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Abstract Background Studies have shown that long noncoding RNAs and N6-methyladenosine play important roles in gastric cancer. The purpose of this study was to determine the correlation and prognostic value of m6A-related lncRNAs and immune infiltration in gastric cancer. Methods We downloaded the clinically related information and RNA-Seq transcriptome data of gastric cancer patients from the TCGA database. Univariate Cox regression analysis and Pearson analysis were used to screen out m6A-related lncRNAs. Consensus cluster analysis was used to divide the sample into two clusters, and LASSO analysis and Cox regression analysis were used to construct a risk scoring model. Results A total of 25 lncRNA expression profiles were screened, and gastric cancer patients were divided into different subtypes. Cluster 2 had a better prognosis, but its stromal score, ESTIMATE score and immune score were low. Cluster 1 was rich in resting memory CD4 T cells, regulatory T cells, monocytes, and resting mast cells, and Cluster 2 was rich in activated memory CD4 T cells and follicular helper T cells. Thirteen lncRNAs were selected to construct a risk model, and the prognosis of gastric cancer patients in the high-risk group was poor. The expression of PD-L1 in tumours is significantly higher than that in normal tissues. Univariate and multivariate Cox regression analysis results showed that the overall survival rate was significantly related to stage and the risk score, which can be used as an independent prognostic factor. The results of the heatmap and scatter plot showed that clusters (P = 0.0045) and grade (G1–2, G3, P = 0.0037) were significantly related to prognosis. The relationship between the risk score and immune cell infiltration showed that memory B cells, resting dendritic cells, M0 macrophages, and M2 macrophages were positively correlated with the risk score, while resting mast cells, monocytes, activated NK cells, and follicular helper T cells were negatively correlated with the risk score. Conclusion The results of this study indicate that m6A-related lncRNAs may play an important role in the prognosis of gastric cancer patients and the tumour immune microenvironment and may provide help for the treatment of gastric cancer patients.

Histidine-rich glycoprotein (HRG) is a multifunctional plasma glycoprotein involved in the regulation of coagulation, fibrinolysis, and inflammation. Recently, decreased plasma levels of HRG at 72 hours after lung transplantation (LT) has been shown to be associated with severe primary graft dysfunction and decreased overall survival after LT. In this study, we investigated the effect of supplementary HRG treatment on lung ischemia-reperfusion injury (IRI) using a mouse hilar clamp model. Mice were divided into the four groups, including the sham-operated group, the IRI group with supplementation of PBS, human serum albumin, or HRG (the HRG group) (n=5 for each group). We assessed lung function, lung injury, pulmonary neutrophil infiltrations, lung cell apoptosis, and inflammatory mediator expression between the groups. Compared to the other groups, the HRG group had significantly better PaO 2 and significant attenuation of lung injury (Figure). In the HRG group, neutrophil infiltration and prevalence of apoptotis in the reperfused lung was significantly less than the other groups. Moreover, the expression of neutrophil-associated inflammatory mediators in the reperfused lung, including CXCL1, MIP-1α, MIP-1β, G-CSF, GM-CSF, IL-1β, IL-6, and IL-10, were significantly decreased in the HRG group. In this study, supplementary HRG treatment suppressed neutrophil-associated inflammatory responses and improved lung IRI in a mouse. HRG may be a potential therapeutic agent for lung IRI. [ABSTRACT FROM AUTHOR]

Donor-specific human leukocyte antigen (HLA) antibodies (DSA) are being recognized as a risk factor of acute rejection and chronic lung allograft dysfunction (CLAD). Re-transplantation (re-LTx) is the only treatment for CLAD, but the outcome could be limited especially in the sensitized patients. Some desensitization protocols were reportedly verified in a single center study basis, but yet to be standardized in DSA-positive lung transplantation (LTx). Herein, we report a case of successful lung re-LTx along with perioperative desensitization for a DQ DSA-positive recipient. A 10-year-old-man underwent living-donor single lobar LTx for pulmonary graft-versus-host disease after bone marrow transplant. Three years later, he developed antibody-mediated rejection due to de novo DSA. The mean fluorescence intensity of DQ4 exceeded 12000 which was persistent even after antibody targeted therapy, resulting in the development of bronchiolitis obliterans syndrome. He needed a mechanical ventilator, and temporary use of Extra-Corporeal Membrane Oxygenation. Following two-year waiting time, he eventually acquired an organ offer from a brain-dead donor and underwent re-LTx. The virtual crossmatch revealed the patient's preformed antibody to DQ4 was donor-specific, and flow cytometry crossmatch test for B cell was also positive. Thus, we performed two sessions of plasma exchanges (PLEX) with 1.5 volume of fresh frozen plasma preoperatively, and five sessions postoperatively. Subsequently, intravenous immune globulin (1 g/kg) and antithymocyte globulin (3mg/kg) was also given. Target trough level of tacrolimus was set in a usual manner. Mean fluorescence intensities for the DSAs were monitored at several times (pre PLEX, post all perioperative desensitization, and two months after re-LTx) and confirmed to be going down (DQ4; 12580, 7578, 6344). He developed a single episode of mild acute cellular rejection, but his postoperative course was almost uneventful and he is doing well 4 months after re-LTx and returns to his normal daily life. Although this case possessed multiple immunological risks including re-LTx and positive DQ-DSA, perioperative desensitization with the combination of multiple PLEXs, IVIG and antithymocyte globulin was effective. Careful monitoring of DSA is planned in the long term. [ABSTRACT FROM AUTHOR]

In Japan, there is an age limit to register for lung transplantation. For lung transplantations from a brain-dead donor, the age limit is 60 years for single lung transplantation and 55 years for bilateral lung transplantation. Currently, there is no clear age limit for lung transplantation from living donor, but most facilities set the age limit at 65 years or younger. At our facility, even if the patient is aged over 65 years, we evaluate the patient's organ function and activities of daily living to assess the suitability for transplantation. Herein, we report a case of successful living lobar lung transplantation in a 67-year-old recipient. The patient was a 67-year-old female with a history of auto peripheral-blood stem cell transplantation for Hodgkin's lymphoma 8 years ago. Four years prior to presentation, lung damage with dilated shadows was observed on computed tomography (CT) scan. The shadows were thought to be caused by graft versus host disease. One year ago, she contracted bacterial pneumonia, which led to worsening of respiratory function. Finally, she contracted bilateral pneumothorax and was referred to our hospital for lung transplantation. She was 66-year-old at the time of referral to our hospital, so lung transplantation from a brain-dead donor was not indicated. Preoperative examination revealed no major problems with operative tolerance. After preoperative examination with two potential living donors, we determined that lung transplantation was feasible. Bilateral lung transplantation from living donors was performed with cardio-pulmonary bypass assistance. The right lung graft was donated by her daughter, and the left lung graft was donated by her son. The total operation duration was 617 minutes. Ischemic time was 150 minutes in the right graft and 240 minutes in the left graft. On postoperative day 6, she developed acute rejection with frosted shadows and was treated with steroid pulse therapy. The length of ICU stay was 45 days. On postoperative day 116, the patient was discharged from the hospital. We successfully performed bilateral lung transplantation from living donors in an elderly recipient by careful evaluation of detailed perioperative management and current condition of recipient. Based on our experience, we discuss the outcomes of living lung transplantations in elderly recipients. [ABSTRACT FROM AUTHOR]

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated., (© 2024 UICC.)

Background: Management of tacrolimus trough levels influences morbidity and mortality after lung transplantation. Several studies have explored pharmacokinetic and artificial intelligence models to monitor tacrolimus levels. However, many models depend on a wide range of variables, some of which, like genetic polymorphisms, are not commonly tested for in regular clinical practice. This study aimed to verify the efficacy of a novel approach simply utilizing time series data of tacrolimus dosing, with the objective of accurately predicting trough levels in the variety of clinical settings., Methods: Data encompassing 36 clinical variables for each patient were gathered, and a multivariate long short-term memory algorithm was applied to forecast subsequent tacrolimus trough levels based on the selected clinical variables. The tool was developed using a dataset of 87,112 data points from　117 patients and its efficacy was confirmed using six additional cases., Results: Shapley Additive exPlanations revealed a significant correlation between trough levels and prior dose-concentration data. By using simple trend learning of dose, administration route, and previous trough levels of tacrolimus, we could predict values within 30% of the actual values for 88.5% of time points, which facilitated the creation of a tool for simulating tacrolimus trough levels in response to dosage adjustments. The tool exhibited the potential for rectifying clinical misjudgments in a simulation cohort., Conclusions: Utilizing our time series forecasting tool, precise prediction of trough levels is attainable independently of other clinical variables, through the analysis of historical tacrolimus dose-concentration trends alone., (Copyright © 2024. Published by Elsevier Inc.)

Purposes: Robot-assisted thoracoscopic (RATS) segmentectomy is becoming increasingly common because of the expanded indications for segmentectomy and the widespread adoption of robotic surgery. The precise division of the intersegmental plane is necessary to ensure oncologic margins from the tumor and to preserve the lung function. In this study, we present a strategy for accurately dividing the intersegmental plane using a robotic stapler and review the surgical outcomes., Methods: RATS portal segmentectomy was performed using the Da Vinci Xi system and the intersegmental plane was dissected using a robotic stapler. We evaluated the perioperative outcomes in 92 patients who underwent RATS portal segmentectomy between May 2020 and January 2023. These results were compared with those of 82 patients who underwent complete video-assisted thoracoscopic surgery (CVATS) during the same period., Results: The operative and console times were 162 and 97 min, respectively. No intraoperative complications occurred, and postoperative complications were observed in four cases (4.3%). The operative time, blood loss, postoperative complications, and maximum incision size were significantly lower in the RATS group than in the CVATS group. However, RATS requires a significantly higher number of staplers than CVATS., Conclusions: The division of the intersegmental plane using a robotic stapler in RATS portal segmentectomy was, therefore, found to be safe and effective., (© 2024. The Author(s).)

Background: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs., Methods: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses., Results: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021)., Conclusion: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Radiation pneumonitis (RP) is an obstacle for patients after surgery following induction chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). We performed a comparative analysis of the association between clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and prognosis, in LA-NSCLC patients with or without RP during induction chemoradiotherapy followed by surgery., Methods: The subjects of this analysis were 168 patients undergoing trimodality therapy for LA-NSCLC between January, 1999 and May, 2019. Patients were divided into two groups: the RP group (n = 41) and the non-RP group (n = 127). We compared the clinicopathological factors including the NLR between the groups and analyzed the association between the NLR and prognosis., Results: The RP group had more patients with tumors located in the lower lobe, more bilobar resections, shorter operative times, no implementation of postoperative adjuvant chemotherapy, and a higher postoperative NLR than the non-RP group. There were no significant differences in serious postoperative complications and the prognosis. Patients with a low postoperative NLR had a significantly better prognosis in the non-RP group, and a trend toward a better prognosis even in the RP group., Conclusion: Postoperative NLR may be a useful prognostic factor, even for patients who suffer RP after trimodality therapy for LA-NSCLC., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Bronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF., Methods: This retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF., Results: BPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively., Conclusion: Perioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF., (© 2024. The Author(s).)

Background: Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in non-small cell lung cancer (NSCLC); however, the underlying biological rationale remains unclear. The present study aimed to explore the potential utility of NLR as a surrogate biomarker for immune response to cancer and to elucidate the underlying mechanism., Methods: This retrospective study included the medical records of 120 patients with NSCLC who underwent surgery at the study institution in 2012. NLR in peripheral blood was determined from blood test within 30 days before surgery. Tumor immune status was evaluated using immunohistochemical staining to identify CD3+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs), and the relationship of NLR, with clinicopathologic characteristics including 5-year overall survival (OS), and the tumor immune status was investigated. The median values of NLR and TIL count were used as cutoff points., Results: The 5-year OS was significantly better in patients with low NLR (<2.2) than in those with high NLR (≥2.2) (70.1% vs. 56.8%, P = 0.042) and in patients with high CD3+ TIL count (≥242) than in those with low CD3+ TIL count (<242) (70% vs. 56.8%, P = 0.019). Additionally, the CD3+ TIL count was negatively correlated with preoperative NLR (P = 0.005)., Conclusion: NLR might potentially reflect the immune status of tumor microenvironment, explaining its impact on prognosis of patients with NSCLC., (© The Author(s) 2024. Published by Oxford University Press.)

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)