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Background: Osimertinib shows higher effectiveness than first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in the initial treatment of EGFR-mutated non-small cell lung cancer. However, its superiority in terms of overall survival in the Asian population, especially Japanese patients, remains uncertain., Objective: To evaluate the survival benefit of osimertinib over other EGFR-TKIs in Japanese patients, using real-world data. METHODS : As part of the Tokushukai REAl-world Data project, a retrospective multi-institutional study across 46 hospitals in Japan was conducted to evaluate the overall survival of patients with advanced EGFR-mutated non-small cell lung cancer using propensity score matching. The study involved patients receiving osimertinib as the first-line treatment (1L-Osi), those initially treated with other EGFR-TKIs (1L-non-Osi), and those receiving osimertinib after initial EGFR-TKI treatment (2L/later-Osi) between April 2010 and December 2022 and followed up until April 2023., Results: Among 1062 Japanese patients with EGFR-mutated non-small cell lung cancer, 416 (39.2%) received 1L-Osi, while 646 (60.8%) received 1L-non-Osi, including 139 (13.1%) who received 2L/later-Osi. Within these groups, 416 (39.2%), 293 (27.6%), and 75 (7.1%) patients received first-line EGFR-TKI treatment post-osimertinib approval as a later-line treatment in Japan (March 2016). After propensity score matching, the overall survival of the 1L-Osi group was comparable to that of the 1L-non-Osi group in the post-March 2016 subset (n = 283, 42.0 vs 42.4 months). Similar trends were observed in the Del19 and L858R subgroups. The median overall survival of the 2L/later-Osi group was notably long: 60.2 months post-March 2016 (n = 75). A subgroup analysis based on initial EGFR-TKI treatment in the 1L-non-Osi and 2L/later-Osi groups revealed no significant differences among the gefitinib, erlotinib, and afatinib groups., Conclusions: Based on real-world data, osimertinib did not show a significant improvement in overall survival compared to other EGFR-TKIs as a first-line treatment for EGFR-mutated advanced non-small cell lung cancer in the Japanese (Asian) population., Clinical Trial Registration: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry on 9 March, 2023 (identification UMIN000050552)., (© 2024. The Author(s).)

We previously demonstrated that transcutaneous CO 2 application promotes muscle fiber-type switching, fracture healing, and osteogenesis by increasing blood flow and angiogenesis. Here, we aimed to investigate the preventive effects of transcutaneous CO 2 application on disuse osteoporosis and muscle atrophy in a rat hindlimb suspension model. Eleven-week-old male Sprague-Dawley rats were divided into hindlimb suspension (HS), HS with transcutaneous CO 2 application (HSCO 2 ), and control groups. HSCO 2 rats were administered transcutaneous 100 % CO 2 gas in their bilateral hindlimbs, five times a week for 20 min. After 3 weeks, we harvested the gastrocnemius, femur, and tibia for assessment. Histological analysis revealed a significant decrease in the gastrocnemius myofiber cross-sectional area in HS rats compared to the control rats, whereas HSCO 2 rats exhibited a significant increase compared to HS rats. Micro-computed tomography showed significant bone atrophy in the trabecular and cortical bones of the femur in HS rats compared to those of the control rats, whereas significant improvement was noted in HSCO 2 rats. Histological analysis of the proximal tibia revealed more marrow adipose tissue in the HS rats than in the control rats. However, in the HSCO 2 rats, fewer marrow adipose tissue and osteoclasts were observed. Moreover, HSCO 2 rats had more osteoblasts and higher expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and vascular endothelial growth factor (VEGF) than the HS rats. The gastrocnemius and distal femur of HSCO 2 rats also exhibited elevated PGC-1α and VEGF expression and upregulation of the myogenesis markers and osteogenesis markers compared to those of HS rats. This treatment effectively prevented disuse osteoporosis and muscle atrophy by promoting local angiogenesis and blood flow. PGC-1α is crucial for promoting this angiogenic pathway. Transcutaneous CO 2 application may be a novel preventive procedure for disuse osteoporosis and muscle atrophy, complementing medication and rehabilitation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

BACKGROUND Infection control and reconstruction of bone and soft tissue are essential for treating infected nonunion. Continuous local antibiotic perfusion (CLAP) is a drug delivery system that continuously delivers antibiotics at the required concentration, area, and duration. This case report describes the instance of infected nonunion in which infection eradication and bone union were achieved using CLAP and synthetic bone grafting while retaining the implant. CASE REPORT The case was a 31-year-old woman with an infected nonunion. After she underwent osteosynthesis using nail for open fractures of tibia and fibula, bone union remained unachieved, and she exhibited skin defects and draining of pus. Following the removal of the infected granulation tissue from the bone defects, 2 bone marrow needles, serving as intramedullary antibiotic perfusion (iMAP) pins, were inserted into the medullary cavity tibia. A double-lumen tube was placed in the subcutaneous pocket as the intra-soft tissue antibiotic perfusion (iSAP) tube. No bone mobility was observed around the bone defect and nail, and replacement of the implant was not necessary. Beta-tricalcium phosphate was transplanted to the bone defect, and negative pressure wound therapy was applied. Gentamicin was injected continuously through iMAP and iSAP. Finally, the infection was eradicated, and cortical bone bridging was observed without additional surgery or adverse effects. CONCLUSIONS CLAP emerges as a viable treatment option for infected nonunion, as it enables the delivery of antibiotics at a concentration sufficient for infection control while providing the surgeon with flexibility to design the area, dosage, and duration of antibiotic delivery.

Molecular assemblies featuring two-dimensionality have attracted increasing attention, whereas such structures are difficult to construct simply relying on spontaneous molecular assembly. Here, we present two-dimensional assemblies of acene chromophores achieved using a tripodal triptycene supramolecular scaffold, which have been shown to exhibit a strong ability to assemble molecular and polymer motifs two-dimensionally. We designed pentacene and anthracene derivatives sandwiched by two triptycene units. These compounds assemble into expected two-dimensional structures, with the pentacene chromophores having both sufficient overlap to cause singlet fission and space for conformational change to facilitate the dissociation of a triplet pair into free triplets, which is not the case for the anthracene analog. Detailed spectroscopic analysis revealed that the pentacene chromophore in the assembly undergoes singlet fission with a quantum yield of 88 ± 5%, giving rise to triplet pairs, from which free triplets are efficiently generated (Φ T = 130 ± 8.8%). This demonstrates the utility of the triptycene-based scaffold to design functional π-electronic molecular assemblies.

The interconnected structures in a 3D scaffold allows the movement of cells and nutrients. Therefore, this study aimed to investigate the in-vivo bioactivity of 3D-printed β-tricalcium phosphate (β-TCP) and hydroxyapatite (HAP) scaffolds that replicate biological bone. This study included 24-week-old male New Zealand white rabbits. A cylindrical bone defect with a diameter of 4.5 mm and a depth of 8 mm was created in the lateral aspect of the distal femur. A 3D-printed scaffold was implanted in the right femur (experimental side), whereas the left femur was kept free of implantation (control side). Micro-CT analysis and histological observations of the bone defect site were conducted at 4, 8, and 12 weeks postoperatively to track the bone repair progress. No evidence of new bone tissue formation was found in the medullary cavity of the bone defect on the control side. In contrast, on the experimental side, the 3D scaffold demonstrated sufficient bioactivity, leading to the growth of new bone tissue. Over time, new bone tissue gradually extended from the periphery toward the center, a phenomenon evident in both micro-CT images and biopsy staining. In the current study, we observed that the cells involved in bone metabolism adhered, spread, and proliferated on our newly designed 3D-printed scaffold with a bone microstructure. Therefore, it is suggested that this scaffold has sufficient bioactivity to induce new bone formation and could be expected to be a more useful artificial bone than the existing version., (© 2024. The Author(s).)

Background: While seasonality of hospital-acquired infections, including incisional SSI after orthopaedic surgery, is recognized, the seasonality of incisional SSI after general and gastroenterological surgeries remains unclear., Aim: To analyse the seasonality and risk factors of incisional SSI after general and gastroenterological surgeries., Methods: This was a retrospective, single-institute, observational study using univariate and multivariate analyses. The evaluated variables included age, sex, surgical approach, surgical urgency, operation time, wound classification, and the American Society of Anesthesiologists physical status (ASA-PS)., Findings: A total of 8436 patients were enrolled. General surgeries (N = 2241) showed a pronounced SSI incidence in summer (3.9%; odds ratio (OR): 1.87; 95% confidence interval (CI): 1.05-3.27; P = 0.025) compared to other seasons (2.1%). Conversely, gastroenterological surgeries (N = 6195) showed a higher incidence in winter (8.3%; OR: 1.38; 95% CI: 1.10-1.73; P = 0.005) than in other seasons (6.1%). Summer for general surgery (OR: 1.90; 95% CI: 1.12-3.24; P = 0.018) and winter for gastroenterological surgery (1.46; 1.17-1.82; P = 0.001) emerged as independent risk factors for incisional SSI. Open surgery (OR: 2.72; 95% CI: 1.73-4.29; P < 0.001) and an ASA-PS score ≥3 (1.64; 1.08-2.50; P = 0.021) were independent risk factors for incisional SSI in patients undergoing gastroenterological surgery during winter., Conclusion: Seasonality exists in the incisional SSI incidence following general and gastroenterological surgeries. Recognizing these trends may help enhance preventive strategies, highlighting the elevated risk in summer for general surgery and in winter for gastroenterological surgery., (Copyright © 2024 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Endoscopic ultrasound (EUS)-guided pancreatic duct drainage is a well-established procedure for managing pancreaticojejunostomy anastomotic strictures (PJAS) post-Whipple surgery. In this study, we examined the effectiveness and safety of EUS-guided pancreaticojejunostomy (EUS-PJS)., Methods: This retrospective, single-arm study was performed at Aichi Cancer Center Hospital on 10 patients who underwent EUS-guided pancreaticojejunostomy through the afferent jejunal loop using a forward-viewing echoendoscope when endoscopic retrograde pancreatography failed. Our primary endpoint was technical success rate, defined as successful stent insertion. The secondary endpoints were early and late adverse events., Results: A total of 10 patients underwent EUS-PJS between February 2019 and October 2023. The technical success rate was 100%. The median procedure time was 23.5 minutes. No remarkable early or late adverse events related to the procedure, except for fever, occurred in two patients. The median follow-up duration was 9.5 months, and the median number of stent exchanges was two. A stent-free state was achieved in three patients., Conclusions: EUS-PJS for PJAS management after pancreaticoduodenectomy appears to be an effective and safe procedure with the potential advantages of fewer reinterventions and the creation of a permanent drainage fistula.

Change in mucosal microbiome is associated with various types of cancer in digestive tract. We hypothesized that microbial communities in the esophageal endoscopic wash fluids reflects resident flora in esophageal mucosa that is associated with esophageal carcinoma (EC) risk and/or directly correlates microbiome derived from EC tumor tissue. Studying microbial communities in esophageal endoscopic wash samples would be therefore useful to predict the incidence or risk of EC. We examined microbial communities of the endoscopic wash samples from 45 primary EC and 20 respective non-EC controls using 16S rRNA V3-V4 amplicon sequencing. The result was also compared with microbial communities in matched endoscopic biopsies from EC and non-cancerous esophageal mucosa. Compared with non-EC controls, 6 discriminative bacterial genera were detected in EC patients. Among them, relative abundance ratio of Prevotella and Shuttlewarthia, as well as decrease of genus Prevotella presented good prognostic performance to discriminate EC from controls (area under curve, 0.86, 0.82, respectively). Multivariate analysis showed occurrence of EC was an independent factor associated with decrease of this bacteria. Abundance of genus Prevotella in the esophageal endoscopic wash samples was significantly correlated with the abundance of this bacteria in the matched endoscopic biopsies from non-cancerous esophageal mucosa but not in the EC tissues. Our findings suggest that microbiome composition in the esophageal endoscopic wash samples reflects resident flora in the esophagus and significantly correlates with the incidence of EC., (© 2024. The Author(s).)

Background/aims: Serum leucine-rich alpha-2 glycoprotein (LRG) is a potential biomarker of Crohn's disease (CD). This study aimed to evaluate the usefulness of LRG in predicting clinical relapse in patients in remission with CD., Methods: This retrospective observational study assessed the relationships among patient-reported outcome (PRO2), LRG, and other blood markers. The influence of LRG on clinical relapse was assessed in patients in remission with CD., Results: Data of 94 patients tested for LRG between January 2021 and May 2023 were collected. LRG level did not correlate with PRO2 score (ρ = 0.06); however, it strongly correlated with C-reactive protein (CRP) level (r=0.79) and serum albumin level (r=-0.70). Among 69 patients in clinical remission, relapse occurred in 22 patients (31.9%). In the context of predicting relapse, LRG showed the highest area under the curve, followed by CRP level, platelet count, and albumin level. Multivariate analysis revealed that only LRG (P= 0.02) was an independent factor for predicting clinical remission. The cumulative non-relapse rate was significantly higher in patients with LRG < 13.8 μg/mL than in patients in remission with LRG ≥ 13.8 μg/mL and normal CRP level (P= 0.002) or normal albumin level (P= 0.001). Cumulative non-relapse rate was also higher in patients with LRG < 13.8 μg/mL compared to those with LRG ≥ 13.8 μg/mL in patients with L3 or B2+B3 of Montreal calcification., Conclusions: LRG is useful in predicting clinical relapse in patients with CD during biological remission. LRG is a useful biomarker for predicting prognosis, even in patients with intestinal stenosis, or previous/present fistulas.

Cancer cells exhibit high glycolytic activity, metabolizing glucose as their primary energy substrate. Toxic metabolites produced during glycolysis, such as methylglyoxal, induce carbonyl stress (CS), promoting inflammation and oxidative stress. The elevated glucose metabolism in cancer cells creates this toxic environment. However, little research has focused on the molecules mediating these reactions and stresses, and their role in selecting and enriching apoptosis-resistant cells. This study investigated the impact of constitutively suppressing oxidized lipid receptor G2A (GPR132) expression on the relationship between CS and oxidative stress in glucose-loaded cancer cells. G2A has recently attracted attention as a tumor promoter. However, our study shows that G2A suppression under glucose loading significantly reduces CS and associated oxidative stress, thereby enhancing cancer cell survival. This suggests a new mechanism contrary to conventional thinking, involving the acute induction of glyoxalase 1 (Glo1). G2A may thus play a role in selecting and enriching apoptosis-resistant cell populations under high glucose conditions by regulating Glo1 expression. These findings improve our understanding of the adaptive capacity of cancer cells to glucose toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study evaluated the effect of intratracheal administration of basic fibroblast growth factor (bFGF) on tracheal healing following implantation of a novel layered polyglycolic acid (PGA) material to replace a critical-size defect in rat trachea., Methods: A critical-size defect in the rat cervical trachea was covered with PGA. Distilled water (DW) or 3.125, 6.25, 12.5 or 25 µg bFGF was administered into the trachea for 2 weeks (n = 6 for each of 5 groups). Regenerated areas of cilia, ciliary beat frequency and ciliary transport function (CTF) in the centre of the PGA were measured. To examine potential side effects of intratracheal administration of bFGF, the right lower lobe was pathologically evaluated., Results: All rats survived during the study period. Histological examination showed ciliated epithelization on the PGA material after 2 weeks. Bronchoscopy revealed stenosis due to granulation following administration of high concentrations of bFGF (12.5 and 25 µg). Compared with the DW group, groups administered 3.125, 6.25, 12.5 and 25 µg bFGF had significantly larger areas of regenerated cilia (15.2%, 27.0%, 41.3%, 33.1% and 31.0%, respectively; P = 0.00143), improved ciliary beat frequency (7.10, 8.18, 10.10, 9.50 and 9.50 Hz, respectively), and improved CTS (6.40, 9.54, 16.89, 16.41 and 14.29 µm/sec, respectively). Pathological examination of the right lower lobe revealed pulmonary fibrosis and hyperplasia with high concentrations of bFGF (12.5 and 25 µg)., Conclusions: Intratracheal administration of bFGF effectively promoted tracheal regeneration at an optimal dose of 6.25 µg following implantation of an artificial trachea., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Coordination among lip, cheek and tongue movements during swallowing in patients with mandibular prognathism remains unclear., Objectives: This study aimed to identify the temporal sequences of tongue pressure and maxillofacial muscle activities during swallowing in patients with mandibular prognathism and compared characteristics with those of healthy volunteers., Methods: Seven patients with mandibular prognathism (mandibular prognathism group) and 25 healthy volunteers with individual normal occlusion (control group) were recruited. Tongue pressures and masseter, orbicularis oris, mentalis and supra- and infrahyoid muscle activities while swallowing gel were measured simultaneously using a sensor sheet system with five measurement points and surface electromyography, respectively. Onset time, offset time and durations of tongue pressure and muscle activities were analysed., Results: In the mandibular prognathism group, tongue pressure was often produced first in more peripheral parts of the palate. Offset of tongue pressure in the posteromedian and peripheral parts of the palate and maxillofacial muscle activities except for orbicularis oris were delayed. Duration of tongue pressure in the anteromedian part of the palate was significantly shorter and durations of masseter, mentalis and suprahyoid muscle activities were significantly longer. Times to onset of orbicularis oris and suprahyoid muscle activities based on first onset of tongue pressure were significantly shorter., Conclusion: These results suggest that patients with mandibular prognathism may exhibit specific patterns of tongue pressure production and maxillofacial muscle activities during swallowing., (© 2024 John Wiley & Sons Ltd.)

Purpose: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs)., Methods: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H 2 -receptor antagonists (H 2 RAs)., Results: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively., Conclusion: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Janus kinase (JAK) inhibitors have been developed and are clinically available for management of active UC patients although most studies have been conducted for the outpatients and few studies have demonstrated its efficacy in endoscopic and histological remission of hospitalized patients with UC. The aim of the present study was to investigate the efficacy of upadacitinib, which is a novel selective JAK1 inhibitor, in the treatment of ulcerative colitis. We present the cases of three hospitalized patients with ulcerative colitis who achieved clinical remission after significant and rapid improvement with upadacitinib. While upadacitinib was used as the second-line treatment for patients with insufficient treatment effects for corticosteroids or ustekinumab, a patient received it just after admission because they were steroid dependent and previously used advanced therapy before hospitalization. All patients demonstrated rapid clinical responses within 7 days and the partial Mayo scores were 0 at week 8. All patients achieved confirmed endoscopic and histological remissions. We conclude that upadacitinib is a potential treatment option for hospitalized patients with an inadequate response to other biologics and JAK inhibitors., (© 2024. Japanese Society of Gastroenterology.)

Purpose: This study aimed to determine whether the combination of H 2 gas inhalation and administration of hydrogen-rich acetated Ringer's solution (HS) could protect against ischemic spinal cord injury in rabbits., Methods: In Experiment 1, rabbits were randomly assigned to a 1.2% H 2 gas group, HS group, 1.2% H 2 gas + HS group (combination group), or control group (n = 6 per group). The H 2 concentration of HS was 0.65 mM. H 2 was inhaled for 60 min, starting 5 min before reperfusion. HS (20 mL/kg) was divided into six bolus injections at 10-min intervals, starting 5 min before reperfusion. Spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. Neurologic and histopathologic evaluations were performed 7 days after reperfusion. In Experiment 2, H 2 concentrations in spinal cord tissue according to the administration of 1.2% H 2 gas or HS were compared by measuring the electric current through a platinum needle electrode (n = 2). In Experiment 3, rabbits were assigned to a 2% H 2 gas group or control group (n = 6 per group). Spinal cord ischemia was produced and neurologic and histopathologic evaluations were performed as in Experiment 1., Results: There were no significant differences among the groups in the neurologic and histopathologic outcomes in Experiments 1 and 3. Bolus administration of HS (10 mL) transiently increased the current to only 1/30th and 1/27th of the plateau current with 1.2% H 2 gas inhalation in two animals., Conclusion: These results suggest that the combination of 1.2% H 2 gas inhalation and administration of a hydrogen-rich solution does not protect against ischemic spinal cord injury and that the increase in H 2 concentration in spinal cord tissue after administration of HS is very low compared to 1.2% H 2 gas inhalation., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Gastric cancer (GC) is characterized by significant intratumoral heterogeneity, and stem cells are promising therapeutic targets. Despite advancements in spatial transcriptome analyses, unexplored targets for addressing cancer stemness remain unknown. This study aimed to identify Nuclear Factor IX (NFIX) as a critical regulator of cancer stemness in GC and evaluate its clinicopathological significance and function. Spatial transcriptome analysis of GC was conducted. The correlation between NFIX expression, clinicopathological factors, and prognosis was assessed using immunostaining in 127 GC cases. Functional analyses of cancer cell lines validated these findings. Spatial transcriptome analysis stratified GC tissues based on genetic profiles, identified CSC-like cells, and further refined the classification to identify and highlight the significance of NFIX, as validated by Monocle 3 and CytoTRACE analyses. Knockdown experiments in cancer cell lines have demonstrated the involvement of NFIX in cancer cell proliferation and kinase activity. This study underscores the role of spatial transcriptome analysis in refining GC tissue classification and identifying therapeutic targets, highlighting NFIX as a pivotal factor. NFIX expression is correlated with poor prognosis and drives GC progression, suggesting its potential as a novel therapeutic target for personalized GC therapies., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Inhibition of autophagy is an important strategy in cancer therapy. However, prolonged inhibition of certain autophagies in established cancer cells may increase therapeutic resistance, though the underlying mechanisms of its induction and enhancement remain unclear. This study sought to elucidate the mechanisms of therapeutic resistance through repeated autophagy inhibition and amino acid deprivation (AD) in an in vitro model of in vivo chronic nutrient deprivation associated with cancer cell treatment. In the human cervical cancer cell line HeLa and human breast cancer cell line MCF-7, initial extracellular AD induced the immediate expression of endosomal microautophagy (eMI). However, repeated inhibition of eMI with U18666A and extracellular AD induced macroautophagy (MA) to compensate for reduced eMI, simultaneously decreasing cytotoxicity. Here, hyperphosphorylated JNK was transformed into a hypophosphorylated state, suggesting conversion of the cell death signal to a survival signal. In a nutrient medium, cell death could not be induced by MA inhibition. However, since LAT1 inhibitors induce intracellular AD, combining them with MA and eMI inhibitors successfully promoted cell death in resistant cells. Our study identified a novel therapeuic approach for promoting cell death and addressing therapeutic resistance in cancers under autophagy-inhibitor treatment., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background/aims: Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) performed at the intrahepatic bile duct segment 3 (B3) is widely used for biliary drainage. Although performing post-puncture procedures is easier in the intrahepatic bile duct segment 2 (B2) when using a conventional oblique-viewing (OV) EUS scope, this method may cause transesophageal puncture and severe adverse events. We evaluated the safety and efficacy of B2 puncture using a novel OV-EUS scope., Methods: In this single-center retrospective study, we prospectively enrolled and collected data from 45 patients who consecutively underwent EUS-HGS procedures with a novel OV-EUS scope between September 2021 and December 2022 at our cancer center., Results: The technical success rates of B2-EUS-HGS and EUS-HGS were 93.3% (42/45) and 97.8% (44/45), respectively. The early adverse event rate was 8.9% (4/45) with no cases of scope changes or transesophageal punctures. The median procedure time was 13 minutes (range, 5-30)., Conclusions: B2-EUS-HGS can be performed safely with the novel EG-740UT (Fujifilm) OV-scope without transesophageal puncture and with a high success rate. B2-EUS-HGS using this novel OV scope may be the preferred strategy for EUS-HGS.

We examined Fusobacterium nucreatum ( F. nucleatum ) and whole Fusobacterium species ( Pan-fusobacterium ) in non-neoplastic Barrett's esophagus (BE) from patients without cancer ( n  = 67; N group), with esophageal adenocarcinoma (EAC) ( n  = 27) and EAC tissue ( n  = 22). F. nucleatum was only detectable in 22.7% of EAC tissue. Pan-fusobacterium was enriched in EAC tissue and associated with aggressive clinicopathological features. Amount of Pan-fusobacterium in non-neoplastic BE was correlated with presence of hital hernia and telomere shortening. The result suggested potential association of Fusobacterium species in EAC and BE, featuring clinicpathological and molecular features.

Aims/introduction: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state., Materials and Methods: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques., Results: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m 2 , F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively., Conclusions: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: There are few studies evaluating the prognostic prediction method in atrial fibrillation (AF) patients after bioprosthetic valve (BPV) replacement. The R 2 -CHA 2 DS 2 -VASc score is increasingly used for the prediction of cardiovascular (CV) events in patients with AF, device implantation, and acute coronary syndrome. We aimed to evaluate the predictive value of the R 2 -CHA 2 DS 2 -VASc score for future CV events in AF patients after BPV replacement., Methods and Results: The BPV-AF, an observational, multicenter, prospective registry, enrolled AF patients who underwent BPV replacement. The primary outcome measure was a composite of stroke, systemic embolism, CV events including heart failure requiring hospitalization, and cardiac death. A total of 766 patients was included in the analysis. The mean R 2 -CHA 2 DS 2 -VASc score was 5.7±1.8. Low (scores 0-1), moderate (scores 2-4), and high (scores 5-11) R 2 -CHA 2 DS 2 -VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively. The median follow-up period was 491 (interquartile range 393-561) days. Kaplan-Meier analysis showed a higher incidence of the composite CV events in the high R 2 -CHA 2 DS 2 -VASc score group (log rank test; P<0.001). Multivariate Cox proportional hazards regression analysis revealed that the R 2 -CHA 2 DS 2 -VASc score as a continuous variable was an independent predictor of composite CV outcomes (hazard ratio 1.36; 95% confidence interval 1.18-1.55; P<0.001)., Conclusions: The R 2 -CHA 2 DS 2 -VASc score is useful for CV risk stratification in AF patients after BPV replacement., Competing Interests: H.T. has received consultancy fees from AstraZeneca PLC and Ono Pharmaceutical Co., Ltd. K.A. has received remuneration from Japan Lifeline Co., Ltd, Terumo Corporation, and Medtronic Japan Co., Ltd. M.I. has received consultancy fees from Abbott Medical Japan LLC, and remuneration from Edwards Lifesciences Corporation. T.S. has received remuneration from Medtronic Japan Co., Ltd. K.M. has received scholarship funds or donations from Edwards Lifesciences Corporation, Terumo Co., Ltd, and Japan Lifeline Co., Ltd. K.M. has received scholarship funds or donations from Edwards Lifesciences Corporation, Terumo Co., Ltd., and Japan Lifeline Co., Ltd. K.T. is a member of Circulation Reports’ Editorial Team, and has received remuneration from Amgen K.K., Bayer Yakuhin Ltd, Daiichi Sankyo Co., Ltd, Kowa Pharmaceutical Co. Ltd, Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd, and Pfizer Japan Inc.; research funding from AMI Co., Ltd, Bayer Yakuhin Ltd, Bristol-Myers Squibb K.K., EA Pharma Co., Ltd, and Mochida Pharmaceutical Co., Ltd; scholarship funding from AMI Co., Ltd, Bayer Yakuhin Ltd, Nippon Boehringer Ingelheim Co., Ltd, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Edwards Lifesciences Corporation, Johnson & Johnson K.K., Ono Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd; and is affiliated with the endowed department sponsored by Abbott Japan Co., Ltd, Boston Scientific Japan K.K., Fides-one Inc., GM Medical Co., Ltd, ITI Co., Ltd, Kaneka Medix Co., Ltd, Nipro Corporation, Terumo Co., Ltd, Abbott Medical Co., Ltd, Cardinal Health Japan LLC, Fukuda Denshi Co., Ltd, Japan Lifeline Co., Ltd, Medical 3 Appliance Co., Ltd, and Medtronic Japan Co., Ltd. Y. Sakata has received remuneration from Daiichi Sankyo Co., Ltd, and Nippon Boehringer Ingelheim Co., Ltd; and scholarship funding from Nippon Boehringer Ingelheim Co., Ltd, Bayer Yakuhin Ltd, and Daiichi Sankyo Co., Ltd. K.S. is an employee of Daiichi Sankyo Co., Ltd. K.N. has received research funding from Philips Japan Ltd, Terumo Co., Ltd, TEPCO Power Grid Inc., and Asahi Kasei Pharma Co. C.I. has received remuneration and research funding from Daiichi Sankyo Co., Ltd. Y.F. has received remuneration from Daiichi Sankyo Co., Ltd, and Bayer Yakuhin Ltd. All other authors have no conflicts of interest to disclosure., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Prediction of RNA structure from sequence remains an unsolved problem, and progress has been slowed by a paucity of experimental data. Here, we present Ribonanza, a dataset of chemical mapping measurements on two million diverse RNA sequences collected through Eterna and other crowdsourced initiatives. Ribonanza measurements enabled solicitation, training, and prospective evaluation of diverse deep neural networks through a Kaggle challenge, followed by distillation into a single, self-contained model called RibonanzaNet. When fine tuned on auxiliary datasets, RibonanzaNet achieves state-of-the-art performance in modeling experimental sequence dropout, RNA hydrolytic degradation, and RNA secondary structure, with implications for modeling RNA tertiary structure.

Background/aims: Dilation of the tract before stent deployment is a challenging step in endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD). In this study, we examined the effectiveness and safety of a novel spiral dilator, Tornus ES (Asahi Intec), for EUS-PDD., Methods: This was a retrospective, single-arm, observational study at Aichi Cancer Center Hospital. The punctured tract was dilated using a Tornus ES dilator in all EUS-PDD cases. Our primary endpoint was the technical success rate of initial tract dilation. Technical success was defined as successful fistula dilation using Tornus ES followed by successful stent insertion. Secondary endpoints were procedure times and early adverse events., Results: A total of 12 patients were included between December 2021 and March 2023. EUS-PDD was performed in 11 patients for post-pancreaticoduodenectomy anastomotic strictures and one patient with pancreatitis with duodenal perforation. The technical success rates of stent insertion and fistula dilation using Tornus ES dilator was 100%. The median procedure time was 24 minutes. No remarkable adverse events related to the procedure were observed, apart from fever, which occurred in 2 patients., Conclusions: Tract dilation in EUS-PDD using Tornus ES is effective and safe.

Background: Cardiac surgery-associated (CSA) acute kidney injury (AKI) is a severe postoperative complication in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Early detection of postoperative CSA-AKI may be key to improving patient outcomes. This study explored the use of renal biomarkers measured immediately after surgery for the early detection of CSA-AKI in patients undergoing OPCAB., Methods and results: In all, 111 patients who underwent OPCAB at Kumamoto University Hospital between June 2020 and October 2022 were included in this study. Urinary neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and N-acetyl-β-D-glucosaminidase (NAG) were measured upon arrival in the intensive care unit (ICU) after surgery. AKI was diagnosed using KDIGO criteria. Of the 111 patients, 32 (28.8%) developed postoperative AKI. Regarding AKI staging, 19 (59.4%), 11 (34.4%), and 2 (6.3%) patients had Stage 1, 2, and 3 AKI, respectively. There were significant differences in chronic kidney disease, preoperative estimated glomerular filtration rate (eGFR), and NAG between the AKI and non-AKI groups. Multivariate analysis showed that preoperative eGFR (odds ratio [OR] for 5-mL/min/1.73 m 2 increase in eGFR 0.75; 95% confidence interval [CI] 0.63-0.89) and increasing urinary NAG concentrations at ICU admission (OR 2.44; 95% CI 1.30-4.60) were significant risk factors for CSA-AKI in OPCAB patients., Conclusions: NAG and eGFR may be valuable biomarkers for the early detection of CSA-AKI in patients undergoing OPCAB.

Background: The recent guidelines from the European and American Hernia Societies recommend a continuous small-bite suturing technique with slowly absorbable sutures for fascial closure of midline abdominal wall incisions to reduce the incidence of wound complications, especially for incisional hernia. However, this is based on low-certainty evidence. We could not find any recommendations for skin closure. The wound closure technique is an important determinant of the risk of wound complications, and a comprehensive approach to prevent wound complications should be developed., Methods: We propose a single-institute, prospective, randomized, blinded-endpoint trial to assess the superiority of the combination of continuous suturing of the fascia without peritoneal closure and continuous suturing of the subcuticular tissue (study group) over that of interrupted suturing of the fascia together with the peritoneum and interrupted suturing of the subcuticular tissue (control group) for reducing the incidence of midline abdominal wall incision wound complications after elective gastroenterological surgery with a clean-contaminated wound. Permuted-block randomization with an allocation ratio of 1:1 and blocking will be used. We hypothesize that the study group will show a 50% reduction in the incidence of wound complications. The target number of cases is set at 284. The primary outcome is the incidence of wound complications, including incisional surgical site infection, hemorrhage, seroma, wound dehiscence within 30 days after surgery, and incisional hernia at approximately 1 year after surgery., Discussion: This trial will provide initial evidence on the ideal combination of fascial and skin closure for midline abdominal wall incision to reduce the incidence of overall postoperative wound complications after gastroenterological surgery with a clean-contaminated wound. This trial is expected to generate high-quality evidence that supports the current guidelines for the closure of abdominal wall incisions from the European and American Hernia Societies and to contribute to their next updates., Trial Registration: UMIN-CTR UMIN000048442. Registered on 1 August 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000055205., (© 2024. The Author(s).)

Background: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear., Objective: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis., Patients and Methods: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020., Results: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03)., Conclusions: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge., (© 2024. The Author(s).)

Background/aims: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a highly accurate method for diagnosing pancreatic neuroendocrine tumors (PNETs); however, some PNETs are difficult to diagnose. Recently, the efficacy of needle-based confocal laser endomicroscopy (nCLE) in diagnosing solid pancreatic masses has been reported. However, the efficacy of nCLE in the diagnosis of PNETs remains unknown and only a small number of cases have been reported. Hence, this study aimed to evaluate the efficacy of nCLE in the diagnosis of PNETs., Methods: This single-center retrospective study evaluated 30 consecutive patients with suspected PNETs on contrast-enhanced computed tomography, who consented to nCLE combined with EUS-FNA and were diagnosed using EUS-FNA or surgical resection. The diagnostic criteria for PNETs using nCLE were based on the nesting and trabecular and glandular arrangement of tumor cell clusters surrounded by capillary vessels and fibrosis, as reported in previous studies., Results: The diagnosis using nCLE was classified into three categories: misdiagnosis in three cases (10%), non-diagnostic in six cases (20%), and diagnostic in 21 cases (70%). nCLE was able to diagnose PNET in one of the two cases with inconclusive EUS-FNA., Conclusions: Although further development of the resolution and optimization of the diagnostic criteria are required, nCLE may constitute a useful diagnostic option in cases of inconclusive EUS-FNA for PNETs.

Purpose: The aim of this study was to demonstrate the spatial pattern of retinal pigment epithelium (RPE) tear development and progression after antivascular endothelial growth factor therapy for neovascular age-related macular degeneration., Methods: We retrospectively reviewed six eyes with neovascular age-related macular degeneration that showed RPE tears after administration of intravitreal antivascular endothelial growth factor agents and were followed up for 12 months. The patterns of RPE tear development and progression were evaluated by analyzing positional relationships among the locations of the choroidal neovascularization membrane and pigment epithelial detachment (PED) area at baseline and the tear area using spectral-domain optical coherence tomography, color photography, fluorescein angiography, and fundus autofluorescence images., Results: Pretear OCT images revealed fibrovascular PED in all eyes, one of which showed complications of hemorrhagic PED after treatment. In five eyes, RPE tears developed at the PED edge located on the opposite side of the choroidal neovascularization membrane. In the eye showing hemorrhagic PED, the RPE tear developed along the wide area of the PED edge. The torn RPE monolayer contracted toward the side of the choroidal neovascularization membrane in all eyes, and RPE loss involved the fovea in five eyes that showed significantly worse visual acuity (VA) after 12 months in comparison with the baseline value before the tear (logMAR VA; 0.3 vs. 1.29; P < 0.02)., Conclusion: The location of choroidal neovascularization membrane in PED determines the spatial pattern of RPE tear development and progression and helps to predict the visual outcome after RPE tears.

Aim: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin., Methods: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and β-hydroxybutyrate., Results: The area under the curve from fasting (0 min) to 120 min (AUC 0-120min ) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial β-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC 0-120min ) from baseline to 12 weeks were significantly correlated with those in β-hydroxybutyrate levels., Conclusions: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC., Methods: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation., Results: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013)., Conclusions: The unnecessary use of NSAIDs along with immunotherapy should be discouraged., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

In proceeding with the advanced development of small unmanned aerial vehicles (UAVs), which are small flying machines, understanding the flight of insects is important because UAVs that use flight are attracting attention. The figure-eight trajectory of the wing tips is often observed in the flight of insects. In this study, we investigated the more efficient figure-eight motion patterns in generating lift during the hovering motion and the relationship between figure-eight motion and Reynolds number. For this purpose, we compared the ratios of the cycle-averaged lift coefficient to the power coefficient generated from each motion by varying the elevation motion angle, which is the rotational motion that represents the figure-eight motion, and the Reynolds number. The result showed that the motion with a smaller initial phase of the elevation motion angle (φe0≤90°) could generate lift more efficiently at all Reynolds numbers. In addition, the figure-eight motion was more effective when the Reynolds number was low.

Background: Next-generation sequencing (NGS) is essential for lung cancer treatment. It is important to collect sufficient tissue specimens, but sometimes we cannot obtain large enough samples for NGS analysis. We investigated the yield of NGS analysis by frozen cytology pellets using an Oncomine Comprehensive Assay or Oncomine Precision Assay., Methods: We retrospectively enrolled patients with lung cancer who underwent bronchoscopy at Kobe University Hospital and were enrolled in the Lung Cancer Genomic Screening Project for Individualized Medicine. We investigated the amount of extracted DNA and RNA and determined the NGS success rates. We also compared the amount of DNA and RNA by bronchoscopy methods. To create the frozen cytology pellets, we first effectively collected the cells and then quickly centrifuged and cryopreserved them., Results: A total of 132 patients were enrolled in this study between May 2016 and December 2022; of them, 75 were subjected to frozen cytology pellet examinations and 57 were subjected to frozen tissue examinations. The amount of DNA and RNA obtained by frozen cytology pellets was nearly equivalent to frozen tissues. Frozen cytology pellets collected by endobronchial ultrasound-guided transbronchial needle aspiration yielded significantly more DNA than those collected by transbronchial biopsy methods. (P < 0.01) In RNA content, cytology pellets were not inferior to frozen tissue. The success rate of NGS analysis with frozen cytology pellet specimens was comparable to the success rate of NGS analysis with frozen tissue specimens., Conclusions: Our study showed that frozen cytology pellets may have equivalent diagnostic value to frozen tissue for NGS analyses. Bronchial cytology specimens are usually used only for cytology, but NGS analysis is possible if enough cells are collected to create pellet specimens. In particular, the frozen cytology pellets obtained by endobronchial ultrasound-guided transbronchial needle aspiration yielded sufficient amounts of DNA., Trial Registration: This was registered with the University Medical Hospital Information Network in Japan (UMINCTR registration no. UMIN000052050)., (© 2024. The Author(s).)

Excessive salt intake is one of the causes of hypertension, and reducing salt intake is important for managing the risk of hypertension and subsequent cardiovascular events. Esaxerenone, a mineralocorticoid receptor blocker, has the potential to exert an antihypertensive effect in hypertensive patients with excessive salt intake, but evidence is still lacking, especially in clinical settings. We aimed to determine if baseline sodium/potassium ratio and baseline estimated 24-h urinary sodium excretion can predict the antihypertensive effect of esaxerenone in patients with essential hypertension inadequately controlled with an angiotensin receptor blocker (ARB) or a calcium channel blocker (CCB). This was an exploratory, open-label, interventional study with a 4-week observation period and a 12-week treatment period. Esaxerenone was orally administered once daily in accordance with the Japanese package insert. In total, 126 patients met the eligibility criteria and were enrolled (ARB subcohort, 67; CCB subcohort, 59); all were included in the full analysis set (FAS) and safety analysis. In the FAS, morning home systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from baseline to end of treatment (primary efficacy endpoint) (-11.9 ± 10.9/ - 6.4 ± 6.8 mmHg, both p < 0.001); a similar trend was observed in both subcohorts. Significant reductions were also shown in bedtime home and office SBP/DBP (all p < 0.001). Each BP change was consistent regardless of the urinary sodium/potassium ratio or estimated 24-h urinary sodium excretion at baseline. The urinary albumin-creatinine ratio (UACR) and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased from baseline to Week 12 in the total population and both subcohorts. No new safety concerns were raised. Esaxerenone significantly decreased morning home, bedtime home, and office BP; UACR; and NT-proBNP in this patient population, regardless of concomitant ARB or CCB use. The antihypertensive effect of esaxerenone was independent of the urinary sodium/potassium ratio and estimated 24-h urinary sodium excretion at baseline., (© 2023. The Author(s).)

We report an unusual case of carcinoma ex pleomorphic adenoma (CXPA) in the submandibular gland. The mass had a unique calcification. Panoramic tomography revealed sponge-like calcification. The central portion displayed heterogeneous high signal intensity on T1-weighted image (T1WI) and T2-weighted image (T2WI), and heterogeneously moderate signal intensity on a short-TI inversion recovery (STIR) image. The ADC was low (0.78 × 10 -3 mm 2 /sec). After surgical excision, a pathological examination revealed that the mass contained CXPA as a minor component. Tumor cells with large hyperchromatic nuclei and eosinophilic or clear cytoplasm proliferated in irregular small tubule formations or cribriform or Roman-bridge structures in hyalinized or focally ossified stroma. The entire mass was calcified, particularly in the central region. Taken together, the reduced T1 relaxation times were related to the surface effects of diamagnetic particles, which were observed at calcium particle concentrations of up to 30%. We report a CXPA with unusual sponge-like calcification, which appeared unusually hyperintense on T1WI due to a surface effect., (© 2023. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

Background and Aims: Non-cardiac chest pain (NCCP) is a frequent complication of endoscopic submucosal dissection (ESD) for early-stage esophageal cancer. However, little is known about relationships between ESD findings and NCCP. This study aims to evaluate the risk factors for NCCP, including ESD findings related to injury to the muscle layer., Methods: We enrolled a total of 296 lesions from 270 patients with esophageal squamous cell carcinoma (ESCC), who underwent ESD in our center. The grade of injury to the muscle layer caused by ESD was categorized as follows: grade 0: no exposure of muscularis propria; grade 1: muscularis propria exposure and/or whitish color change by the electrocoagulation; grade 2: torn muscularis propria with whitish color change by the electrocoagulation; and grade 3, esophageal perforation. The risk factors for NCCP, including ESD findings, were analyzed by univariate and multivariate analyses., Results: NCCP occurred in 89 patients (33.0%) after esophageal ESD. Multivariate analysis demonstrated that younger age [odds ratio (OR) 0.95, 95% confidence interval (95%CI) 0.92-0.98, p=0.003), postoperative fever (>= 38°C) (OR=25.9, 95%CI: 2.89-232.10, p=0.004), ESD findings (grade 1: OR=3.99, 95%CI: 1.63-9.75, p=0.003 and grade 2: OR=3.18, 95%CI: 1.54-6.57, p=0.002) were independently associated with the incidence of post ESD NCCP., Conclusions: ESD findings relate to slight Injury to the muscle layer, such as muscularis propria exposure and whitish color change by the electrocoagulation were identified as risk factor for post ESD NCCP. We should therefore perform esophageal ESD carefully to avoid injuring the muscle layers.

Objective: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions., Methods: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs., Results: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively., Conclusions: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The present study assessed the late results of the operation, which consisted of the construction of a stentless mitral valve using autologous pericardium and valve implantation., Methods: Between 2011 and 2018, among 1617 consecutive patients who underwent mitral valve operation at our institution, 15 adult patients (0.9%) with unrepairable mitral valves who wished to avoid conventional mitral valve replacement underwent this operation. Ten patients (67%) had a history of valve repair. After discharge, patients were prospectively followed-up with a echocardiographic evaluation up to the end point. The mean follow-up term was 70.8 ± 42.5 months., Results: There were no hospital deaths or thromboembolic events and only 1 late noncardiac death. Intraoperative transesophageal echocardiography of all patients revealed no or trivial mitral regurgitation. Eight patients (53.3%) underwent redo valve replacement within 12 years. Except 1 late death, the postoperative course was divided into 3 groups depending on the occurrence of redo surgery, as follows: an early reoperation group (reoperation within 4 years; n = 4), a late reoperation group (reoperation after 4 years; n = 4), and a free from reoperation group (n = 6). The latest transthoracic echocardiographic examination performed 7.2 ± 2.9 years after the operation revealed the grade of mitral regurgitation to be none in 2 patients, mild in 2 patients, mild to moderate in 1 patients, and moderate in 1 patient in the free from reoperation group., Conclusions: Despite the high incidence of reoperation, Normo operation can be a viable option during valve replacement, especially for young patients., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing 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).)

Fish swimming has attracted attention as a locomotion system with excellent propulsive efficiency. They swim by moving their body, fins, and other organs simultaneously, which developed during evolution. Among their many organs, the pectoral fin plays a crucial role in swimming, such as forward-backward movement and change of direction. In order to investigate the hydrodynamic interaction between pectoral fins and fish bodies, we examined the asymmetric flapping motion of the pectoral fin concerning the body axis and investigated the effect of the pectoral fin on the propulsive performance of the body of a small swimming object by numerical simulation. In this study, the amplitude ratio, frequency ratio, and phase of the body and pectoral fin varied. Therefore, although propulsive performance increased in tandem with the frequency ratio, the amplitude ratio change had negatively affected the propulsive performance. The results revealed that the propulsive performance of the fish was high even in low-frequency ratios when the phase difference was varied. The highest propulsion efficiency increased by a factor of about 3.7 compared to the phase difference condition of 0.

Aims: Continuous local antibiotic perfusion (CLAP) has recently attracted attention as a new drug delivery system for orthopaedic infections. CLAP is a direct continuous infusion of high-concentration gentamicin (1,200 μg/ml) into the bone marrow. As it is a new system, its influence on the bone marrow is unknown. This study aimed to examine the effects of high-concentration antibiotics on human bone tissue-derived cells., Methods: Cells were isolated from the bone tissue grafts collected from six patients using the Reamer-Irrigator-Aspirator system, and exposed to different gentamicin concentrations. Live cells rate, apoptosis rate, alkaline phosphatase (ALP) activity, expression of osteoblast-related genes, mineralization potential, and restoration of cell viability and ALP activity were examined by in vitro studies., Results: The live cells rate (the ratio of total number of cells in the well plate to the absorbance-measured number of live cells) was significantly decreased at ≥ 500 μg/ml of gentamicin on day 14; apoptosis rate was significantly increased at ≥ 750 μg/ml, and ALP activity was significantly decreased at ≥ 750 μg/ml. Real-time reverse transcription-polymerase chain reaction results showed no significant decrease in the ALP and activating transcription factor 4 transcript levels at ≥ 1,000 μg/ml on day 7. Mineralization potential was significantly decreased at all concentrations. Restoration of cell viability was significantly decreased at 750 and 1,000 μg/ml on day 21 and at 500 μg/ml on day 28, and ALP activity was significantly decreased at 500 μg/ml on day 28., Conclusion: Our findings suggest that the exposure concentration and duration of antibiotic administration during CLAP could affect cell functions. However, further in vivo studies are needed to determine the optimal dose in a clinical setting., Competing Interests: A. Maruo reports royalties from Total Medical Supply Company (Japan) and consulting fees from Cubex Medical Company (Japan), which are unrelated to this study., (© 2024 Oe et al.)

This report examines delayed leukoencephalopathy as a postoperative complication after the use of flow diverter (FD) devices for endovascular cerebral aneurysm treatment. A case involving a 78-year-old female treated with a pipeline embolization device for a left internal carotid artery aneurysm is presented. Despite adherence to dual anti-platelet therapy, the patient developed intermittent headaches and memory issues 3 months post-operation. MRI revealed T1-enhancing foci and T2 hyperintense signal abnormalities in the left cerebral hemisphere, without new ischemic lesions, indicating potential embolic events or foreign body reactions. Following aphasia, a change from clopidogrel to prasugrel and the initiation of steroid pulse therapy led to the resolution of symptoms and MRI abnormalities over 6 months. This case underscores the reversibility of delayed leukoencephalopathy with appropriate intervention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aims: Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) is useful for patients with biliary cannulation failure or inaccessible papillae. However, it can lead to serious complications such as bile peritonitis in patients with ascites; therefore, development of a safe method to perform EUS-HGS is important. Herein, we evaluated the safety of EUS-HGS with continuous ascitic fluid drainage in patients with ascites., Methods: Patients with moderate or severe ascites who underwent continuous ascites drainage, which was initiated before EUS-HGS and terminated after the procedure at our institution between April 2015 and December 2022, were included in the study. We evaluated the technical and clinical success rates, EUS-HGS-related complications, and feasibility of re-intervention., Results: Ten patients underwent continuous ascites drainage, which was initiated before EUS-HGS and terminated after completion of the procedure. Median duration of ascites drainage before and after EUS-HGS was 2 and 4 days, respectively. Technical success with EUS-HGS was achieved in all 10 patients (100%). Clinical success with EUS-HGS was achieved in 9 of the 10 patients (90 %). No endoscopic complications such as bile peritonitis were observed., Conclusion: In patients with ascites, continuous ascites drainage, which is initiated before EUS-HGS and terminated after completion of the procedure, may prevent complications and allow safe performance of EUS-HGS.

Objective Adverse events such as bile leakage and bleeding are among the issues that need to be resolved in EUS-guided choledochoduodenostomy (EUS-CDS). To overcome this problem, we developed a new EUS-CDS technique using a 19-G Franseen needle without tract dilation. This study aimed to evaluate the safety and efficacy of the new EUS-CDS technique. Methods This single-center retrospective study included 20 consecutive patients who underwent EUS-CDS for primary drainage using a 19-G Franseen needle between March 2020 and May 2023. The primary endpoint was the technical success rate of EUS-CDS without tract dilation. Results The technical success rate of EUS-CDS was 20/20 (100%). None of the patients required any additional tract dilation, such as by using a balloon or electric cautery. The median procedure time was 7.8 (range, 3.2-19.4) min. No early adverse events were observed. Conclusion The 19-G Franseen needle appeared to have a sufficient dilatory effect during puncturing. This EUS-CDS technique appears to be safe and effective and has the advantages of no adverse events and it is also a simplified procedure, which suggests its potential for widespread use in primary drainage.

Background: Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL)., Methods: This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis., Results: Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year., Conclusions: We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID., Trial Registration Number: The study protocol is registered at UMIN clinical trials registry (UMIN000042299)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)