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We discussed two cases of symptomatic female carriers to Duchenne Muscular Dystrophy. The first case is a 20 year-old girl with classical phenotypic manifestation of the disease, similar to the condition in boys. The case 2 is a 62 year-old woman with progressive muscular weakness. The disease is much less common in woman than men so both cases described here are considered rare forms of the disease, with several clinical implications. In both cases, a progressive muscle weakness, impairment in walking and sleeping was observed, in addition to obstructive sleep apnea syndrome and alveolar hypoventilation, that required noninvasive ventilatory support.

Background: Sublobar resection is the standard procedure for cT1N0 stage I non-small cell lung cancer (NSCLC) size ≤2 cm. However, its efficacy for high-risk pathologic stage I cases with a preoperative diagnosis of cT1N0 stage I NSCLC size ≤2 cm remains unclear. This study compared the outcomes of sublobar resection with those of lobectomy from a pathologic perspective., Methods: A multicenter retrospective analysis of patients with pathologic stage I NSCLC was performed following the eighth edition of tumor-node-metastasis (TNM) classification. The study enrolled patients with completely resected clinical stage I NSCLC and a tumor size of ≤2 cm determined by computed tomography. High-risk pathologic feature was defined as evidence of pleural invasion, lymphovascular invasion, or invasive component (>2 cm). Survival rates were compared between the patients who underwent sublobar resection and those who underwent lobectomy., Results: The study enrolled 875 patients (715 [81.7%] low-risk and 160 [18.3%] high-risk NSCLC patients). The high-risk patients in the lobectomy group had significantly better 5-year recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) rates than those in the sublobar resection group (RFS: 80.5% vs 44.3% [P < 0.001], OS: 84.9% vs 54.6% [P = 0.001], CSS: 91.6% vs 72.4% [P = 0.019]). In the low-risk group, lobectomy and sublobar resection resulted in equivalent 5-year RFS, OS, and CSS (RFS: 92.8% vs 88.6% [P = 0.13], OS: 93.8% vs 91.7% [P = 0.26], CSS: 98.9% vs 98.4% [P = 0.67]). Multivariate analysis indicated that sublobar resection was independently associated with poor RFS, OS, and CSS for the high-risk patients., Conclusions: Sublobar resection is feasible for low-risk pathologic stage I NSCLC, whereas lobectomy may have a prognostic benefit for high-risk NSCLC., Competing Interests: Disclosure: There are no conflicts of interest., (© 2024. Society of Surgical Oncology.)

Background: Cluster of differentiation (CD) 155 is a transmembrane protein that belongs to the nectin-like molecule family, which is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathologic stage I lung adenocarcinoma remains poorly understood., Methods: We analyzed 320 patients diagnosed with pathologic stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinical and pathologic characteristics and clinical outcomes between these groups., Results: Mutation status of the epidermal growth factor receptor gene (EGFR) was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, and 131 patients (40.9%) had EGFR mutant-type. CD155 expression was classified as high in 77 patients (24.1%) and as low in 243 (75.9%) as low. Multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. Multivariate analysis showed high CD155 expression was an independent poor prognostic factor for recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type., Conclusions: Our findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathologic stage I lung adenocarcinoma, particularly in cases without EGFR mutation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The reliance on fossil fuels is a major contributor to increased anthropogenic CO 2 emissions, driving global challenges such as climate change through the greenhouse effect. Carbon capture and storage (CCS) is a promising interdisciplinary technology aimed at mitigating these emissions by securely sequestering gigatons of CO 2 . This study focuses on the feasibility of storing point-source CO 2 emissions in saline formations, with a particular emphasis on the Mae Moh coal-fired power plant in Lampang, Thailand, which is located near its associated coal mine. The region presents challenges due to tight sandstone reservoirs buried over 2000 m deep. With reservoir simulation, this study evaluates the impact of various factors on CO 2 containment and trapping in these geological settings. Results show that elevated temperatures decrease structural trapping of 43.0%-28.9% and increase solubility trapping of 28.55%-46.5%, at 40 °C and 80 °C respectively. Hysteresis is found to enhance residual trapping by immobilizing up to 31.1% of CO 2 within pore spaces at 0.5. Permeability heterogeneity has a minimal impact on overall trapping efficiency due to the less heterogeneity of the tight sandstone. However, the kV/kH ratio significantly influences vertical CO 2 migration which resulted in residual trapping at its highest at the ratio of 0.1, while lower ratios support lateral dispersion. Moderate rock compressibility values are identified as optimal for structural and residual trapping, while extreme compressibility enhances solubility trapping by up to 30%. These findings emphasize the complexity of CO 2 trapping mechanisms in tight sandstone formations, emphasizing the need for careful consideration of key factors in CCS projects., Competing Interests: Declaration of competing interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% ( p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% ( p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% ( p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% ( p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matsudo, Takamori, Takenaka, Shimokawa, Hashinokuchi, Nagano, Kinoshita, Akamine, Kohno, Toyokawa and Yoshizumi.)

Background: Cluster of differentiation 155 (CD155) is expressed in many tumor types. CD155 is involved in the immune avoidance of tumor cells and contributes to tumor development and progression. Therefore, CD155 is a novel target for cancer immunotherapy. The clinical significance of CD155 expression in lung squamous cell carcinoma (LUSC) has not been fully elucidated., Materials and Methods: We performed a retrospective analysis of 264 patients with surgically resected LUSC. Immunohistochemistry was used to evaluate CD155 expression. The association of CD155 expression with clinicopathological features and clinical outcomes was assessed. We also analyzed the relationship between CD155 expression and programmed cell death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes., Results: Among the 264 patients, 137 patients (51.9%) were classified in the high CD155 expression group. High CD155 expression was significantly associated with pleural invasion, vascular invasion, PD-L1 positivity, and high CD3, CD4, and CD8 expressions. In multivariate analysis, the presence of pleural invasion and PD-L1 positivity were independent predictors of high CD155 expression. Kaplan-Meier curve analysis showed that high CD155 expression was significantly associated with shorter disease-free survival and overall survival. In multivariate analysis, high CD155 expression was an independent poor prognostic factor for overall survival, but not for disease-free survival. Subgroup analyses revealed that the prognostic effect of CD155 expression was observed in the PD-L1 positive group but not the PD-L1 negative group., Conclusion: Our analysis revealed that high CD155 expression significantly predicted poor prognosis in patients with surgically resected LUSC, especially in patients with PD-L1-positive tumors., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Intramuscular hemangioma is an uncommon benign tumor found mainly in the limbs of adolescents and young adults. The local recurrence rate is high, ranging from 30 to 50%, necessitating wide local excision of intercostal intramuscular hemangiomas. However, preoperative diagnosis of intramuscular hemangiomas is challenging. Herein, we report a rare case of an intramuscular hemangioma arising from the chest wall., Case Presentation: A healthy 29-year-old asymptomatic man was referred to our hospital after an abnormal shadow was observed on his chest radiography. Computed tomography and magnetic resonance imaging revealed a 30-mm-sized mass in the right second intercostal space. Neoplastic lesions, such as schwannomas or solitary fibrous tumors, were included in the preoperative differential diagnosis. Tumor resection was performed using video-assisted thoracoscopic surgery. The tumor, which had a smooth surface covered with parietal pleura, was dissected from the external intercostal muscle and costal bone. Postoperative histopathological examination revealed proliferation of spindle-shaped endothelial cells arranged in a capillary vascular structure accompanied by entrapped smooth muscle fibers, adipose tissue, and muscle vessels. The final diagnosis was an intramuscular hemangioma with negative surgical margins. There was no evidence of recurrence during the 1-year postoperative follow-up period., Conclusion: Intramuscular hemangiomas should be considered in the differential diagnosis of chest wall tumors, particularly in young people, owing to their potential for recurrence. Moreover, postoperative follow-up may be necessary for resected intramuscular intercostal hemangiomas., (© 2024. The Author(s).)

In recirculating aquaculture systems (RAS), maintaining water quality in aquaculture tanks is a paramount factor for effective fish production. A down-flow hanging sponge (DHS) reactor, a trickling filter system used for water treatment of RAS that employs sponges to retain biomass, has high nitrification activity. However, nitrification in seawater RAS requires a long start-up time owing to the high salinity stress. Therefore, this study aimed to evaluate the nitrification characteristics and changes in the microbial community during the conversion of freshwater to seawater in a DHSreactor fed with ammonia-based artificial seawater. The total ammonia nitrogen concentration reached 1.0 mg-N·L -1 (initial concentration 10 mg-N·L -1 ) within 11 days of operation, and nitrate production was observed. The 16 S rRNA gene sequence of the DHS-retained sludge indicated that the detection rate of the ammonia-oxidizing archaeon Candidatus Nitrosocosmicus decreased from 23.9 % to 14.0 % and 25.8-17.6 % in the upper and lower parts of the DHS reactor, respectively, after the introduction of seawater. In contrast, the nitrite-oxidizing bacteria Nitrospira spp. increased from 0.1 % to 9.5 % and from 0.5 % to 10.5 %, respectively. The ammonia oxidation rates of 0.12 ± 0.064 and 0.051 ± 0.0043 mg-N·g-MLVSS -1 ·h -1 on the 37th day in the upper and bottom layers, respectively. Thus, nitrification in the DHS reactor performed well, even under high-salinity conditions with short operational days. This finding makes the transition from freshwater to saltwater fish in the RAS system simple and economical, and has the potential for early start-up of the RAS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takahiro Watari reports financial support was provided by Japan Society for the Promotion of Science. Takahiro Watari reports financial support was provided by Japan Science and Technology Agency. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Signal-regulatory protein alpha (SIRPα) is an immune checkpoint molecule expressed on macrophages that functions to inhibit phagocytosis by binding to CD47 expressed on tumor cells. SIRPα has attracted increasing attention as a novel target for cancer immunotherapy; however, the expression and immune function of SIRPα in lung squamous cell carcinoma (LUSC) remain unclear. Therefore, this study aimed to identify the clinical importance of SIRPα expression in LUSC and to explore the factors that elevate SIRPα expression., Patients and Methods: Primary LUSC specimens surgically resected from 172 patients underwent immunohistochemical evaluation of the association of SIRPα expression on tumor-associated macrophages with clinicopathological features and clinical outcomes. Furthermore, we analyzed the association of SIRPα expression with tumor-infiltrating lymphocytes and the expression of programmed cell death ligand 1 (PD-L1). In vitro, monocytes were treated with cytokines, and SIRPα protein expression was assessed by flow cytometry., Results: There were no differences in SIRPα expression and clinicopathological factors. High SIRPα expression was significantly associated with PD-L1-positive expression, and high CD8, PD-1, and CD163 expression. The high SIRPα expression group showed significantly shorter recurrence-free survival (RFS) and overall survival (OS). On multivariate analysis, high SIRPα expression was an independent poor prognostic factor for RFS and OS. The expression of SIRPα protein in monocytes was upregulated by treatment with IFNγ., Conclusion: Our analysis revealed that high SIRPα expression significantly predicts poor prognosis in patients with surgically resected LUSC., (© 2024. Society of Surgical Oncology.)

Introduction: High recurrence rate following curative surgery for non-small cell lung cancer (NSCLC) presents a major clinical challenge. Understanding the site and timing of recurrence and their impact on post-recurrence survival (PRS) is important for optimal postoperative surveillance and therapeutic intervention. In this study, we investigated the influence of the time to recurrence (TTR) and initial recurrence site on PRS., Materials and Methods: This multicentre prospective cohort study included patients who experienced recurrence after NSCLC resection between 2010 and 2015. The relationship between TTR and initial recurrence site, and their impact on PRS, was further evaluated. The hazard ratio (HR) for PRS was analysed using the Cox proportional hazards model., Results: Among 495 patients, the median TTR was 14 (range, 1-158) months; the mode of recurrence was 11 months. Early recurrence within 6 months was observed in 17 % of patients, and 68 % of patients showed recurrence within 2 years post-surgery. The HR for PRS was the highest in patients with a TTR within 6 months, and a noticeable decline was observed after the first 6 months. The HRs of TTRs beyond 2 years were not significantly different. The liver was a significantly unfavourable prognostic site for metastases (HR 2.2; P = 0.01), and metastases frequently recurred within 6 months after surgery. The timing of brain metastasis did not significantly impact the PRS., Conclusion: Earlier recurrence after surgery was associated with shorter PRS. In contrast, recurrences occurring >2 years after surgery do not significantly affect PRS., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: The preoperative serum creatine kinase (CK) concentration is a prognostic factor for malignant diseases. We investigated the significance of CK in surgically resected thymic epithelial tumors and the relationship between CK and clinicopathological factors., Methods: We retrospectively evaluated the relationship between preoperative CK levels and prognosis in 120 patients with thymic epithelial tumors who underwent surgical resection at two centers. The cutoff for CK was determined by the standard value in our institution (<62 IU/L for men and <45 IU/L for women). The paravertebral muscle at the Th12 level was used to assess skeletal muscle area to investigate sarcopenia., Results: Eighteen patients (15.0%) were categorized into the low CK group. The CK level was not associated with age, sex, performance status, myasthenia gravis, and pathological findings. Preoperative serum albumin and total cholesterol concentrations were significantly lower in the low CK group than in the normal CK group (both P<0.001). Moreover, the Th12 muscle index was lower in the low CK group (P=0.03), indicating that low CK was related to sarcopenia. Kaplan-Meier curve analysis illustrated that patients in the low CK group had significantly shorter disease-free survival (DFS) and overall survival (OS) than those in the normal CK group (P=0.03 and P=0.002, respectively). Multivariate analysis identified low CK as an independent prognostic factor for DFS (P=0.03) and OS (P=0.005)., Conclusions: Preoperative serum CK might reflect the host nutritional status in patients with resected thymic epithelial tumors; therefore, CK could be a biomarker of postoperative prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1797/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme with an important role in tumor progression in various cancers. However, the clinical significance of GPX2 in lung adenocarcinoma has not been clarified., Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze GPX2 mRNA expression. Then, we conducted immunohistochemistry (IHC) to assess GPX2 expression in specimens acquired from 351 patients with lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We investigated the association between GPX2 expression and clinicopathological characteristics and further analyzed the prognostic relevance., Results: qRT-PCR revealed that GPX2 mRNA expression was notably higher in tumor cells than in normal tissues. IHC revealed that high GPX2 expression (n = 175, 49.9%) was significantly correlated with male sex, smoking, advanced pathological stage, and the presence of pleural, lymphatic, and vascular invasion. Patients with high GPX2 expression exhibited significantly shorter recurrence-free survival (RFS) and overall survival. Multivariate analysis identified high GPX2 expression as an independent prognostic factor of RFS., Conclusions: GPX2 expression was significantly associated with pathological malignancy. It is conceivable that high GPX2 expression reflects tumor malignancy. Therefore, high GPX2 expression is a significant prognostic factor of poor prognosis for completely resected lung adenocarcinoma., (© 2024. Society of Surgical Oncology.)

The Ras homology (Rho) family of GTPases serves various functions, including promotion of cell migration, adhesion, and transcription, through activation of effector molecule targets. One such pair of effectors, the Rho-associated coiled-coil kinases (ROCK1 and ROCK2), induce reorganization of actin cytoskeleton and focal adhesion through substrate phosphorylation. Studies on ROCK knockout mice have confirmed that ROCK proteins are essential for embryonic development, but their physiological functions in adult mice remain unknown. In this study, we aimed to examine the roles of ROCK1 and ROCK2 proteins in normal adult mice. Tamoxifen (TAM)-inducible ROCK1 and ROCK2 single and double knockout mice (ROCK1 flox/flox and/or ROCK2 flox/flox ;Ubc-CreERT2) were generated and administered a 5-day course of TAM. No deaths occurred in either of the single knockout strains, whereas all of the ROCK1/ROCK2 double conditional knockout mice (DcKO) had died by Day 11 following the TAM course. DcKO mice exhibited increased lung tissue vascular permeability, thickening of alveolar walls, and a decrease in percutaneous oxygen saturation compared with noninducible ROCK1/ROCK2 double-floxed control mice. On Day 3 post-TAM, there was a decrease in phalloidin staining in the lungs in DcKO mice. On Day 5 post-TAM, immunohistochemical analysis also revealed reduced staining for vascular endothelial (VE)-cadherin, β-catenin, and p120-catenin at cell-cell contact sites in vascular endothelial cells in DcKO mice. Additionally, VE-cadherin/β-catenin complexes were decreased in DcKO mice, indicating that ROCK proteins play a crucial role in maintaining lung function by regulating cell-cell adhesion., (© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: Oncological feasibility of segmentectomy for internal non-small cell lung cancer (NSCLC) has not been assessed adequately. We assessed the oncological feasibility of segmentectomy for inner-located NSCLC by investigating surgical margins and patient prognosis after undergoing the procedure., Methods: Of the 3555 patients who underwent resection for lung cancer between 2013 and 2019 at our institution, 659 patients who underwent segmentectomy for clinical stage 0 to stage1A NSCLC were included in this study. Patients were separated into 2 groups according to whether the tumor was in the inner or outer third of the lung area. Clinical characteristics and prognoses were retrospectively compared between the groups., Results: Of the included 659 cases, 183 (27.8%) were inner-located, and 476 (72.2%) had outer-located NSCLC. The surgical margin was significantly shorter in the inner-located group than in the outer group (median, 16 vs 25 mm; P  < .001). The 5-year recurrence-free survival and overall survival probabilities were 91.1%/91.8% ( P  = .530) and 94.1%/95.6% ( P  = .345) for inner/outer-located groups, respectively. Multivariate analysis showed that clinical stage IA2 or 3 ( P  = .043), lymphovascular invasion ( P  < .001), and surgical margins <20 mm ( P  = .017) were independent prognostic factors for recurrence-free survival. The location of the inner or outer tumors was not related to the prognosis., Conclusions: For clinical stage 0 to stage1A NSCLC, tumor location in the inner two-thirds of the lung was not associated with prognosis after segmentectomy. Because one of the independent prognostic factors is margin distance, segmentectomy for inner-located NSCLC would be oncologically acceptable when an adequate surgical margin is secured., Competing Interests: Dr Yatabe reports personal fees from AstraZeneca, Daiichi-Sankyo, MSD, Amgen, AstraZeneca, Chugai Pharma, MSD, Novartis, Pfizer, Thermo Fisher Scientific, and Konika Minolta outside of this work. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Timosaponin AIII (TAIII), a steroidal saponin isolated from the root of Anemarrhena asphodeloides Bunge, exhibits various pharmacological activities, including anti-cancer properties. TAIII inhibits the migration and invasion of various cancer cell types. However, the mechanism underlying how TAIII regulates the motility of cancer cells remains incompletely understood. In this study, we demonstrate that TAIII disrupted cell-extracellular matrix (ECM) interactions by inhibiting internalization of cell surface proteins, such as integrins. We found that TAIII inhibited cell adhesion on various ECMs. Structure-activity relationship analysis demonstrated that TAIII exhibited unique activity among the saponins from Anemarrhena asphodeloides Bunge and that the number and position of saccharide moieties were important for TAIII to exert its activity. Time lapse imaging revealed that TAIII also suppressed cell spreading on the ECM, membrane ruffling, and lamellipodia formation. Furthermore, we examined integrin β1 behaviors in response to TAIII treatment and found that TAIII blocked its internalization. These findings contribute to delineating the potential molecular mechanisms by which TAIII exerts anti-metastatic activity.

Background: Preoperative fluorine-18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) of thymic epithelial tumors (TETs) is well known for identifying malignant-grade TETs; however, its predictive power for determining locally advanced tumors, lymph node (LN) metastasis, and prognosis remains unknown., Patients and Methods: We retrospectively evaluated patients with resectable TETs who were preoperatively assessed using 18 F-FDG PET from January 2012 to January 2023. The receiver operating characteristic curve was used to evaluate the cutoff value of the maximum standardized uptake value (SUVmax) to predict advanced-stage disease. Recurrence/progression-free survival (RFS/PFS) was analyzed using the Kaplan-Meier method. The staging was classified according to the tumor-node-metastasis system., Results: Our study included 177 patients; 145 (81.9%) had pathological early-stage TET (stage I or II), and 32 (19.1%) had advanced stage (stage III or IV). The area under the curve value for predicting the advanced stage was 0.903, and the cutoff value was 5.6 (sensitivity 81.3%, specificity 84.8%). SUVmax > 5.6 was associated with worse prognosis for RFS/PFS. LN metastasis was preoperatively detected by FDG uptake in 30.8% of patients with pathological LN positivity, whereas LN metastasis was not pathologically detected in patients with SUVmax < 5.9. In patients with advanced-stage TETs, LN recurrence was more frequent in patients who were preoperatively detected by 18 F-FDG PET than those who were not (75.0% versus 7.1%)., Conclusions: 18 F-FDG PET is a potentially valuable tool for predicting advanced stage and poor prognosis of recurrence in patients with TETs. SUVmax can help thoracic surgeons to guide them in selecting appropriate therapeutic strategies for TETs., (© 2023. Society of Surgical Oncology.)

To investigate the frequency of pneumonia and chest computed tomography (CT) findings in patients with coronavirus disease 2019 (COVID-19) during the fifth Delta variant-predominant and sixth Omicron variant-predominant waves of the COVID-19 pandemic in Okinawa, Japan. A survey on chest CT examinations for patients with COVID-19 was conducted byhospitals with board-certified radiologists who provided treatment for COVID-19 pneumonia in Okinawa Prefecture. Data from 11 facilities were investigated. Indications for chest CT; number of COVID-19 patients undergoing chest CT; number of patients with late-onset pneumonia, tracheal intubation, and number of deaths; and COVID-19 Reporting and Data System classifications of initial chest CT scans were compared by the chi-squared test between the two pandemic waves (Delta vs. Omicron variants). A total of 1944 CT scans were performed during the fifth wave, and 1178 were performed during the sixth wave. CT implementation rates, which were the number of patients with COVID-19 undergoing CT examinations divided by the total number of COVID-19 cases in Okinawa Prefecture during the waves, were 7.1% for the fifth wave and 2.1% for the sixth wave. The rates of tracheal intubation and mortality were higher in the fifth wave. Differences between the distributions of the CO-RADS classifications were statistically significant for the fifth and sixth waves (p < 0.0001). In the fifth wave, CO-RADS 5 (typical of COVID-19) was most common (65%); in the sixth wave, CO-RADS 1 (no findings of pneumonia) was most common (50%). The finding of "typical for other infection but not COVID-19" was more frequent in the sixth than in the fifth wave (13.6% vs. 1.9%, respectively). The frequencies of pneumonia and typical CT findings were higher in the fifth Delta variant-predominant wave, and nontypical CT findings were more frequent in the sixth Omicron variant-predominant wave of the COVID-19 pandemic in Okinawa, Japan., (© 2023. The Author(s).)

Background/aim: Recent advances in surgery, such as thoracoscopic surgery, have made it possible to treat patients with chronic obstructive pulmonary disease (COPD) more safely than before. This study evaluated the short- and long-term prognosis of lobectomy in non-small cell lung cancer (NSCLC) patients with COPD., Patients and Methods: This retrospective, propensity-matched, cohort analysis was conducted from January 2014 to December 2018. Among 441 patients who underwent lobectomy for NSCLC, 158 (35.8%) had a preoperative diagnosis of COPD. Propensity-matched analysis, incorporating preoperative variables, was used to compare postoperative hospital stay and complications, and long-term prognosis between the groups., Results: Propensity matching estimated 145 patients in each group. There was no difference between the two groups for length of postoperative hospital stay (12 vs. 11 days, p=0.306). Postoperative complications were more frequent in the COPD group (24.1%) than in the non-COPD group (16.6%), but the difference was not significant (p=0.108). The 5-year overall survival rate was 86.2% in the COPD group and 82.1% in the non-COPD group after matching (p=0.580). The corresponding 5-year recurrence-free survival rate was 72.8% in the COPD group and 67.2% in the non-COPD group after matching (p=0.601)., Conclusion: In case of Global Initiative for Chronic Obstructive Lung Disease (GOLD) I/II classification, COPD did not significantly worsen the prognosis of patients with NSCLC after lobectomy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood., Methods: We analyzed 273 patients with pathological stage (pStage) I-IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm 2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed., Results: GZMB-Low was significantly associated with pStage II-III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis., Conclusions: We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient's immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma., (© 2023. Society of Surgical Oncology.)

Objectives: We evaluated the potential of preoperative fluorine-18-fluorodeoxyglucose positron emission tomography to predict invasive thymic epithelial tumours in patients with computed tomography-defined clinical stage I thymic epithelial tumours ≤5 cm in size who are generally considered to be candidates for minimally invasive approaches., Methods: From January 2012 to July 2022, we retrospectively analysed patients who exhibited tumour-node-metastasis (TNM) clinical stage I thymic epithelial tumours with lesion sizes ≤5 cm as determined by computed tomography. All patients underwent fluorine-18-fluorodeoxyglucose positron emission tomography preoperatively. We analysed the association of maximum standardized uptake values with both the World Health Organization histological classification and the TNM staging classification., Results: A total of 107 patients with thymic epithelial tumours (thymomas, 91; thymic carcinomas, 14; carcinoids, 2) were evaluated. Nine patients (8.4%) were pathologically upstaged: TNM pathological stage II in 3 (2.8%), III in 4 (3.7%) and IV in 2 (1.9%). Among these 9 upstaged patients, 5 had thymic carcinoma with stage III/IV, 3 had type B2/B3 thymoma with stage II/III and 1 had type B1 thymoma with stage II. Maximum standardized uptake values were a predictive factor that distinguished pathological stage >I thymic epithelial tumours from pathological stage I [best cut-off value, 4.2; area under the curve = 0.820] and thymic carcinomas from other thymic tumours (best cut-off value, 4.5; area under the curve = 0.882)., Conclusions: Thoracic surgeons should carefully determine the surgical approach for high fluorodeoxyglucose-uptake thymic epithelial tumours and keep in mind the issues associated with thymic carcinoma and potential combined resections of neighbouring structures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: With recent improvements in surgical techniques for segmentectomy, we hypothesized that segmentectomy is feasible and more effective than wedge resection for non-small-cell lung cancer (NSCLC). We compared perioperative and oncological outcomes for segmentectomy and wedge resection., Methods: We performed a retrospective analysis of 720 patients who underwent sublobar resection (segmentectomy, 479; wedge resection, 241) for clinical stage 0 or I NSCLC from January 2017 to June 2020. An adequate surgical margin was defined as a surgical margin distance of ≥2 cm or ≥ the total tumour size. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method for clinical stage IA., Results: There was no significant difference in the rate of major (grade ≥III) complications between segmentectomy (1.7%) and wedge resection (1.2%) (P = 0.76). The probability of obtaining adequate surgical margins was significantly higher with segmentectomy (71.4%) versus wedge resection (59.5%) (P = 0.002), and the difference was especially prominent for clinical stage IA2 (75.3% vs 56.9%; P = 0.012). Among patients with clinical stage IA, segmentectomy significantly improved the RFS compared with wedge resection (hazard ratio 2.7; 95% confidence interval 1.60-4.61; log-rank P < 0.001). Subgroup analysis based on the tumour status revealed that segmentectomy had a better RFS in clinical stage IA2 (P < 0.001) and in pure-solid tumours (P = 0.022) than wedge resection., Conclusions: We demonstrate that segmentectomy is a feasible procedure with comparable safety outcomes and better surgical margins and cancer control than wedge resection, particularly for clinical stage IA2 NSCLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We report a 33-year-old man who presented with recurrent right pneumothorax. Computed tomography (CT) showed the presence of a large bulla with a maximum diameter of 8 cm in the right middle lobe; he subsequently underwent bullectomy. Histopathology revealed that pulmonary parenchyma adjacent to the bulla represented nodular proliferation of clear cells characterized by a papillary structure resembling placental chorionic villi. Immunohistochemically, clear cells were positive for CD10, suggesting placental transmogrification of the lung (PTL). We reviewed 36 surgical cases of PTL, and only 2 cases (5.6%), including our case, were operated for spontaneous pneumothorax. Bullous lesions secondary to PTL tend to appear as unilateral large cystic masses in non-upper lobes, which is atypical for primary spontaneous pneumothorax (PSP). Although PTL is considered a very rare cause of secondary pneumothorax, we must carefully differentiate this condition.

Dysregulation of fatty acid utilization is increasingly recognized as a significant component of diabetic kidney disease. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in the diabetic kidney, and studies over the past decade have illuminated ROCK signaling as an essential pathway in diabetic kidney disease. Here, we confirmed the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism using glomerular mesangial cells and ROCK1 knockout mice. Mesangial cells with ROCK1 deletion were protected from mitochondrial dysfunction and redox imbalance driven by transforming growth factor β, a cytokine upregulated in diabetic glomeruli. We found that high-fat diet-induced obese ROCK1 knockout mice exhibited reduced albuminuria and histological abnormalities along with the recovery of impaired fatty acid utilization and mitochondrial fragmentation. Mechanistically, we found that ROCK1 regulates the induction of critical mediators in fatty acid metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1α, carnitine palmitoyltransferase 1, and widespread program-associated cellular metabolism. Thus, our findings highlight ROCK1 as an important regulator of energy homeostasis in mesangial cells in the overall pathogenesis of diabetic kidney disease., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Eating during a rest phase disrupts the biological clock system and leads to obesity and metabolic diseases. Although a rest phase restricted feeding (RF) is reported to enhance hepatic lipid accumulation, the mechanism(s) of the phenomenon is still unknown. This study evaluated the potential involvement of the CD36-related transport of lipids into the liver in mice with the RF procedure. This study showed that hepatic lipid accumulation was more significant in the RF group compared with mice under an active phase restricted feeding (AF). The RF procedure also elevated the expression of CD36 mRNA and its protein on the cellular membrane throughout the day. The transcription factor profiling array revealed that the RF activated the proliferator-activated receptor-γ (PPARγ), one of the CD36 transcript enhancers. In the liver of RF mice, the expression of miR-27b-3p, which is known to interfere with PPARγ gene expression, significantly decreased. These results suggest that the RF procedure inhibits the expression of miR-27b-3p in the liver and subsequently elevates PPARγ activity. Activated PPARγ might lead to CD36 upregulation, which, in turn, stimulates the transport of lipids into the liver.

Extralobar pulmonary sequestration is generally located in the left thoracic cavity and is often identified prenatally or in infants. We identified a rare case of multiple extralobar pulmonary sequestrations in the thoracic and abdominal cavities, incidentally detected in a 60-year-old woman by cancer screening. The patient underwent surgery by thoracoscopic and laparoscopic approaches simultaneously, and extralobar sequestration was histologically confirmed in each lesion. Preoperative diagnosis was difficult because of unusual multiple localization and an undetectable aberrant artery on imaging examinations., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Assessing microbiological culture results is essential in the diagnosis of empyema and appropriate antibiotic selection; however, the guidelines for the management of empyema do not mention assessing microbiological culture intraoperatively. Therefore, we tested the hypothesis that intraoperative microbiological culture may improve the management of empyema., Methods: We performed a retrospective analysis of 47 patients who underwent surgery for stage II/III empyema from January 2011 to May 2019. We compared the positivity of microbiological culture assessed preoperatively at empyema diagnosis versus intraoperatively. We further investigated the clinical characteristics and postoperative outcomes of patients whose intraoperative microbiological culture results were positive., Results: The positive rates of preoperative and intraoperative microbiological cultures were 27.7% (13/47) and 36.2% (17/47), respectively. Among 34 patients who were culture-negative preoperatively, eight patients (23.5%) were culture-positive intraoperatively. Intraoperative positive culture was significantly associated with a shorter duration of preoperative antibiotic treatment (p = 0.002). There was no significant difference between intraoperative culture-positive and -negative results regarding postoperative complications., Conclusions: Intraoperative microbiological culture may help detect bacteria in patients whose microbiological culture results were negative at empyema diagnosis. Assessing microbiological culture should be recommended intraoperatively as well as preoperatively, for the appropriate management of empyema.

Background: Video-assisted surgery helps surgeons learn surgical skills efficiently. The aim of this study was to evaluate the effect of mutual evaluation of trainees' surgical techniques using tabulated common evaluation criteria., Methods: We created a check sheet in which a standard pulmonary lobectomy procedure was divided into six parts and the checkpoints to note listed. Both the trainees and trainers used tabulated common evaluation criteria to evaluate lobectomies performed by the trainees., Results: From September 2019 to March 2020, 30 lobectomies were performed by three trainees. The trainee's evaluations of their own procedures were relatively high at first, then decreased, then gradually increased; however, the trainers' evaluations showed no such tendency., Conclusions: Mutual evaluation of surgery using tabulated common evaluation criteria enables trainees to review their own surgery objectively and receive evaluations by trainers, thus helping them to avoid the Dunning-Kruger effect and efficiently acquire basic surgical skills.

Objectives: The prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in lung cancer patients. Tumour-infiltrating lymphocytes (TILs) is a specific histological feature of cancers, influencing an individual's immunological tumour responses. However, whether PNI can reflect lung cancer patients' prognosis through local immunity such as TIL is unclear., Methods: We selected 64 lung squamous cell carcinoma patients who underwent curative operations. We investigated the significance of preoperative PNI level and evaluated the relationship between PNI and immune cells surrounding the lung cancer tissue using immunohistochemical analysis of a cluster of differentiation (CD)3, CD4, CD8 and CD68., Results: A low-PNI level was significantly associated with a worse postoperative prognosis (P = 0.042). The PNI (hazard ratio 2.768, 95% confidence interval 1.320-5.957; P = 0.007) was an independent prognostic factor. The low-PNI group had a significantly shorter recurrence-free survival and overall survival (P = 0.013 and P = 0.002, log-rank test) compared with the high-PNI group. A significant positive correlation between PNI components including preoperative peripheral blood lymphocyte count and serum albumin concentration, and TILs, was observed. Absolute numbers of TILs in the preoperative high-PNI group were significantly increased compared with those in the preoperative low-PNI group (CD3+ cells; P = 0.002, CD4+ cells; P = 0.049 and CD8+ cells; P = 0.024)., Conclusions: The preoperative PNI level was strongly associated with the postoperative outcome in lung cancer patients. Considering the positive relationship between preoperative PNI level and TIL status, preoperative immune-nutritional condition may influence lung cancer patients' postoperative prognosis through local immunity as well as systemic immune response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: A tracheal bronchus is rarely observed, occurring in only 1% of all patients who undergo thoracic surgeries. We rarely encounter lung cancer in a patient with a tracheal bronchus; however, it is essential to know the distinctive perioperative management strategy for patients with a tracheal bronchus., Case Presentation: We report a 72-year-old man with lung cancer located in the right apical segment supplied by a tracheal bronchus. Annual chest computed tomography performed as follow-up after colon cancer resection showed an enlarging pulmonary nodule with pure ground-glass opacity, which was suspected to be lung adenocarcinoma. The nodule was located in the right apical segment. The apical segment was independently supplied by a single pulmonary artery superior trunk and a tracheal bronchus that branched directly from the trachea at 1.2 cm above the carina. The pulmonary vein branching pattern was uncommon in that the central vein that usually runs through B2 (posterior bronchus) and B3 (anterior bronchus) was missing. The patient underwent video-assisted thoracoscopic apical segmentectomy under one-lung ventilation using a left-sided double-lumen tube., Discussion: Anomalous venous return accompanied with tracheal bronchus has been described in some reports. Since pulmonary vein is important during segmentectomy, the surgeon should pay particular attention to the venous return., Conclusion: Preoperative three-dimensional graphic imagery helped us accurately identify the anatomical anomaly to enable the successful segmentectomy in a patient with a tracheal bronchus. We review the relevant literature regarding the perioperative management of patients with a tracheal bronchus., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report a 69-year-old woman with spontaneous pneumothorax associated with cavitating pulmonary metastasis from breast cancer. She was treated for right breast cancer (invasive ductal carcinoma, ypT4bN1M0, stage IIIB) 2 years earlier, and was admitted for right pneumothorax and chest computed tomography, which showed multiple small cavitating lesions in bilateral lungs. The pneumothorax was treated conservatively with chest drainage, but subsequently recurred ipsilaterally. During video-assisted thoracic surgery, we detected small white nodules with visceral pleural rupture; therefore, we performed partial lung resection. The pathological findings revealed metastatic breast cancer with pleural invasion. Forty days later, ipsilateral pneumothorax recurred, and chemical pleurodesis was performed, which resolved the pneumothorax and prevented subsequent recurrence. Early diagnosis and definitive treatment, including pleurodesis, should be considered to prevent recurrence of spontaneous pneumothorax and improve patients' quality of life, even in patients with advanced malignancy.

Background: Interleukin (IL)-38 was discovered in 2001 and is a member of the IL-1 family of cytokines. IL-38 shows anti-inflammatory activity in several inflammatory diseases. In lung adenocarcinoma, we previously demonstrated that high IL-38 expression in tumor cells was associated with poor prognosis. However, the role of IL-38 in the tumor microenvironment has not been clarified., Methods: IL-38-plasmid-transfected Lewis lung carcinoma cells (LLC-IL38) and empty vector-transfected LLC cells (LLC-vector) were established. Cell proliferation in vitro and tumor growth in vivo were examined, and immunohistochemical staining was used to assess tumor-infiltrating lymphocytes (TILs). A CD8 + lymphocyte depletion model was established to show the association between IL-38 and CD8 + lymphocytes. Moreover, we examined the association between IL-38 expression and CD8 + TILs in human samples, analyzing immunohistochemical staining in 226 patients with radically resected lung adenocarcinoma., Results: Tumor growth of LLC-IL38 in vivo was significantly increased compared with that of LLC-vector, although cell proliferation of LLC-IL38 in vitro was lower than that of LLC-vector. CD8 + TILs were significantly decreased in LLC-IL38 tumor compared with LLC-vector tumor. The difference in tumor growth between LLC-IL38 and LLC-vector became insignificant after depletion of CD8 + lymphocytes. In immunohistochemical staining in tissues from patients with lung adenocarcinoma, multivariate analysis showed high IL-38 expression was an independent negative predicter of high density of CD8 + TILs., Conclusion: We demonstrated that high IL-38 expression in tumor cells was significantly associated with reduction of CD8 + TILs and tumor progression. These results suggest that IL-38 could be a therapeutic target for lung cancer.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS., Competing Interests: The authors have declared that no competing interests exist.

Background: Initial surgical intervention for a first episode of primary spontaneous pneumothorax (PSP) is controversial. However, if air leak persists after initial drainage, surgical treatment is recommended. Therefore, we investigated risk factors for persistent air leak (PAL) in patients with a first episode of PSP., Methods: We retrospectively analyzed 122 patients with a first episode of PSP between January 2011 and April 2019. PAL was defined as air leak lasting 72 hours or longer. Early admission was defined hospital admission within 24 hours of symptom onset. Three methods were used to estimate pneumothorax size on chest X-rays taken at admission: interpleural distance, apex-cupola distance, and Light index., Results: Among 122 patients, 55 developed PAL (PAL group) and 67 did not (non-PAL group). The size of pneumothorax was significantly larger in the PAL group than in the non-PAL group in all three methods of assessment (P<0.001). Early hospital admission was significantly associated with PAL (P=0.026). Logistic regression analysis revealed that the odds ratio for PAL per unit increase in pneumothorax size evaluated with the interpleural distance was 1.304 (P<0.001). Multivariate logistic regression analysis showed that interpleural distance at the hilum and early admission (P<0.001, P=0.008, respectively) were independent predictors of PAL in patients with a first episode of PSP., Conclusions: In our study, we demonstrated that the interpleural distance at the hilum is a simple and effective predictor of PAL in patients with a first episode of PSP. Our data may help decision-making for initial surgical treatment in these patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.04.48). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

The expression levels of many cell-surface proteins vary with the time of day. Glycoprotein 2 (Gp2), specifically expressed on the apical surface of M cells in Peyer's patches, functions as a transcytotic receptor for mucosal antigens. We report that cAMP response element-binding protein (CREB) regulates the transcription of the Gp2 gene, thereby generating the circadian change in its expression in mouse Peyer's patches. The transcytotic receptor activity of Gp2 was increased during the dark phase when the Gp2 protein abundance increased. Rhythmic expression of clock gene mRNA was observed in mouse Peyer's patches, and expression levels of Gp2 mRNA also exhibited circadian oscillation, with peak levels during the early dark phase. The promoter region of the mouse Gp2 gene contains several cAMP response elements (CREs). Chromatin immunoprecipitation assays revealed that CREB bound to the CREs in the Gp2 gene in Peyer's patches. Forskolin, which promotes CREB phosphorylation, increased the transcription of the Gp2 gene in Peyer's patches. As phosphorylation of CREB protein was increased when Gp2 gene transcription was activated, CREB may regulate the rhythmic expression of Gp2 mRNA in Peyer's patches. These findings suggest that intestinal immunity is controlled by the circadian clock system., (© 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: It is unclear whether or not the breakpoint (BP), at which the proportion of each of fat mass (FM) and fat-free soft tissue mass (FFSTM) to body mass (BM) alter, exists in male athletes. We examined the hypothesis that in male athletes, the regional FM and FFSTM-BM relationships have a BP, but the body mass at BP (BM BP ) differs among the arms, trunk, and legs., Methods: By using a dual X-ray absorptiometry, whole-body and regional FMs and FFSTMs in the arms, trunk, and legs were estimated in 198 male athletes (20.8 ± 2.1 years; 1.73 ± 0.07 m; 72.7 ± 14.8 kg). To detect the BP in the relationship between each of FM and FFSTM and BM, a piecewise linear regression analysis was used. If a BP was detected in the corresponding relationship, the significant difference between the regression slopes above and below the BP was examined., Results: The regression analysis indicated that the BM BP existed in the FM- and FFSTM-BM relationships regardless of region and whole body. For the whole body, BM BP was 81.8 kg for FM and 82.2 kg for FFSTM. In regional FM-BM relationships, BM BP was 80.5 kg for arms, 82.6 kg for trunk, and 63.3 kg for legs, and the regression slopes above the BM BP became higher than those below the BP, and vice versa in regional FFSTM-BM relationships (BM BP 104.6 kg for arms, 80.9 kg for trunk, and 79.0 kg for legs). The relative differences in the slopes between below and above BM BP in the regional FM-BM relationships were higher in the arms and trunk than in the legs, and those in the regional FFSTM-BM relationships in the legs than in the trunk., Conclusion: Whole-body and regional FM- and FFSTM-BM relationships for male athletes have breakpoints at which the proportion of the tissue masses to BM alters. The BM BP and differences in the distribution of regional FM and FFSTM around the breakpoint are region specific.

Background: Preoperative skeletal muscle loss was reported to be associated with a postoperative poor prognosis in non-small cell lung cancer (NSCLC) patients. The aim of this study was to elucidate the relationship between the change in skeletal muscle mass after surgery and the postoperative outcomes in NSCLC patients., Methods: The data were analyzed for 204 NSCLC patients who had undergone curative lung resection and whose preoperative and postoperative (1-year) computed tomographic images were available. The skeletal muscle area (SMA) at the 12th thoracic vertebra level was used. Postoperative/preoperative ratio was defined as postoperative normalized SMA (cm 2 /m 2 ) divided by preoperative normalized SMA. The cutoff value was set to a postoperative/preoperative ratio of 0.9. The neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index were used to estimate change in the nutritional status., Results: There were 70 patients (34.3%) classified into the SMA-decreased group. Low body mass index was significantly associated with the SMA-decreased patients (P = .019). The SMA-decreased status was an independent prognostic factor for poor overall survival (P < .001) and disease-free survival (P = .001). The SMA-decreased status was significantly associated with the postoperative exacerbation of the neutrophil-lymphocyte ratio (P = .009), platelet-lymphocyte ratio (P = .026), modified Glasgow prognostic score (P = .003), and prognostic nutritional index (P = .013)., Conclusions: Skeletal muscle loss after surgery is significantly associated with poor postoperative outcomes in NSCLC patients. Further studies investigating the clinical impact of postoperative nutritional intervention are needed., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Glycolaldehyde (GA) is a highly reactive hydroxyaldehyde and one of the glycolytic metabolites producing advanced glycation endproducts (AGEs), but its toxicity toward neurons and Schwann cells remains unclear. In the present study, we found that GA exhibited more potent toxicity than other AGE precursors (glyceraldehyde, glyoxal, methylglyoxal and 3-deoxyglucosone) against immortalized IFRS1 adult rat Schwann cells and ND7/23 neuroblastoma × neonatal rat dorsal root ganglion (DRG) neuron hybrid cells. GA affected adult rat DRG neurons and ND7/23 cells more severely than GA-derived AGEs, and exhibited concentration- and time-dependent toxicity toward ND7/23 cells (10 < 100 < 250 < 500 µM; 6 h < 24 h). Treatment with 500 µM GA significantly up-regulated the phosphorylation of c-jun N-terminal kinase (JNK) and p-38 mitogen-activated kinase (p-38 MAPK) in ND7/23 cells. Furthermore, GA-induced ND7/23 cell death was significantly inhibited due to co-treatment with 10 µM of the JNK inhibitor SP600125 or the p-38 MAPK inhibitor SB239063. These findings suggest the involvement of JNK and p-38 MAPK-signaling pathways in GA-induced neuronal cell death and that enhanced GA production under diabetic conditions might be involved in the pathogenesis of diabetic neuropathy.

Previous studies proposed calf circumference cutoff values for predicting dual-energy X-ray absorptiometry (DXA)-derived low muscle mass. However, DXA-derived appendicular lean mass (aLM) includes non-skeletal muscle components such as the appendicular fat-free component of adipose tissue fat cells (aFFAT). The purpose of this study was to compare the calf circumference method of classification before (Model #1) and after (Model #2) eliminating the influence of FFAT in healthy Japanese adults (50 to 79 years; mean age 70 (SD 7) years). Model 1, and Model 2 for classifying low muscle mass had a sensitivity of 78% and 64%, specificity of 76% and 75%, positive predictive value of 31% and 28%, and negative predictive value of 96% and 93%, respectively. Appendicular fat-free component of adipose tissue has the potential to influence the ability of calf circumference to accurately classify individuals with low muscle mass. Consideration should be made when using this as a screening tool for low muscle mass., Competing Interests: No conflicts of interest, financial or otherwise, are disclosed by the authors.

Background & Aims: B-mode ultrasound accurately measures both muscle mass, body density and percent body fat (% BF) in younger adults, but how well it can estimate % BF in middle-aged and older adults using DXA-derived %BF as the criterion is unclear. We sought to develop % BF prediction equations for middle-aged and older adults using ultrasound subcutaneous fat thickness (SFT)., Methods: A cross-sectional study of Japanese adults (n = 414, 50-79 years) where 276 subjects were randomly assigned to a model development group and the other 138 subjects were assigned to a cross-validation group. B-mode ultrasound measured SFT at nine sites. Dual energy X-ray absorptiometry (DXA) measured % BF, arm fat mass (FM) and leg FM. Stepwise multiple linear regression developed prediction equations from anthropometric data (body mass, height, waist and hip circumference) and ultrasound SFT sites. Bland-Altman plots assessed validity of the prediction equations to measure % BF in the cross-validation group., Results: The best prediction equation for % BF was the following: [% BF = 15.709 + (1.753*anterior trunk SFT) + (5.626*Sex) + (3.635*posterior upper arm SFT) - (4.428*anterior lower leg SFT) - (0.170*height) + (0.264*waist) + (anterior thigh SFT*2.241); r 2  = 0.809, standard error of the estimate (SEE) = 3.3 kg]. Arm FM and leg FM prediction equations had r 2 values ranging from 0.690 to 0.812 and SEEs of 0.29 and 0.75 kg. A small mean bias was noted for estimating % BF (-0.14%), but large limits of agreement were found (-8.0-7.7%) and systematic error was noted in all of the equations (r = 0.275 to 0.515, p < 0.05)., Conclusions: Despite high r 2 values and a small mean bias found between predicted and DXA % BF, wide limits of agreement were found with some systematic error present. Therefore, these prediction equations for middle-aged and older adults may not be sufficiently accurate to use in a clinical setting., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

P-glycoprotein (P-gp/ABCB1) is an ATP-binding cassette drug efflux transporter expressed in a variety of tissues that affects the pharmacokinetic disposition of many drugs. Although several studies have reported gender-dependent differences in the expression of P-gp, the role of sex hormones in regulating the expression of P-gp and its transport activity has not been well understood. In this study, we demonstrated that 17β-estradiol has the ability to induce the expression of P-pg in mouse kidneys and cultured human renal proximal tubular epithelial cells. After intravenous injection of a typical P-gp substrate, digoxin, renal clearance in female mice was approximately 2-fold higher than that in male mice. The expression of murine P-gp and its mRNA (Abcb1a and Abcb1b) were also higher in female mice than in male mice. The expression of P-gp in cultured renal tissues prepared from female and male mice was significantly increased by 17β-estradiol, but not testosterone. Similar 17β-estradiol-induced expression of P-gp was also detected in cultured human tubular epithelial cells, accompanied by the enhancement of its transport activity of digoxin. The present findings suggest the contribution of estradiol to female-predominant expression of P-gp in renal cells, which is associated with sex-related disparities in the renal elimination of digoxin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db / db mice demonstrated increased gene expression of transforming growth factor (TGF)-β and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db / db mice was elevated compared with control db / m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db / db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.

Background: The epithelial-mesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with non-small-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma., Patients and Methods: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching., Results: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity score-matched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio = 2.57, P = .0451) and overall survival (hazard ratio = 4.23, P = .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival., Conclusion: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Epithelial-mesenchymal transition (EMT) and the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) are important regulators of lung cancer progression and metastasis. Although recent studies support the correlation between EZH2 expression and EMT, no reports have investigated their association using immunohistochemistry or explored their prognostic impact on lung adenocarcinoma. The aim of this study was to elucidate the association between EZH2 and EMT, and their prognostic significance., Methods: EZH2 and the EMT markers E-cadherin and Vimentin were examined by IHC in lung adenocarcinoma specimens that were resected from 2003-2012. Associations between EZH2 and EMT markers and their correlations with survival were analyzed., Results: We enrolled 350 patients, approximately 70% of whom were diagnosed as pathological stage I. The rates of positive E-cadherin, Vimentin, and EZH2 expression were 60.3%, 21.4%, and 52.0%, respectively. There was a significant positive correlation between EZH2 and Vimentin expression (p = 0.008), and EZH2 scores were higher in the Mesenchymal group (p = 0.030). In multivariate analysis, EZH2 was an independent predictor of Vimentin expression, and vice versa. EMT and EZH2 overexpression were significantly correlated with poor disease-free and overall survival. Furthermore, the Epithelial group with high EZH2 expression had significantly worse disease-free and overall survival. Positive staining for EMT markers was unfavorable regarding disease-free survival among patients with low EZH2 expression., Conclusions: EMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The proportion of never smokers among non-small-cell lung cancer (NSCLC) patients has steadily increased in recent decades, suggesting an urgent need to identify the major underlying causes of disease in this cohort. Chronic obstructive pulmonary disease is a risk factor for lung cancer in both smokers and never smokers. The aim of this study was to investigate the association between obstructive lung disease and survival in never smokers and smokers with NSCLC after complete resection., Methods: We retrospectively reviewed data from 548 NSCLC patients treated at our institution. The effects of obstructive lung disease on recurrence-free survival and cancer-specific survival following the resection of NSCLC were determined by univariable and multivariable Cox regression analyses., Results: Among the 548 patients analysed, 244 patients (44.5%) were never smokers and 304 patients (55.4%) were current or former smokers. In the never-smoker group, 48 patients (19.7%) had obstructive lung disease, 185 patients (75.8%) were women and 226 patients (92.6%) had adenocarcinoma. Obstructive lung disease was significantly associated with shorter recurrence-free survival (P = 0.006) and cancer-specific survival (P = 0.022) in the never smokers, but not the smokers, on both univariable and multivariable analyses. The associations between obstructive lung disease and prognosis in never smokers remained significant after propensity score matching., Conclusions: Obstructive lung disease is an independent prognostic factor for recurrence-free survival and cancer-specific survival in never smokers, but not in smokers, with NSCLC. Based on this finding, further examination is warranted to advance our understanding of the mechanisms associated with NSCLC in never smokers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: CD44 isoforms serve as a marker for cancer stem cells. CD44 variant 9 (CD44v9) contributes to the defense against reactive oxygen species, resulting in resistance to chemoradiotherapy. However, the significance of CD44v9 in patients with lung adenocarcinoma is unknown., Methods: We used immunohistochemical analysis to retrospectively analyze CD44v9 expression in 268 surgically resected lung adenocarcinomas and investigated the association between CD44v9 expression and patients' clinicopathological features., Results: The expression of CD44v9 in 193 of 268 (72.0%) patients was significantly associated with early-stage cancer, low-grade tumors, absence of vessel and pleural invasion, and a mutated epidermal growth factor receptor (EGFR) gene. Multivariate logistic analysis revealed that CD44v9 expression was significantly associated with early-stage disease [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.14-0.59; p < 0.001] and mutant EGFR (OR 2.53, 95% CI 1.06-6.04; p = 0.036). The percentage of CD44v9-positive tumors was higher in the earlier stages of disease; however, there was no significant difference in the survival of patients in each stage of disease who had positive or negative CD44v9 expression., Conclusion: CD44v9 was highly expressed in EGFR-mutant tumors, particularly in early-stage lung adenocarcinoma, suggesting that CD44v9 expression may play an important role in EGFR-mutant tumors.

Background/objectives: To investigate the impact of eliminating fat-free adipose tissue (aFFAT) on the prevalence of low muscle mass in older adults., Subjects/methods: Three hundred and forty-three (153 men and 190 women) well-functioning Japanese older adults (aged 65-79) had their appendicular lean mass (aLM) and appendicular fat mass (aFM) measured using dual-energy X-ray absorptiometry (DXA). aFFAT was then estimated from DXA-derived aFM (aFM = (FM/0.15)*0.85). Both traditional cutoffs and those corrected for aFFAT were used for diagnosing low muscle mass., Results: With traditional cutoff values, the prevalence of low muscle mass using the unadjusted aLM index was 20.1%. After adjusting the aLM index for aFFAT, the prevalence increased to 49.0% (p < 0.001). However, when the cutoff values were also adjusted for aFFAT, the prevalence of low muscle mass only increased to 23.0% (p < 0.001). Further, ~5% of the participants (7 men and 8 women) were newly classified as having low muscle mass after correction for aFFAT. However, several women (n = 5) were not classified as having low muscle mass using the corrected cutoff value, although they would have been when using the non-corrected cutoff., Conclusions: Adjusting for the effect of aFFAT on DXA-derived aLM significantly increases the prevalence of low muscle mass in older adults. For clinical research and practice, the influence of aFFAT on DXA-derived aLM may need to be taken into consideration when diagnosing low muscle mass.

Background/aim: In the new TNM classification (8th edition) of lung cancer, T category is defined based on the solid component size; therefore, part solid type (PST) with and solid type (ST) without ground glass opacity (GGO) are categorized as same T value according to their solid component sizes. However, differences between these tumors have not been clarified. Patients and Methods The study included 274 pStage I lung adenocarcinoma patients who had undergone surgery at our Institution from 2003 to 2012. Their tumors were classified as pure GGO, PST, and ST. After propensity score matching for solid component size, we compared prognoses between PST and ST., Results: The same percentage was noted for PST and ST tumors (119/274; 43.4%). After propensity score matching, the disease-free survival (DFS) was significantly worse in ST than PST (5-year DFS: 69.2% versus 88.7%; p=0.0241)., Conclusion: Prognoses of PST and ST adenocarcinomas differ even when their solid component sizes are the same., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study was performed to evaluate the influence of the body mass index (BMI) on disease-free survival and overall survival (DFS and OS) in patients with resected non-small cell lung cancer (NSCLC)., Patients and Methods: Overall, 546 of 780 (70%) patients with stage I to III NSCLC who underwent surgical resection were randomly selected. The patients were subdivided into three groups: low BMI (<18.5 kg/m 2 ), normal BMI (18.5 to <25.0 kg/m 2 ), and high BMI (≥25.0 kg/m 2 ). Cox proportional hazards regression analyses were performed to identify variables associated with survival., Results: In all patients, a low BMI was an independent prognostic factor for both DFS and OS (p=0.0175 and p=0.0134, respectively). In patients with stage I, a low BMI was also an independent prognostic factor for both DFS and OS (p=0.0066 and p<0.0001, respectively)., Conclusion: A low BMI was an independent prognostic factor after surgical resection of stage I NSCLC. Molecular targeted therapies, such as epidermal growth factor receptor inhibitors, anaplastic lymphoma kinase-tyrosine kinase inhibitors, and immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway have greatly improved the clinical course for patients with non-small cell lung cancer (NSCLC), especially advanced-stage NSCLC (1-7). However, lung cancer remains the leading cause of cancer-related death worldwide (8). Even in patients with stage I to IIIA NSCLC, the clinical course is unsatisfactory despite the fact that surgical resection is the main treatment option (9). Therefore, it is important to identify useful, simple, and inexpensive prognostic markers in patients with resectable NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Although high-mobility group box-1 (HMGB1), which is a nuclear protein, was reported to enhance the allogeneic responses in transplantation, the effect of HMGB1 on bronchiolitis obliterans syndrome (BOS) is unknown., Methods: A murine heterotopic tracheal transplantation model was used. Protein concentrations of HMGB1, interferon-γ (IFN-γ), interleukin (IL)-10, and IL-17 were analyzed in the isografts, allografts, controls, and HMGB1-neutralizing antibody administered allografts (n = 6; Days 1, 3, 5, 7, 14, 21, and 28). The luminal fibrous occlusion was analyzed (n = 6; Days 7, 14, 21, and 28). Infiltrating CD8 and CD4 T lymphocytes around the allografts and serum levels of IFN-γ and IL-10 were evaluated (n = 6; Day 7)., Results: The HMGB1 levels in the allografts were significantly increased compared with the isografts at Day 7. HMGB1 blockade did not change the IL-17 level, but decreased the IFN-γ/IL-10 ratio in the early phase (Days 5 and 7) and significantly improved the fibrous occlusion in the late phase (Days 14, 21, and 28). HMGB1 blockade significantly suppressed the CD8 T lymphocytes infiltration and decreased the serum IFN-γ/IL-10 ratio compared with the control at Day 7., Conclusions: HMGB1 may be a trigger of the BOS pathogenesis and candidate target for the treatment of the disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)