[Thoracoscopic Segmentectomy Using Three-dimensional Image Simulation of the Pulmonary Artery Perfusion Area and Indocyanine Green( ICG) Intravenous Injection Method].

PURPOSE: When performing segmentectomy, we aim to keep adequate distance from the tumor using three-dimensional( 3D) images of the pulmonary artery perfusion area and the indocyanine green( ICG) injection method. The effectiveness and improvement of this method were examined. PATIENTS AND METHOD: We retrospectively investigated 50 consecutive patients who underwent segmentectomy with this method. In simulation, we measured the predicted margin distance( PMD) on a 3D image. Then, we measured the actual margin distance (AMD) on resected specimens fixed in formalin. We compared these two distances and evaluated factors influencing shorter AMD. RESULTS: The median AMD was 1.7 cm, and there was no positive margin case. The median ratio of AMD/PMD was 0.73. In multivariate analysis, shorter PMD and no resection of subsegment bronchi next to the tumor were significant factors associated with shorter AMD( p<0.001, p=0.014). CONCLUSIONS: Our method was effective for segmentectomy. For adequate AMD, a longer PMD in simulation and subsegmental bronchi resection next to the tumor should be considered.

Signal Detection of Potential Hepatotoxic Drugs: Case-Control Study Using Both a Spontaneous Reporting System and Electronic Medical Records.

Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.

A prophylaxis study of acute exacerbation of interstitial pneumonia after lung cancer surgery.

INTRODUCTION: Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures. METHOD: Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days. RESULTS: Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I. CONCLUSIONS: Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP.

Drug Repositioning and Target Finding Based on Clinical Evidence.

Recent pharmacological studies have been developed based on finding new disease-related genes, accompanied by the production of gene-manipulated disease model animals and high-affinity ligands for the target proteins. However, the emergence of this gene-based strategy in drug development has led to the rapid depletion of drug target molecules. To overcome this, we have attempted to utilize clinical big data to explore a novel and unexpected hypothesis of drug-drug interaction that would lead to drug repositioning. Here, we introduce our data-driven approach in which adverse event self-reports are statistically analyzed and compared in order to find and validate new drug targets. The hypotheses provided by such a data-driven approach will likely impact the style of future drug development and pharmaceutical study.

Sphingosine-1-phosphate induces Ca2+ signaling and CXCL1 release via TRPC6 channel in astrocytes.

A biologically active lipid, sphingosine-1-phosphate (S1P) is highly abundant in blood, and plays an important role in regulating the growth, survival, and migration of many cells. Binding of the endogenous ligand S1P results in activation of various signaling pathways via G protein-coupled receptors, some of which generates Ca2+ mobilization. In astrocytes, S1P is reported to evoke Ca2+ signaling, proliferation, and migration; however, the precise mechanisms underlying such responses in astrocytes remain to be elucidated. Transient receptor potential canonical (TRPC) channels are Ca2+ -permeable cation channels expressed in astrocytes and involved in Ca2+ influx after receptor stimulation. In this study, we investigated the involvement of TRPC channels in S1P-induced cellular responses. In Ca2+ imaging experiments, S1P at 1 µM elicited a transient increase in intracellular Ca2+ in astrocytes, followed by sustained elevation. The sustained Ca2+ response was markedly suppressed by S1P2 receptor antagonist JTE013, S1P3 receptor antagonist CAY10444, or non-selective TRPC channel inhibitor Pyr2. Additionally, S1P increased chemokine CXCL1 mRNA expression and release, which were suppressed by TRPC inhibitor, inhibition of Ca2+ mobilization, MAPK pathway inhibitors, or knockdown of the TRPC channel isoform TRPC6. Taken together, these results demonstrate that S1P induces Ca2+ signaling in astrocytes via Gq -coupled receptors S1P2 and S1P3 , followed by Ca2+ influx through TRPC6 that could activate MAPK signaling, which leads to increased secretion of the proinflammatory or neuroprotective chemokine CXCL1.

Omitting Lymph Node Dissection for Small Ground-Glass Opacity-Dominant Tumors.

BACKGROUND: The purpose of this study was to determine the optimal extent of lymph node dissection required in patients with small (≤3 cm) radiologically ground-glass opacity-dominant, peripheral, non-small cell lung cancer tumors. METHODS: The study analyzed the clinicopathologic findings and surgical outcomes of 988 patients with radiologic, ground-glass opacity-dominant non-small cell lung cancer without lymph node involvement who underwent complete resection of the primary tumor between 2010 and 2020. Patients were followed up for 54.5 months (median). Kaplan-Meier curves and the log-rank test were used in statistical analyses of the prognosis. RESULTS: Median age, whole tumor size, solid tumor size, and maximum standardized uptake values were 68 years, 1.7 cm, 0.4 cm, and 0.9, respectively. Sixty percent of the cohort was female (n = 590). Wedge resection, segmentectomy, and lobectomy were performed in 206, 372, and 410 patients, respectively. A total of 982 of 988 (99%) tumors were adenocarcinomas. One patient had hilar lymph node involvement; however, no mediastinal lymph node metastasis or hilar or mediastinal lymph node recurrence was detected. The 5-year overall survival rate was 96.5% (95% CI, 94.8%-97.7%). Excellent survival outcomes were achieved regardless of procedure (wedge resection, 94.7% [95% CI, 89.1%-97.5%]; segmentectomy, 96.9% [95% CI, 93.7%-98.5%]; and lobectomy, 97.1% [95% CI, 94.4%-98.5%]). CONCLUSIONS: Omitting lymph node dissection may be acceptable with curative intent for small tumors with radiologic ground-glass opacity dominance. Appropriate surgical procedures such as wedge resection, segmentectomy, or lobectomy can provide satisfactory outcomes in patients with indolent tumors if surgical margins are secured.

Right S3 segmentectomy for lung cancer with partial anomalous pulmonary venous return in the right upper pulmonary vein: A case report.

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital malformation where the pulmonary vein partially refluxes into the venous system. Here, we present the first robotic-assisted right S3 segmentectomy in a 70-year-old male with early-stage lung cancer and PAPVR in the right upper pulmonary vein. The patient, with suspected primary lung cancer (11 mm diameter, pure solid appearance in right S3 segment), exhibited clinical stage T1bN0M0 stage IA2. Preoperative computed tomography revealed severe lung emphysema, and right V1-3 returned directly to the superior vena cava. However, no signs of right-sided heart failure were observed, and echocardiogram was normal with a pulmonary-to-systemic blood flow ratio of 1.4. Successful robot-assisted right S3 segmentectomy with hilar nodal dissection was performed, and the patient was discharged on the sixth postoperative day without complications. One year postoperatively, there has been no recurrence of lung cancer or respiratory/right-sided heart failure symptoms.

Sublobar Resection in Early Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutant.

BACKGROUND: Lobectomy is a standard surgical procedure for peripherally located early-stage non-small cell lung cancers (NSCLCs) measuring 2 to 4 cm. However, it is unclear whether sublobar resections, such as wedge resection and segmentectomy, are effective in treating tumors with driver mutations in the epidermal growth factor receptor (EGFR). METHODS: We analyzed the clinicopathologic findings and surgical outcomes of 1395 patients with radiologically solid-dominant NSCLC measuring 2 to 4 cm, without clinical lymph node involvement, who underwent complete resection between 2010 and 2020. The patients, who underwent sublobar resections (n = 231) or lobectomy (n = 1164), were categorized by their EGFR mutation status and the surgical procedures performed. The follow-up was conducted for a median of 45.3 months. RESULTS: The 5-year overall survival (OS) rates after sublobar resections (n = 39) were comparable to those after lobectomy (n = 359) in patients with EGFR mutation-positive tumors (80.5% [95% CI, 51.3%-93.2%] vs 88.8% [95% CI, 84.1%-92.1%], respectively; P = .16). Multivariable Cox regression analysis of OS revealed that the surgical procedure was an independent prognostic predictor in the entire cohort (hazard ratio, 0.6; 95% CI, 0.4-1.0; P = .028), but it was not an independent prognostic predictor in patients with EGFR-mutated tumors (hazard ratio, 0.6; 95% CI, 0.2-1.7; P = .32). CONCLUSIONS: Sublobar resection with a secure surgical margin could be a viable option for appropriately selected patients with peripheral early-stage NSCLC tumors measuring 2 to 4 cm and harboring EGFR mutations, because it provides comparable OS to that of lobectomy.

Feasibility and Comparative Prognosis of Segmentectomy vs. Lobectomy in Centrally Located Small and Solid Dominant cN0 Non-Small Cell Lung Cancer.

OBJECTIVES: This study aimed to determine the feasibility of segmentectomy in patients with central, whole tumor size ≤2 cm and radiologically solid-dominant cN0 non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 1240 patients who underwent lobectomy or segmentectomy for small and radiologically solid-dominant cN0 NSCLC between January 2010 and December 2022. The inclusion criteria encompassed centrally located tumors defined as tumors located in the inner two-thirds of the pulmonary parenchyma. Propensity score matching was applied to balance the baseline characteristics. RESULTS: Among the 299 eligible patients, no significant differences in recurrence-free survival (RFS) and overall survival (OS) were observed between the segmentectomy (n = 121) and lobectomy (n = 178) groups (P = .794 and .577, respectively). After propensity score matching, no significant differences in hilar and mediastinal lymph node upstaging were found among the 93 matched patients (P = 1.00) and locoregional recurrence was comparable between those who underwent segmentectomy (n = 4) and lobectomy (n = 4). RFS and OS did not significantly differ between the two groups (P = .700 and .870, respectively). Propensity score-adjusted multivariable Cox analysis for RFS and OS indicated that segmentectomy was not an independent prognostic factor (RFS: hazard ratio, 0.89; 95% confidence interval, 0.43-1.85; P = .755; OS: hazard ratio, 1.09; 95% confidence interval, 0.38-3.14; P = .860). CONCLUSIONS: Segmentectomy may be a viable treatment option with local control and prognosis comparable to that of lobectomy in appropriately selected patients with central, small (≤2 cm), and radiologically solid-dominant NSCLC.

Comparison of SP263 and 22C3 pharmDx assays to test programmed death ligand-1 (PD-L1) expression in surgically resected non-small cell lung cancer.

BACKGROUND: Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II-IIIA non-small cell lung cancer with 1% or more programmed death ligand-1 (PD-L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non-small cell lung cancer. Therefore, our study aimed to compare two PD-L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. METHODS: We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD-L1 expression between SP263 and 22C3 assays. RESULTS: The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522-0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639-0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD-L1 expression with 22C3 resulted slightly higher than that with SP263. CONCLUSIONS: This study showed a high concordance of PD-L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required.

Mutation profile and programmed death ligand 1 status of patients with non-small cell lung cancer diagnosed with "adenocarcinoma" and "non-small cell carcinoma favor adenocarcinoma".

BACKGROUND: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression. METHODS: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center. RESULTS: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001). CONCLUSION: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression.

Early Detection of Adverse Drug Reaction Signals by Association Rule Mining Using Large-Scale Administrative Claims Data.

INTRODUCTION: Adverse drug reactions (ADRs) are a leading cause of mortality worldwide and should be detected promptly to reduce health risks to patients. A data-mining approach using large-scale medical records might be a useful method for the early detection of ADRs. Many studies have analyzed medical records to detect ADRs; however, most of them have focused on a narrow range of ADRs, limiting their usefulness. OBJECTIVE: This study aimed to identify methods for the early detection of a wide range of ADR signals. METHODS: First, to evaluate the performance in signal detection of ADRs by data-mining, we attempted to create a gold standard based on clinical evidence. Second, association rule mining (ARM) was applied to patient symptoms and medications registered in claims data, followed by evaluating ADR signal detection performance. RESULTS: We created a new gold standard consisting of 92 positive and 88 negative controls. In the assessment of ARM using claims data, the areas under the receiver-operating characteristic curve and the precision-recall curve were 0.80 and 0.83, respectively. If the detection criteria were defined as lift > 1, conviction > 1, and p-value < 0.05, ARM could identify 156 signals, of which 90 were true positive controls (sensitivity: 0.98, specificity: 0.25). Evaluation of the capability of ARM with short periods of data revealed that ARM could detect a greater number of positive controls than the conventional analysis method. CONCLUSIONS: ARM of claims data may be effective in the early detection of a wide range of ADR signals.

Detection of potential drug-drug interactions for risk of acute kidney injury: a population-based case-control study using interpretable machine-learning models.

Background: Acute kidney injury (AKI), with an increase in serum creatinine, is a common adverse drug event. Although various clinical studies have investigated whether a combination of two nephrotoxic drugs has an increased risk of AKI using traditional statistical models such as multivariable logistic regression (MLR), the evaluation metrics have not been evaluated despite the fact that traditional statistical models may over-fit the data. The aim of the present study was to detect drug-drug interactions with an increased risk of AKI by interpreting machine-learning models to avoid overfitting. Methods: We developed six machine-learning models trained using electronic medical records: MLR, logistic least absolute shrinkage and selection operator regression (LLR), random forest, extreme gradient boosting (XGB) tree, and two support vector machine models (kernel = linear function and radial basis function). In order to detect drug-drug interactions, the XGB and LLR models that showed good predictive performance were interpreted by SHapley Additive exPlanations (SHAP) and relative excess risk due to interaction (RERI), respectively. Results: Among approximately 2.5 million patients, 65,667 patients were extracted from the electronic medical records, and assigned to case (N = 5,319) and control (N = 60,348) groups. In the XGB model, a combination of loop diuretic and histamine H2 blocker [mean (|SHAP|) = 0.011] was identified as a relatively important risk factor for AKI. The combination of loop diuretic and H2 blocker showed a significant synergistic interaction on an additive scale (RERI 1.289, 95% confidence interval 0.226-5.591) also in the LLR model. Conclusion: The present population-based case-control study using interpretable machine-learning models suggested that although the relative importance of the individual and combined effects of loop diuretics and H2 blockers is lower than that of well-known risk factors such as older age and sex, concomitant use of a loop diuretic and histamine H2 blocker is associated with increased risk of AKI.

Benzodiazepine-related dementia risks and protopathic biases revealed by multiple-kernel learning with electronic medical records.

Objectives: To simultaneously estimate how the risk of incident dementia nonlinearly varies with the administration period and cumulative dose of benzodiazepines, the duration of disorders with an indication for benzodiazepines, and other potential confounders, with the goal of settling the controversy over the role of benzodiazepines in the development of dementia. Methods: The classical hazard model was extended using the techniques of multiple-kernel learning. Regularised maximum-likelihood estimation, including determination of hyperparameter values with 10-fold cross-validation, bootstrap goodness-of-fit test, and bootstrap estimation of confidence intervals, was applied to cohorts retrospectively extracted from electronic medical records of our university hospitals between 1 November 2004 and 31 July 2020. The analysis was mainly focused on 8160 patients aged 40 or older with new onset of insomnia, affective disorders, or anxiety disorders, who were followed up for 4.10±3.47 years. Results: Besides previously reported risk associations, we detected significant nonlinear risk variations over 2-4 years attributable to the duration of insomnia and anxiety disorders, and to the administration period of short-acting benzodiazepines. After nonlinear adjustment for potential confounders, we observed no significant risk associations with long-term use of benzodiazepines. Conclusions: The pattern of the detected nonlinear risk variations suggested reverse causation and confounding. Their putative bias effects over 2-4 years suggested similar biases in previously reported results. These results, together with the lack of significant risk associations with long-term use of benzodiazepines, suggested the need to reconsider previous results and methods for future analysis.

Increased expression of glutathione peroxidase 3 prevents tendinopathy by suppressing oxidative stress.

Tendinopathy, a degenerative disease, is characterized by pain, loss of tendon strength, or rupture. Previous studies have identified multiple risk factors for tendinopathy, including aging and fluoroquinolone use; however, its therapeutic target remains unclear. We analyzed self-reported adverse events and the US commercial claims data and found that the short-term use of dexamethasone prevented both fluoroquinolone-induced and age-related tendinopathy. Rat tendons treated systemically with fluoroquinolone exhibited mechanical fragility, histological change, and DNA damage; co-treatment with dexamethasone attenuated these effects and increased the expression of the antioxidant enzyme glutathione peroxidase 3 (GPX3), as revealed via RNA-sequencing. The primary role of GPX3 was validated in primary cultured rat tenocytes treated with fluoroquinolone or H2O2, which accelerates senescence, in combination with dexamethasone or viral overexpression of GPX3. These results suggest that dexamethasone prevents tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This steroid-free approach for upregulation or activation of GPX3 can serve as a novel therapeutic strategy for tendinopathy.

Vitamin D supplementation is effective for olanzapine-induced dyslipidemia.

Olanzapine is an atypical antipsychotic drug that is clinically applied in patients with schizophrenia. It increases the risk of dyslipidemia, a disturbance of lipid metabolic homeostasis, usually characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides, and accompanied by decreased high-density lipoprotein (HDL) in the serum. In this study, analyzing the FDA Adverse Event Reporting System, JMDC insurance claims, and electronic medical records from Nihon University School of Medicine revealed that a co-treated drug, vitamin D, can reduce the incidence of olanzapine-induced dyslipidemia. In the following experimental validations of this hypothesis, short-term oral olanzapine administration in mice caused a simultaneous increase and decrease in the levels of LDL and HDL cholesterol, respectively, while the triglyceride level remained unaffected. Cholecalciferol supplementation attenuated these deteriorations in blood lipid profiles. RNA-seq analysis was conducted on three cell types that are closely related to maintaining cholesterol metabolic balance (hepatocytes, adipocytes, and C2C12) to verify the direct effects of olanzapine and the functional metabolites of cholecalciferol (calcifediol and calcitriol). Consequently, the expression of cholesterol-biosynthesis-related genes was reduced in calcifediol- and calcitriol-treated C2C12 cells, which was likely to be mediated by activating the vitamin D receptor that subsequently inhibited the cholesterol biosynthesis process via insulin-induced gene 2 regulation. This clinical big-data-based drug repurposing approach is effective in finding a novel treatment with high clinical predictability and a well-defined molecular mechanism.

Successful repair of acquired intrathoracic nonmalignant tracheoesophageal fistulas using thoracoacromial artery perforator flap through a midsternal incision approach: a report of three cases.

Background: Acquired intrathoracic nonmalignant tracheoesophageal fistulas (TEFs) are rare and challenging surgical problems. They can constitute a life-threatening condition due to severe pulmonary complications and poor nutrition. Surgical treatment is effective for most patients undergoing operative repair. However, in recent studies, the difficult-to-ignore early complications of surgical treatment can be as high as 62.5%. Among them, esophageal stricture occurring in 42-54% of patients, anastomosis leakage occurs at a rate of 22.7-26%, and the mortality rate can be as high as 29.4%. Here, we introduce our innovative experience repairing acquired TEFs with a thoracoacromial artery perforator flap, in which provides a clear surgical field of view, reliable reconstruction, and no serious complications during the perioperative period and no mortality or complications were observed within 180 days after the operation. Case Description: Surgical repair with a thoracoacromial artery perforator flap through a midsternal incision approach was performed in 3 patients. During the procedure, a midsternal incision was made. After the thymus and anterior mediastinal fat were resected, and the left innominate vein was transected, the trachea and esophagus were mobilized. The trachea was incised and pulled to the cranial and caudal sides. Then, the thoracoacromial artery perforator flap was harvested and transferred into the superior mediastinum for esophageal reconstruction. Subsequently, the trachea was anastomosed end to end after debridement, and the left innominate vein was either anastomosed or not. Two patients developed esophageal anastomotic leakage postoperatively and healed well after nonsurgical treatment. No mortality or other complications were observed at 180 days after the operation. Conclusions: Repair of acquired TEFs using a thoracoacromial artery perforator flap through a midsternal incision approach is an effective, safe surgical treatment.

Wedge resection vs. segmentectomy for lung cancer measuring ≤ 2 cm with consolidation tumor ratio > 0.25.

Objectives: We aimed to clarify the differences in prognosis between wedge resection and segmentectomy performed for cN0 non-small cell lung cancer (NSCLC) measuring ≤ 2 cm, with consolidation tumor ratio (CTR) > 0.25. Methods: This multicenter study included 570 patients with cN0 NSCLC (tumor size ≤ 2 cm, CTR > 0.25) who underwent wedge resection (n = 244) and segmentectomy (n = 326) between January 2010 and December 2018. After propensity score matching (PSM, 1:1 method), 182 patients were matched for clinical characteristics (age, sex, laterality, smoking index, tumor size, CTR, carcinoembryonic antigen value, positron-emission tomography-documented maximum standardized uptake value, clinical stage, and tumor disappearance rate) and intergroup comparison of disease-free survival (DFS) and overall survival (OS). Using Gray's test, an intergroup comparison of the cumulative incidence of lung cancer-specific mortality was performed. Results: After PSM, similar DFS (5-year DFS, 79.9% vs. 87.1%, p = 0.103) and OS (5-year OS, 88.7% vs. 88.9%, p = 0.719) rates were observed in the wedge resection and segmentectomy groups. We observed no significant intergroup differences in lung cancer-specific mortality (5-year cumulative incidence: 4.6% vs. 3.5%; p = 0.235). Subgroup analysis revealed no specific subgroup demonstrating improved DFS or OS after undergoing wedge resection or segmentectomy. Conclusion: DFS, OS, and lung cancer-specific mortality were comparable between wedge resection and segmentectomy of cN0 NSCLC-tumor size ≤ 2 cm and CTR > 0.25. Large-scale prospective clinical trials are warranted to compare the prognoses of wedge resection and segmentectomy for these tumors.

Impact of RBM10 and PD-L1 expression on the prognosis of pathologic N1-N2 epidermal growth factor receptor mutant lung adenocarcinoma.

Background: Impact of RNA-binding motif protein 10 (RBM10) and programmed death-ligand 1 (PD-L1) on the postoperative prognosis of patients with epidermal growth factor receptor gene mutation (EGFR-Mt) lung adenocarcinoma with pathological lymph node metastasis is still unclear. Methods: Patients who underwent curative surgery for pN1-N2 EGFR-Mt lung adenocarcinoma (n=129) harboring the EGFR exon 19 deletion mutation (Ex19) (n=66) or EGFR exon 21 L858R mutation (Ex21) (n=63) between January 2010 and December 2020 were included in this retrospective study. The prognoses of patients with low/high cytoplasmic RBM10 expression and PD-L1 negativity/positivity based on immunohistochemistry (IHC) of resected specimens were compared using the log-rank test. The effects of RBM10 and PD-L1 expression on overall survival (OS) were examined via multivariable analysis using the Cox proportional hazards regression model. The effects of RBM10 and PD-L1 expression on progression-free survival (PFS) of EGFR-tyrosine kinase inhibitors (TKIs) therapy among patients with recurrent pN1-N2 EGFR-Mt lung adenocarcinoma (n=67) were examined using log-rank tests. Results: The RBM10 low expression group showed significantly better 5-year OS than the RBM10 high expression group (89.4% vs. 71.5%, P=0.020), and the PD-L1 negative group tended to have longer 5-year OS than the PD-L1 positive group (86.4% vs. 68.4%, P=0.050). Multivariable analysis showed that high RBM10 expression [hazard ratio (HR), 3.12; 95% confidence interval (CI): 1.19-8.17; P=0.021] and PD-L1 positivity (HR, 3.80; 95% CI: 1.64-8.84; P=0.002) were independent poor prognostic factors for OS. PFS of patients with relapse and first-line EGFR-TKI treatment was significantly better in the PD-L1-negative group than in the PD-L1-positive group (34.5 vs. 12.1 months, P=0.045). PFS of patients with Ex21 relapse and first-line EGFR-TKI treatment was significantly better in the RBM10 low expression group than in the RBM10 high expression group (25.5 vs. 13.0 months, P=0.025). Conclusions: High RBM10 expression and PD-L1 positivity are poor prognostic factors for OS in patients with pN1-N2 EGFR-Mt lung adenocarcinoma after curative surgery. In patients with recurrent pN1-N2 EGFR-Mt lung adenocarcinoma, PD-L1 and RBM10 expression may influence response to EGFR-TKIs.

Detection of Synergistic Interaction on an Additive Scale Between Two Drugs on Abnormal Elevation of Serum Alanine Aminotransferase Using Machine-Learning Algorithms.

Drug-induced liver injury (DILI) is a common adverse drug reaction, with abnormal elevation of serum alanine aminotransferase (ALT). Several clinical studies have investigated whether a combination of two drugs alters the reporting frequency of DILI using traditional statistical methods such as multiple logistic regression (MLR), but this model may over-fit the data. This study aimed to detect a synergistic interaction between two drugs on the risk of abnormal elevation of serum ALT in Japanese adult patients using three machine-learning algorithms: MLR, logistic least absolute shrinkage and selection operator (LASSO) regression, and extreme gradient boosting (XGBoost) algorithms. A total of 58,413 patients were extracted from Nihon University School of Medicine's Clinical Data Warehouse and assigned to case (N = 4,152) and control (N = 54,261) groups. The MLR model over-fitted a training set. In the logistic LASSO regression model, three combinations showed relative excess risk due to interaction (RERI) for abnormal elevation of serum ALT: diclofenac and famotidine (RERI 2.427, 95% bootstrap confidence interval 1.226-11.003), acetaminophen and ambroxol (0.540, 0.087-4.625), and aspirin and cilostazol (0.188, 0.135-3.010). Moreover, diclofenac (adjusted odds ratio 1.319, 95% bootstrap confidence interval 1.189-2.821) and famotidine (1.643, 1.332-2.071) individually affected the risk of abnormal elevation of serum ALT. In the XGBoost model, not only the individual effects of diclofenac (feature importance 0.004) and famotidine (0.016), but also the interaction term (0.004) was included in important predictors. Although further study is needed, the combination of diclofenac and famotidine appears to increase the risk of abnormal elevation of serum ALT in the real world.