusia. The patient underwent renal biopsy and was diagnosed with crescentic glomerulonephritis due to anti-glomerular basement membrane (GBM) antibodies complicated with membranous nephropathy (MN) and ATIN. Treatment with systemic corticosteroids resulted in a favorable clinical response. Various ICI-associated glomerular diseases have been described; however, this is the first reported case of anti-GBM glomerulonephritis associated with MN and ATIN following ICI treatment., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Backgrounds: With increase of patients with a small-sized lung cancer, there is an increasing need for minimally invasive lung segmentectomy that can preserve respiratory function. We perform S(9+)10 segmentectomy with retrograde dissection of the pulmonary vein, bronchus, pulmonary artery, in order, without interlober fissurelectomy and staple dissection of the peripheral lung parenchyma., Methods: Seven patients who underwent retrograde S(9+)10 segmentectomy between June, 2021 and May, 2022 in our hospital were retrospectively reviewed., Results: No patient was converted to the open thoracotomy, without any complications including prolonged air leakage. The average operation time was 171 minutes( range 125 to 221), amount of bleeding was 25 ml( range 0 to 75). Median duration of chest tube insertion was 4 days( range 3 to 6), length of stay after surgery was 6 days (range 5 to 9). Pathologic stage showed pT1mi in 3 patients, pT1a in 3 patients, pT2a in 1 patient. No local recurrence was seen at this time., Conclusions: Retrograde S(9+)10 segmentectomy is feasible and facilitates interlobar procedure at the time of repeated segmentectomy or completion lobectomy.

Background: Immune checkpoint inhibitor (ICI) has become the standard therapy for metastatic non-small cell lung cancer (NSCLC) patients. However, no robust evidence on the efficacy and safety of ICI in elderly NSCLC patients has been established., Materials and Methods: This retrospective study aimed to assess the efficacy and safety of ICI in elderly NSCLC patients. NSCLC patients treated with ICI monotherapy or chemoimmunotherapy (CIT) between 2016 and 2022 were divided into two cohorts according to the age: the Elderly cohort (patients aged ≥ 75 years) and the Nonelderly cohort (patients aged < 75 years). The progression-free survival (PFS), tumor response, and frequency of immune-related adverse events (irAEs) were compared between the two cohorts., Results: A total of 111 NSCLC patients were included in this study (41 patients in the Elderly cohort and 70 patients in the Nonelderly cohort). The PFS (5.6 months vs. 6.3 months, P = 0.98), response rate (36.6% vs. 44.9%, P = 0.51), and disease control rate (80.5% vs. 76.8%, P = 0.83) were not significantly different between the two cohorts. In a subgroup analysis, stratified according to PD-L1 expression (low vs. high) and ICI treatment mode (ICI monotherapy vs. CIT), the PFSs of both cohorts were also not significantly different, regardless of PD-L1 expression. Moreover, the frequency of irAEs did not significantly differ between elderly and nonelderly NSCLC patients (21/41 [51.2%] vs. 38/70 [54.3%], P = 0.91)., Conclusion: The efficacy and safety of ICI in elderly NSCLC patients were not inferior to those in younger patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Claudin-2 (CLDN2), a component of tight junctions, is abnormally expressed in human lung adenocarcinoma tissue. CLDN2 contributes to chemoresistance in human lung adenocarcinoma-derived A549 cells, and it may be a target for cancer therapy. Here, we found that coffee ingredients, namely caffeine and theobromine, decreased the protein level of CLDN2 in human lung adenocarcinoma-derived A549 cells. In contrast, other components, such as theophylline and chlorogenic acid, had no effect. These results indicate that the 7-methyl group in methylxanthines may play a key role in the reduction in CLDN2 expression. The caffeine-induced reduction in the CLDN2 protein was inhibited by chloroquine, a lysosome inhibitor. In a protein-stability assay using cycloheximide, CLDN2 protein levels decreased faster in caffeine-treated cells than in vehicle-treated cells. These results suggest that caffeine accelerates the lysosomal degradation of CLDN2. The accumulation and cytotoxicity of doxorubicin were dose-dependently increased, which was exaggerated by caffeine but not by theophylline in spheroids. Caffeine decreased nuclear factor-erythroid 2-related factor 2 (Nrf2) levels without affecting hypoxia-inducible factor-1α levels. Furthermore, caffeine decreased the expression of Nrf2-targeted genes. The effects of caffeine on CLDN2 expression and anticancer-drug-induced toxicity were also observed in lung adenocarcinoma RERF-LC-MS cells. We suggest that caffeine enhances doxorubicin-induced toxicity in A549 spheroids mediated by the reduction in CLDN2 and Nrf2 expression.

Objective: The COVID-19 pandemic has far-reaching collateral health impacts on the ongoing delivery of surgical care worldwide. The current study was designed to analyze the impact of the COVID-19 pandemic on the number of surgeries of general thoracic surgery in Japan., Methods: Changes in the number of surgeries for total and three representative tumors were analyzed using the National Clinical Database data with reference to the pandemic infection rate and lung cancer screening., Results: In 2020, the number of surgeries in total and for primary lung cancer and mediastinal lung tumor decreased by 4.9, 5.1, and 5.0 %, respectively. Considering the five-year trend towards a 5 % annual increase, there was a potential 10 % decrease in the number of primary lung cancer surgeries. The number of primary lung cancer surgeries bottomed in July 2020 but recovered towards the end of the year. In contrast, the number of metastatic lung tumor surgeries in 2020 increased by 3.2 %, following a similar trend observed over the previous five years. The number of lung cancer screening examinees decreased markedly with the lowest number in May. Our findings indicate that surgical triage had a limited impact on the decrease in primary lung cancer surgeries during the pandemic; rather, the decrease in lung cancer screening, which was a few months preceding, is most likely responsible., Conclusions: The decrease in primary lung cancer was mainly caused by the decrease in lung cancer screening, indicating that continuing screening is vital even during a pandemic., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroyuki Yamamoto is affiliated with the Department of Healthcare Quality Assessment of the University of Tokyo. The department is a social collaboration department supported by grants from the National Clinical Database, Johnson & Johnson K.K., and Nipro Co. The other authors declare no conflicts of interest regarding the submitted article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: We studied the prognosis and clinicopathological background of lung adenocarcinoma predominance among patients who underwent lobectomy using data from the Japanese Joint Committee of Lung Cancer Registry., Methods: Two thousand eight hundred sixty-three cases were extracted. Recurrence free survival (RFS) rates, overall survival (OS) rates and clinicopathological factors and epidermal growth factor receptor (EGFR) mutation status were examined., Results: Median follow-up period was 65.5 months. Adenocarcinoma predominance was sub-grouped according to OS and RFS rate. In pathological stage I, 5-year RFS and OS rates were respectively 92.2% and 95.8% in group A (adenocarcinoma-in-situ + minimally invasive adenocarcinoma), 89.3% and 92.1% in group B (lepidic), 79.2% and 89.7% in group C (papillary + acinar + variants) and 69.0% and 79.0% in group D (solid + micropapillary). In pathological stage II + IIIA, they were, 43.6% and 72.4% in B, 39.5% and 66.9% in C and 31.0% and 53.7% in D. Group D showed significant worst outcome both in stage I and II + IIIA. Up stage rate from clinical stage I to pathological stage II + IIIA was 0.0%, 3.7%, 15.9% and 33.3%. The frequency of lymph-vessel, vascular, pleura invasion and positive EGFR mutation were 0.0%, 0.0%, 0.0% and 57.1% in group A, 15.6%, 10.0%, 12.1% and 55.1% in B, 36.6%, 31.8%, 29.7% and 44.9% in C, 50.2%, 57.8%, 38.9% and 21.3% in D. In group D, lymph-vessel, vascular and pleura invasion were most, EGFR mutation was least frequent not only in pathological stage I but also stage II + IIIA. In multivariate analysis, age, pathological stage, vascular invasion, and group D were independent factors affected RFS and OS., Conclusion: Limited to lobectomy cases, solid + micropapillary was independent prognostic factor both in early and locally advanced stage. Its malignant degree was related to the frequency of pathological invasive factors and EGFR mutation status., (© 2022. The Author(s).)

Claudin-2 (CLDN2), a component of tight junction, is involved in the reduction of anticancer drug-induced toxicity in spheroids of A549 cells derived from human lung adenocarcinoma. Fisetin, a dietary flavonoid, inhibits cancer cell growth, but its effect on chemosensitivity in spheroids is unknown. Here, we found that fisetin (20 μM) decreases the protein level of CLDN2 to 22.3%. Therefore, the expression mechanisms were investigated by real-time polymerase chain reaction and Western blotting. Spheroids were formed in round-bottom plates, and anticancer drug-induced toxicity was measured by ATP content. Fisetin decreased the phosphorylated-Akt level, and CLDN2 expression was decreased by a phosphatidylinositol 3-kinase (PI3K) inhibitor, suggesting the inhibition of PI3K/Akt signal is involved in the reduction of CLDN2 expression. Hypoxia level, one of the hallmarks of tumor microenvironment, was reduced by fisetin. Although fisetin did not change hypoxia inducible factor-1α level, it decreased the protein level of nuclear factor erythroid 2-related factor 2, a stress response factor, by 25.4% in the spheroids. The toxicity of doxorubicin (20 μM) was enhanced by fisetin from 62.8% to 40.9%, which was rescued by CLDN2 overexpression (51.7%). These results suggest that fisetin can enhance anticancer drug toxicity in A549 spheroids mediated by the reduction of CLDN2 expression.

Objectives: Radiologically invasive non-small-cell lung cancer, defined as consolidation size to maximum tumour diameter ratio of over 0.5, is associated with pathological invasiveness and worse prognosis. However, there are no real-world, nationwide database studies on limited resections that consider radiological invasiveness. This study aimed to investigate the prognostic validity of limited resection, such as segmentectomy and wedge resection, in cStage IA (TNM 8th edition) radiologically invasive lung cancer., Methods: We conducted a retrospective analysis of patients who underwent complete resection according to the Japanese Joint Committee of Lung Cancer Registry Database. The relationship between surgical procedures and prognosis was examined using stratification by cT factor and radiological invasiveness., Results: Among the 5,692 patients enrolled, lobectomy, segmentectomy and wedge resection were performed in 4,323 (80.0%), 657 (11.5%) and 712 (12.5%) patients, respectively. Multivariable analysis with or without propensity score matching indicated that older age, poor performance status and wedge resection were significantly associated with worse prognosis and that patients who underwent segmentectomy showed an equivalent prognosis to those who underwent lobectomy. Subset analyses revealed that segmentectomy showed an equivalent prognosis to lobectomy in patients with cT1b or less, but not in those with cT1c, especially for non-pure radiological invasive cT1c; 5-year overall survival rates were 91.4% vs 90.4% in cT1b with non-pure radiological invasiveness and 80.0% vs 83.8% in cT1b with pure radiological invasiveness, respectively., Conclusions: Segmentectomy can be an alternative to lobectomy in patients with radiologically invasive lung cancer with cT1b or less but not in those with cT1c., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: The objective of our study was to develop a clinical prediction model for prolonged air leak (PAL) after lobectomy for lung cancer using preoperative variables in a large patient dataset from the National Clinical Database (NCD) in Japan., Methods: The preoperative characteristics of 57,532 and 30,967 patients who had undergone standard lobectomy for lung cancer were derived from the 2014 to 2015 and 2016 NCD datasets, respectively. PAL was defined as air leak persisting ≥ 7 days postoperatively or requiring postoperative interventional treatment, such as pleurodesis or reoperation. Risk models were developed from the 2014 to 2015 dataset and validated using the 2016 dataset. When performing model derivation, the least absolute shrinkage and selection operator (LASSO) method were applied for parameter selection., Results: The rate of PAL was 4.5% in 2014-2015 and 5.3% in 2016. The age, sex, body mass index, comorbid interstitial pneumonia, smoking habits, forced expiratory volume in 1 s, tumor histology, multiple lung cancer, and tumor location were selected as important variables for PAL. Our risk model for predicting PAL was fair with a concordance index of 0.6895., Conclusion: The LASSO-based risk model for PAL after lobectomy provided important preoperative variables for PAL and risk weighting for each variable., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Thromboembolism (TE) is a serious complication in lung cancer patients; however, risk factors for developing TE during treatment with immuno-oncology (IO) drugs are unclear., Materials and Methods: A retrospective study of lung cancer patients hospitalized in Tokyo Medical and Dental University was performed to clarify the association between TE and systemic therapy, especially IOs. Patients were divided into an IO cohort, a chemotherapy cohort (CT cohort), and a control cohort (patients without recurrence after surgery). Association studies of variables relevant to TE were performed., Results: A total of 592 patients were enrolled (IO cohort, 120; CT cohort, 294; control cohort, 178). Eight patients (6.7%) in the IO cohort, seven (2.4%) in the CT cohort, and three (1.7%) in the control cohort developed TE. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis identified IO, a history of TE, poor performance status (PS), and prior anticoagulation therapy as being associated with TE. Subsequent multivariate logistic regression analysis identified a history of TE (odds ratio (OR), 6.03; 95% confidence interval (CI), 2.09-17.40; P = 0.01) and poor PS (OR, 3.84; 95% CI, 1.34-11.00; P < 0.001) as potential risk factors for developing TE. The incidence of TE in the IO cohort patients with both of these characteristics was significantly higher (OR, 52.82; 95% CI, 6.72-506.37; P < 0.001) than that in the control cohort., Conclusion: Lung cancer patients with a history of TE and poor PS are at increased risk of TE during treatment with IOs., Micro Abstract: The profiles of lung cancer patients susceptible to development of thromboembolism (TE) during immunotherapy are unclear, even though TE is associated with a worse prognosis. Here, association studies of variables relevant to TE revealed that patients with a history of TE and poor performance status are at higher risk of developing TE during immunotherapy., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Smoking is a known risk factor for postoperative mortality and morbidity. However, the significance of cumulative smoking dose in preoperative risk assessment has not been established. We examined the influence of preoperative cumulative smoking dose on surgical outcomes after lobectomy for primary lung cancer., Methods: A total of 80,989 patients with primary lung cancer undergoing lobectomy from 2014 to 2016 were enrolled. Preoperative cumulative smoking dose was categorized by pack-years (PY): nonsmokers, PY = 0; light smokers, 0 < PY < 10; moderate smokers, 10 ≤ PY < 30; and heavy smokers, 30 ≤ PY. The risk of short-term outcomes was assessed according to PY by multivariable analysis adjusted for other covariates., Results: Postoperative 30-day mortality, as well as pulmonary, cardiovascular, and infectious complications, increased with preoperative PY. Multivariable analysis revealed that the odds ratios (ORs) for postoperative mortality compared with nonsmokers were 1.76 for light smokers (P = .044), 1.60 for moderate smokers (P = .026), and 1.73 for heavy smokers (P = .003). The ORs for pulmonary complications compared with nonsmokers were 1.20 for light smokers (P = .022), 1.40 for moderate smokers (P < .001), and 1.72 for heavy smokers (P < .001). Heavy smokers had a significantly increased risk of postoperative cardiovascular (OR, 1.26; P = .002) and infectious (OR, 1.39; P = .007) complications compared with nonsmokers., Conclusions: The risk of mortality and morbidity after lung resection could be predicted according to preoperative cumulative smoking dose. These findings contribute to the development of strategies in perioperative management of lung resection patients., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated the association between the number of certified general thoracic surgeons (GTSs) and the mortality after lung cancer surgery, based on the data from the National Clinical Database (NCD)., Methods: We analyzed the characteristics and operative and postoperative data of 120,946 patients who underwent lung cancer surgery in one of the 905 hospitals in Japan. The number of GTSs in each hospital was categorized as 0, 1-2, or 3 or more. Multivariable analysis was applied to adjust the patients' preoperative risk factors, as identified in a previous study. We calculated 95% confidence intervals (CI) for the mortality rate based on the odds ratios (ORs)., Results: The patients' characteristics were distributed almost uniformly regardless of the number of GTSs. Crude mortality according to the number of GTSs of 0, 1-2, or 3 or more was 0.9%, 0.8%, and 0.7%, respectively (p = 0.03). However, after adjustment, the ORs for 1-2 and 3 or more GTSs (reference: 0) were 0.86 (p = 0.23, 95% CI: 0.67-1.10) and 0.84 (p = 0.18, 95% CI: 0.64-1.09), respectively. The number of GTSs did not have a significant association with mortality. Similar results were observed for patients in the lobectomy cohort., Conclusion: Low surgical mortality was consistent, regardless of the number of GTSs in each hospital., (© 2021. Springer Nature Singapore Pte Ltd.)

Objectives: Selection criteria for palliative limited surgery in patients with non-small cell lung cancer (NSCLC) can vary by institution or surgeon. We retrospectively reviewed outcomes of poor-risk patients who underwent palliative segmentectomy (PS), using the National Clinical Database Risk Calculator (RC)., Methods: We retrospectively analyzed medical records of patients with NSCLC tumors ≥ 20 mm and consolidation/tumor ratios ≥ 0.5 on computed tomography, who underwent PS from January 2009 to March 2016. Median follow-up time was 47 months (range 2-102 months)., Results: We enrolled 67 patients (median age: 73.0 years), of whom 54 received thoracoscopic surgery and 28 received medial lymph-node dissection. The RC's mean predictive probability rate for perioperative mortality or severe complications was 7.1%. Of the 67 patients, 24 patients (43.0%) suffered post-surgical complications, including 2 (3%) who died in hospital; 17 eventually suffered NSCLC recurrences and/or metastases, 11 eventually died from NSCLC, and 17 died from other diseases. Five-year overall survival (OS) was 59.4%. When the patients were divided into high-risk (HR) and low-risk (LR) groups based on the RC, 5-year OS was significantly less in the HR group (43.9%) than in the LR group (82.2%; P < 0.05)., Conclusion: The RC, which was developed primarily to determine perioperative risk, can predict long-term prognosis for compromised patients who undergo PS.

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18 978 registered cases, 9689 patients with clinical stage I non-small-cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was carried out within 2 years after the initial surgery; metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Female sex, nonsmoker, low consolidation-tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, whereas patients with metachronous MPLC had higher frequencies of male sex, smoker, chronic obstructive pulmonary disease (COPD), and nonadenocarcinoma. There was no significant difference in survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC. Logistic regression analysis showed that female sex, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings could have major implications regarding MPLC diagnosis and identification of independent prognostic factors, and provide valuable information for postoperative management of patients with MPLC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introductions: When the first intervention for lung cancer is anatomical resection, the ipsilateral repeat anatomical resection for metachronous second lung cancer becomes technically challenging. Herein, we report the outcomes of second anatomical pulmonary resection for ipsilateral metachronous lung cancer at our institution., Subjects: Sixteen consecutive patients[ 10 men and 6 women, average age 70( range 59~81) years] were reviewed in this retrospective study. These patients underwent ipsilateral repeat anatomical resection for metachronous second lung cancer between 2009 and 2020., Results: All case required right-sided lung resections. The previous interventions of patients included upper lobectomy, lower lobectomy, middle lobectomy, S2 segmentectomy, and S6 and S10a segmentectomy in 9, 4, 1, 1, and 1 case, respectively. The second surgical interventions were middle lobectomy, S6 segmentectomy, upper lobectomy, lower lobectomy, S1 segmentectomy, and S2 segmentectomy, in 6, 4, 2, 2, 1, and 1 case, respectively. Postoperative complications occurred in three patients. The median follow-up period was 53.5 months. Three patients died during the follow-up period. Of the 13 patients still alive, 6 had recurrence. The five-year overall survival rate was 80%., Conclusions: Although only a few cases were assessed, the prognosis after second anatomical pulmonary resection for ipsilateral metachronous lung cancer at our institution was satisfactory.

Introductions: The morbidity and mortality after completion pneumonectomy (CP) are reportedly high. We, herein, report the outcomes of CP at our institution., Subjects: Nine consecutive patients [7 men and 2 women, average age of 72 years(range 44~84 years)] who underwent CP for recurrence of lung cancer during 2012~2018 were retrospectively reviewed., Results: Right-sided sleeve CP was performed in two cases and left-sided CP in seven cases. The indications for surgery were lymph node metastasis of the cancer, pulmonary metastasis, and bronchial stump recurrence in 4, 3, and 2 cases, respectively. Postoperative complications occurred in six patients. One of the patients who underwent right sleeve pneumonectomy developed bronchopleural fistula and died 68 days after the surgery. The mean follow-up period was 33 months, and four patients died during follow-up. Of the 5 patients still alive, 4 had no recurrence and 1 had recurrence in the stump of the main bronchus. The five-year overall survival rate was 78%., Conclusions: Although only few cases were assessed, the prognosis after CP at our institution was relatively good.

Background: To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973)., Methods: Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study., Results: An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P < .001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < .001), a higher rate of pure solid tumors (P < .001), advanced pathologic stage (trend P < .001), and poorer recurrence-free survival (P = .001)., Conclusions: In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

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 < 0.001)., Conclusions: Our analysis of data from the NCD indicates that MIA has become the new standard treatment for clinical stage IA lung cancer.

Objectives: The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC)., Materials and Methods: The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated., Results: Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to <25), underweight (BMI < 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p < 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p < 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor., Conclusions: The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor-1 (TTF-1)/NK2 homeobox 1 (NKX2-1)-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). Expression of TFF-1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF-1 correlated with the expression of HNF4-α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (P < .0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. The TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF-1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Claudins (CLDNs) play crucial roles in the formation of tight junctions. We have reported that abnormal expression of CLDN2 confers chemoresistance in the spheroids of human lung adenocarcinoma A549 cells. A food composition, which can reduce CLDN2 expression, may function to prevent the malignant progression. Here, we found that ethanol extract of Brazilian green propolis (EBGP) and kaempferide, a major component of EBGP, decrease CLDN2 expression. In the two-dimensional culture model, EBGP decreased the tight junctional localization of CLDN2 without affecting that of zonula occludens-1, an adaptor protein, and enhanced paracellular permeability to doxorubicin, a cytotoxic anticancer drug. EBGP reduced hypoxic stress, and enhanced the accumulation and sensitivity of doxorubicin in the spheroid of A549 cells. Kaempferide dose-dependently decreased CLDN2 expression, although dihydrokaempferide and pinocembrin did not. The phosphorylation of Akt, a regulatory factor of CLDN2 expression, was inhibited by kaempferide but not by dihydrokaempferide. The 2,3-double bond in the C ring may be important to inhibit Akt. Kaempferide decreased the mRNA level and promoter activity of CLDN2, indicating that it inhibits the transcription of CLDN2. In accordance with EBGP, kaempferide decreased the tight junctional localization of CLDN2 and increased a paracellular permeability to doxorubicin, suggesting that it diminished the paracellular barrier to small molecules. In addition, kaempferide reduced hypoxic stress, and enhanced the accumulation and sensitivity of doxorubicin in the spheroids. In contrast, dihydrokaempferide did not improve the sensitivity to doxorubicin. Further study is needed using an animal model, but we suggest that natural foods abundantly containing kaempferide are candidates for the prevention of the chemoresistance of lung adenocarcinoma.

A 71-year-old man underwent laparoscopic lower anterior resection(D3 dissection)for rectal cancer and bilateral lung metastases. Histopathological findings indicated Ra, type 2, tub2, ly0, v2, pN0, pM1(PUL1), pStage Ⅳ. The lung metastases had disappeared after postoperative chemotherapy and the patient entered cCR. Two years after the surgery, the patient's anal fistulas appeared sclerotic. Biopsy revealed recurrent rectal cancer. We performed an abdominoperineal resection and rectus abdominis muscle flap. Currently, the patient is alive at 9 months after surgery with no re-recurrence.

In general, distant metastasis is uncommon in colorectal submucosal(SM)invasion without lymph node metastasis. We experienced an extremely rare case of synchronous pulmonary metastases for colon cancer in SM invasion. A man in his 70s was seen at the hospital for a positive fecal occult blood test. Colonoscopy revealed 3 lesions in the sigmoid colon and endoscopic mucosalresection revealed 2,000 mm SM invasion in all 3 lesions. Computed tomography showed no signs of distant lymph node or liver metastasis but showed small nodules in both lungs. Radical treatment included laparoscopic anterior resection with lymph node dissection. Histological examination showed no residual tumor in the colon and no lymph node metastasis. Two years after surgery, the number of lung nodules gradually increased and we performed partial resection of the left lung, which was diagnosed as pulmonary metastasis from colon cancer by histological examination. Therefore, we resected the opposite-side pulmonary metastases. The patient has exhibited no other signs of recurrence in the 2 years since the last operation.

The aberrant expression of claudins (CLDNs), which are tight junctional proteins, is seen in various solid tumors, but the regulatory mechanisms and their pathophysiological role are not well understood. Both CLDN1 and CLDN11 were highly expressed in human lung squamous cell carcinoma (SCC). Chrysin, found in high concentration in honey and propolis, decreased CLDN1 and CLDN11 expression in RERF-LC-AI cells derived from human lung SCC. The phosphorylation level of Akt was decreased by chrysin, but those of ERK1/2 and c-Jun were not. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, inhibited the phosphorylation of Akt and decreased the expression levels of CLDN1 and CLDN11. The association between phosphoinositide-dependent kinase 1 (PDK1) and Akt was inhibited by chrysin, but the phosphorylation of PDK1 was not. Immunoprecipitation and quartz-crystal microbalance assays revealed that biotinylated-chrysin binds directly to Akt. The knockdown of CLDN1 and CLDN11 using small interfering RNAs increased the transepithelial flux of doxorubicin (DXR), an anthracycline anticancer drug. Similarly, both chrysin and LY-294002 increased DXR flux. Neither CLDN1 knockdown, CLDN11 knockdown, nor chrysin changed the anticancer drug-induced cytotoxicity in a two-dimensional culture model, whereas they enhanced cytotoxicity in a spheroid culture model. Taken together, chrysin may bind to Akt and inhibit its phosphorylation, resulting in the elevation of anticancer drug-induced toxicity mediated by reductions in CLDN1 and CLDN11 expression in RERF-LC-AI cells. We suggest that chrysin may be useful as an adjuvant chemotherapy in lung SCC.

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 44- and a 66-year-old woman underwent nasopancreatic drainage (NPD) to treat obstructive pancreatitis secondary to a pancreatic metastasis from lung cancer. Both patients were diagnosed with stage IV lung cancer and underwent chemotherapy for 17 and 15 months, respectively. Abdominal ultrasonography and computed tomography revealed a solid pancreatic tail tumor measuring 2.5 cm and 1.3 cm in diameter, respectively. Additionally, we observed dilatation of the upstream main pancreatic duct (MPD) and edematous parenchyma with peripancreatic inflammatory changes limited to the pancreatic tail. Both patients were diagnosed with moderately severe acute pancreatitis and received fluid resuscitation, an opioid analgesic, antibiotics, and a protease inhibitor. However, owing to unrelenting pain, we performed endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic duct drainage in both patients. ERCP showed a stricture in the MPD in the pancreatic tail with upstream dilatation. A 5-Fr NPD tube was inserted to drain the dilated MPD, and cloudy pancreatic juice was drained. NPD tube placement led to pain relief in both patients. Pancreatic juice cultures grew Enterococcus faecium and Enterobacter cloacae, respectively. The NPD tube was later cut in both cases using a pair of scissor forceps.

Background: The most important step in lung segmentectomy is to determine an appropriate intersegmental plane to obtain sufficient pre- and intraoperative margins. Inappropriate dissection of the lung parenchyma leads to loss of oncological validity and additionally causes various complications such as pneumonia, prolonged air leakage, lung congestion, and atelectasis., Objectives: In this study, we evaluated the validity of segmentectomy for non-small cell lung cancer (NSCLC) based on evaluation of survival outcomes and recurrence patterns., Operative Technique: In principle, we usually perform video-assisted thoracic surgery segmentectomy. Hilar dissection is performed along the intersegmental vein under ultrasonographic guidance, and the peripheral lung parenchyma is subsequently stapled. We usually create inflation-deflation lines from before to determine the intersegmental lines. Recently, near-infrared fluorescence imaging with indocyanine green is also used., Methods: We retrospectively reviewed data of 101 patients who underwent segmentectomy for lung cancer between 2007 and 2014., Results: The 5- and 10-year overall survival rates were 84% and 62%, respectively. The 5- and 10-year recurrence-free survival rates were 83% and 63%, respectively. Recurrence at the surgical margin occurred in 5 patients( pulmonary stump:4 patients, bronchial stump:1 patient)., Conclusion: Segmentectomy may be acceptable for patients with Stage I NSCLC. Accurate determination of the intersegmental plane is essential to avoid stump recurrence.

Rationale: Suppression and of cancer metastasis is one of the most important issues in cancer care. Considering the typical clinical course of metastases, cancer cells might prefer certain environments or conditions. However, favorable environments for cancer metastasis have not been clearly identified. We had previously described a case of dual, yet separate, pancreatic and colon cancer, in which the metastatic pancreatic cancer was localized at the invasive portion of the colon cancer. We hypothesized that metastatic pancreatic cancer took over the colon cancer microenvironment., Patient Concerns: We experienced an another case of double cancer in a 65-year-old man who had lung squamous cell carcinoma and an independent pancreatic adenocarcinoma that metastasized to the liver as well as to the lung cancer lesion and pulmonary fibrotic regions associated with pneumothorax and bronchiolization., Interventions: The pneumothorax could not be controlled by conservative treatment. Thus, an emergency surgery with partial resection of the lower lobe of right lung was performed., Diagnoses: We found multiple pancreatic cancer metastases in the lung cancer and fibrotic lesions in the surgical specimen. However, we detected no metastasis in normal lung tissues except inside small arteries, although the lung cancer and fibrotic tissue areas were smaller than the normal lung tissue areas in the surgical specimen., Outcomes: The patient died 50 days after the surgery., Lessons: This case may thus provide evidence to strengthen our hypothesis that pancreatic cancer prefers to metastasize to other independent cancer lesions, overtaking the cancer microenvironment constructed by other independent cancers. The lung cancer microenvironment, rich in myofibroblasts and/or cancer-associated fibroblasts, might be suitable for pancreatic carcinoma metastasis. In addition, we propose the hypothesis that compared with normal tissues, noncancerous fibrotic lesions are preferable destinations for cancer metastasis. Furthermore, metastasis of pancreatic carcinoma to lung cancer and fibrotic tissues might be more common, although such cases have not been previously reported.

Ewing's sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are highly malignant neoplasms that usually affect the bones and soft tissues in children and young adults. ES/PNET of the lung is very rare and is associated with a poor prognosis. We herein report a case of ES/PNET of the left lung in a 45-year-old man. He was treated with neoadjuvant chemotherapy and pneumonectomy, but unfortunately his disease recurred 1.5 months after surgery. He was started on pazopanib, which resulted in a five-month progression-free survival. To our knowledge, this is the first demonstration of pazopanib efficacy in ES/PNET of the lung.

Background: Broncho-pleural fistula (BPF) and respiratory failure (RF) are life-threatening complications after lung cancer surgery and can result in long-term hospitalization and decreased quality of life. Risk assessments for BPF and RF in addition to mortality and major morbidities are indispensable in surgical decision-making and perioperative care., Methods: The characteristics and operative data of 80,095 patients who had undergone lung cancer surgery were derived from the 2014 and 2015 National Clinical Database (NCD) of Japan datasets. After excluding 1501 patients, risk models were developed from these data and validated by another dataset for 42,352 patients derived from the 2016 NCD dataset. Receiver operating characteristic curves were generated for postoperative BPF and RF development. The concordance-index was used to assess the discriminatory ability and validity of the model., Results: BPF and RF occurred in 259 (0.3%) and 420 patients (0.5%), respectively, in the model development dataset and in 129 (0.3%) and 198 patients (0.5%), respectively, in the model validation dataset. Characteristic variables including types of surgery and comorbidities were identified as risk factors for BPF and RF, respectively. The concordance indexes of assessments for BPF and RF were 0.847 (p < 0.001) and 0.848 (p < 0.001), respectively, for the development dataset and 0.850 (p < 0.001) and 0.844 (p < 0.001), respectively, for the validation dataset., Conclusions: These models are satisfactory for predicting BPF and RF after lung cancer surgery in Japan and could guide preoperative assessment and optimal measures for preventing BPF and RF.

Chemoresistance is a serious issue in the therapy of many cancers, but the molecular mechanism is little understood. The mRNA level of occludin (OCLN), a tight junctional protein, was increased in the cisplatin (CDDP), doxorubicin (DXR), 7-ethyl-10-hydroxy-camptothecin, or gemcitabine-resistant human lung adenocarcinoma A549 cells. Here, we investigated the regulatory mechanism and pathophysiological role of OCLN. OCLN was mainly localized at tight junctions in A549 and CDDP-resistant A549 (A549/CDDP) cells. The level of p-Akt in A549/CDDP cells was higher than that in A549 cells, and the mRNA and protein levels of OCLN were suppressed by a phosphoinositide 3-kinase (PI3K)/Akt pathway inhibitor, LY-294002, suggesting that a PI3K/Akt pathway is involved in the elevation of OCLN expression. The overexpression of OCLN in A549 cells decreased paracellular permeability to DXR. Cytotoxicity to CDDP was unaffected by OCLN-overexpression in 2D culture model. In 3D culture model, the spheroid size, hypoxic level, and cell viability were significantly elevated by CDDP resistance, but not by OCLN-overexpression. The accumulation inside the spheroids and toxicity of DXR were correlated with OCLN expression. Our data suggest that OCLN is not directly involved in the chemoresistance, but it enhances chemoresistance mediated by suppression of accumulation of anticancer drugs inside the spheroids.