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Background and Aims: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps., Methods: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC., Results: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC., Conclusions: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis., (© 2024 John Wiley & Sons Ltd.)

We used a mathematical approach to investigate the quantitative spatial profile of cancer cells and stroma in lung squamous cell carcinoma tissues and its clinical relevance. The study enrolled 132 patients with 3-5 cm peripheral lung squamous cell carcinoma, resected at the National Cancer Center Hospital East. We utilized machine learning to segment cancer cells and stroma on cytokeratin AE1/3 immunohistochemistry images. Subsequently, a spatial form of Shannon's entropy was employed to precisely quantify the spatial distribution of cancer cells and stroma. This quantification index was defined as the spatial tumor-stroma distribution index (STSDI). The patients were classified as STSDI-low and -high groups for clinicopathological comparison. The STSDI showed no significant association with baseline clinicopathological features, including sex, age, pathological stage, and lymphovascular invasion. However, the STSDI-low group had significantly shorter recurrence-free survival (5-years RFS: 49.5% vs. 76.2%, p < 0.001) and disease-specific survival (5-years DSS: 53.6% vs. 81.5%, p < 0.001) than the STSDI-high group. In contrast, the application of Shannon's entropy without spatial consideration showed no correlation with patient outcomes. Moreover, low STSDI was an independent unfavorable predictor of tumor recurrence and disease-specific death (RFS; HR = 2.668, p < 0.005; DSS; HR = 3.057, p < 0.005), alongside the pathological stage. Further analysis showed a correlation between low STSDI and destructive growth patterns of cancer cells within tumors, potentially explaining the aggressive nature of STSDI-low tumors. In this study, we presented a novel approach for histological analysis of cancer tissues that revealed the prognostic significance of spatial tumor-stroma distribution in lung squamous cell carcinoma., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Gremlin 1 (GREM1) is an antagonist of bone morphogenetic protein (BMP). GREM1 is expressed in the stromal cells of various carcinomas and promotes tumor progression by suppressing BMP signaling. We designed this study to establish an evaluation strategy for GREM1 expression, focusing on the tumor stroma, and to examine its clinicopathological significance in gastric cancer (GC) progression. We employed RNA in situ hybridization (ISH) to evaluate the prognostic value of GREM1 expression in a cohort of 104 surgically resected GC cases and assessed ISH scores according to previous reports. GREM1 expression was observed in tumor stromal cells, including fibroblasts. We defined GREM1-positive cells as those expressing ISH score ≥ 3 and quantified the number of GREM1-positive cells using image analysis software. We examined the relationship between the number of GREM1-positive cells in the tumor stroma and clinicopathological features. The number of GREM1-positive cells per tumor stroma ranged from 0 to 714.7 cells/mm 2 (median, 1.65 cells/mm 2 ). We divided the 104 GC cases into GREM1-High and GREM1-Low expression groups based on the abovementioned median value. GREM1-High expression group was significantly associated with a more advanced pT grade, pN grade, lymphatic invasion, and venous invasion. Kaplan-Meier analysis showed significantly poorer survival in the GREM1-High expression group than in the GREM1-Low expression group. These results indicated that GREM1 expression in GC is localized in tumor stromal cells, and that high GREM1 expression in the tumor stroma could be a poor prognostic factor., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking., Objectives: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab., Patients and Methods: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge., Conclusion: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Researchers have attempted to identify the factors involved in lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma (SCC). However, studies combining histopathological and clinicopathological information in prediction models are limited. We aimed to develop a highly accurate lymph node recurrence prediction model for clinical stage T1-2, N0 (cT1-2N0) tongue SCC by integrating histopathological artificial intelligence (AI) with clinicopathological information. A dataset from 148 patients with cT1-2N0 tongue SCC was divided into training and test sets. The prediction models were constructed using AI-extracted information from whole slide images (WSIs), human-assessed clinicopathological information, and both combined. Weakly supervised learning and machine learning algorithms were used for WSIs and clinicopathological information, respectively. The combination model utilised both algorithms. Highly predictive patches from the model were analysed for histopathological features. In the test set, the areas under the receiver operating characteristic (ROC) curve for the model using WSI, clinicopathological information, and both combined were 0.826, 0.835, and 0.991, respectively. The highest area under the ROC curve was achieved with the model combining WSI and clinicopathological factors. Histopathological feature analysis showed that highly predicted patches extracted from recurrence cases exhibited significantly more tumour cells, inflammatory cells, and muscle content compared with non-recurrence cases. Moreover, patches with mixed inflammatory cells, tumour cells, and muscle were significantly more prevalent in recurrence versus non-recurrence cases. The model integrating AI-extracted histopathological and human-assessed clinicopathological information demonstrated high accuracy in predicting lymph node recurrence in patients with cT1-2N0 tongue SCC., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Objectives: In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD., Methods: CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured., Results: CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044)., Discussion: The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.

Purpose: The purpose of the study was to evaluate the efficacy and safety of pre-emptive transcatheter arterial embolization (P-TAE) of aortic side branches to prevent type II endoleak in patients with abdominal aortic aneurysm after endovascular abdominal aneurysm repair (EVAR)., Materials and Methods: This multicenter, prospective, single-arm trial enrolled 100 patients with abdominal aortic aneurysm from nine hospitals between 2018 and 2021. There were 85 men and 15 women, with a mean age of 79.6 ± 6.0 (standard deviation) years (range: 65-97 years). P-TAE was attempted for patent aortic side branches, including the inferior mesenteric artery, lumbar arteries, and other branches. The primary endpoint was late type II endoleak incidence at 6 months post-repair. Secondary endpoints included changes in aneurysmal sac diameter at 6- and 12 months, complications, re-intervention, and aneurysm-related mortality. Aneurysm sac changes at 6- and 12 months was compared between the late and no-late type II endoleak groups., Results: Coil embolization was successful in 80.9% (321/397) of patent aortic side branches, including 86.3% of the inferior mesenteric arteries, 80.3% of lumbar arteries, and 55.6% of other branches without severe adverse events. Late type II endoleak incidence at 6 months was 8.9% (8/90; 95% confidence interval: 3.9-16.8%). Aneurysm sac shrinkage > 5 mm was observed in 41.1% (37/90) and 55.3% (47/85) of the patients at 6- and 12-months post-EVAR, respectively. Patients with late type II endoleak had less aneurysm sac shrinkage than those without type II endoleak at 12 months (-0.2 mm vs. -6.0 mm; P = 0.040). No patients required re-intervention for type II endoleak, and no aneurysm-related mortalities occurred., Conclusion: P-TAE is safe and effective in preventing type II endoleak, leading to early sac shrinkage at 12 months following EVAR., Competing Interests: Declaration of competing interests The authors declare no actual or potential conflict of interest related to this study., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

International travel is a risk factor for acquiring sexually transmitted infections (STIs) owing to factors such as increased sexual opportunities, a sense of freedom, and the allure of the sex industry. We investigated the incidence of travel-associated STIs in Japan using data from the Japan Registry for Infectious Diseases from Abroad (J-RIDA) reported by 17 participating medical institutions between October 2017 and December 2022. Data were collected on the patients' age, sex, nationality, chief complaint, whether they had visited a travel clinic before travel, travel history, and final diagnosis. Of 4545 cases of travel-associated illness reported, 52 (1.1%) were STIs. Most patients with STIs were male (81%) with a median age of 31 years. HIV (17%), genital herpes (13%), syphilis (13%), and gonorrhea (12%) were the most frequently reported STIs. Only one patient had visited a travel clinic before travel. Promoting awareness and vaccination is crucial for preventing travel-associated STIs., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

Histopathologic examinations of primary central nervous system lymphoma (PCNSL) reveal concentric accumulation of lymphocytes in the perivascular area with fibrosis. However, the nature of this fibrosis in "stiff" PCNSL remains unclear. We have encountered some PCNSLs with hard masses as surgical findings. This study investigated the dense fibrous status and tumor microenvironment of PCNSLs with or without stiffness. We evaluated by silver-impregnation nine PCNSLs with stiffness and 26 PCNSLs without stiffness. Six of the nine stiff PCNSLs showed pathological features of prominent fibrosis characterized by aggregation of reticulin fibers, and collagen accumulations. Alpha-smooth muscle actin (αSMA)-positive spindle cells as a cancer-associated fibroblast, the populations of T lymphocytes, and macrophages were compared between fibrous and control PCNSLs. Fibrous PCNSLs included abundant αSMA-positive cells in both intra- and extra-tumor environments (5/6, 87% and 3/6, 50%, respectively). Conversely, only one out of the seven control PCNSL contained αSMA-positive cells in the intra-tumoral area. Furthermore, the presence of extra-tumoral αSMA-positive cells was associated with infiltration of T lymphocytes and macrophages. In conclusion, recognizing the presence of dense fibrosis in PCNSL can provide insights into the tumor microenvironment. These results may help stratify patients with PCNSL and improve immunotherapies for these patients., (© 2024. The Author(s).)

Purpose: We investigated whether peripheral pulse synchronization (PPUS) can be an alternate method for electrocardiographic synchronization (ECGS) in measuring myocardial T1 values in cardiac magnetic resonance imaging (CMRI)., Methods: T1 map imaging was performed on 49 patients undergoing CMRI using the 5s (3s) 3s modified Look-Locker inversion recovery (MOLLI) method for both ECGS and PPUS. The short-axis images of basal, mid, and apical segments were obtained. The T1 map images were analyzed using an image processing system, and T1 values were obtained for each cardiac segment. To assess the degree of agreement between T1 values obtained from ECGS and PPUS, the Bland-Altman analysis and the estimating intraclass correlation coefficient (ICC) were performed for the average T1 value of the entire myocardium and T1 values of each cardiac segment. Also, to evaluate whether PPUS imaging is possible in the diastole phase, we measured the length of systole in the electrocardiogram and the length of transmission (R-R') from R in the electrocardiogram to R (R') in the pulse waveform., Results: From the comparison of T1 values, a good agreement of ICC was confirmed between the ECGS and PPUS (whole myocardium: 0.97, apical: 0.93, mid: 0.98, and basal: 0.97). The results of the Bland-Altman analysis also indicated good agreement. Moreover, it was shown that the heart was imaged in the diastole phase even with the default scan parameters of PPUS., Conclusion: Our results indicated that PPUS can be an alternate method for ECGS.

BACKGROUND The spring-and-loop with clip (S-O clip) consists of a spring and a nylon loop located on one side of the claws of the clip, and is used in gastric endoscopic submucosal dissection (ESD) to allow countertraction. This retrospective study included 290 patients with early gastric neoplasms (eGNs) and aimed to compare postoperative outcomes of ESD with and without the use of the S-O clip. MATERIAL AND METHODS We retrospectively reviewed the data of 347 patients with eGN who underwent ESD, with or without an S-O clip, at our institution between April 1, 2017 and March 31, 2023. Overall, 290 patients were analyzed after excluding ineligible participants. The control group (n=149; adenoma: 1, carcinoma: 148) underwent ESD without an S-O clip between April 2017 and March 2020, while the S-O group (n=141; adenoma: 4, carcinoma: 137) used the clip between April 2020 and March 2023. Primary outcomes included procedure time, en bloc resection rate, and complete resection rate. Subgroup analysis for examined procedure time concerning endoscopist expertise, submucosal fibrosis, and neoplasm locations. RESULTS The S-O group had a shorter procedure time (44.4±23.9 vs 61.1±40.9 min, P<0.001) and a higher complete resection rate (97.9% vs 92.6%, P<0.05) than the control group. Subgroup analysis revealed that the S-O clip significantly reduced procedure time for trainees compared to the control group (40.8±18.3 vs 61.1±35.6 min, P<0.05). CONCLUSIONS The scheduled use of S-O clips in gastric ESD is effective in improving procedural time and complete resection rates, benefiting endoscopists across all experience levels.

Crystallization in Earth's deep magma ocean could have caused trace element fractionation in the lower mantle that might be inherited to the isotopic compositions of the present-day mantle. However, the trace element partitioning has been experimentally investigated only up to the uppermost lower-mantle pressures. Here, we determined the bridgmanite/melt partition coefficients D of La, Nd, Sm, Lu, and Hf from 24 to 115 gigapascals, covering the wide pressure range of the lower mantle. Results demonstrate substantial reductions in D Lu and D Hf from >1 to ≪1 with increasing pressure to 91 gigapascals. We also found D Lu / D Hf > 1 and D Sm / D Nd < 1 under deep lower-mantle conditions, evolving melts toward low Lu/Hf and high Sm/Nd ratios by crystallizing bridgmanite. If residual melts form a dense hidden reservoir in the lowermost mantle, the complementary accessible mantle has the Hf and Nd isotopic compositions matching the observed terrestrial mantle array that deviates from the bulk silicate Earth reference.

Introduction: This case report presents the successful detection of an EGFR exon 19 deletion using virtual bronchoscopic navigation (VBN) and endobronchial ultrasound with guide sheath (EBUS-GS) brushing, integrated with highly sensitive next-generation sequencing (NGS), even in challenging biopsy scenarios. The growing prevalence of driver gene alterations in non-small cell lung cancer necessitates effective bronchoscopic technology and reliable multiplex gene NGS panels. However, data regarding the optimal bronchoscopic techniques when using highly sensitive NGS panels are limited. Herein, we report a case utilizing VBN-guided EBUS-GS brushing as an exploratory approach to address this challenge., Case Presentation: A 71-year-old man was evaluated for a band-like lesion near the left pleura during spinal cord infarction. Transbronchial specimens were obtained from lesions invisible on conventional chest radiography and X-ray fluoroscopy using VBN and EBUS-GS brushing. Cytological brushing specimens revealed lung adenocarcinoma, and highly sensitive NGS identified an EGFR exon 19 deletion. He was diagnosed with stage IB disease and underwent radical radiotherapy owing to his fragile condition. If recurrence occurs, the patient will be treated with an EGFR inhibitor., Conclusion: VBN-guided EBUS-GS brushing, a minimally invasive approach, combined with highly sensitive NGS has the potential to provide accurate molecular diagnoses to more patients with lung cancer, thereby offering opportunities for personalized treatment. Our findings warrant further investigation to determine optimal bronchoscopic technologies for obtaining tumor specimens., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

We report a case of cholangitis, an immune-related adverse event (irAE), caused by the administration of nivolumab in a patient with lung metastasis of oral cancer. A 72-year-old man developed pulmonary metastasis after surgery for oral cancer. Hepatic enzyme abnormalities were observed after the second session of treatment, and irAE cholangitis was diagnosed based on the results of the blood test results and endoscopy findings. We suggested steroid treatment, but the patient refused it. Therefore, he was treated with ursodeoxycholic acid. The cholangitis gradually deteriorated, the patients' general condition worsened, and he died 169 days after the onset of cholangitis., (© The Association of Oral and Maxillofacial Surgeons of India 2023.)

Introduction: The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes., Methods: The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n = 296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis., Results: Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204 +TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204 +TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2., Conclusion: The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Nomura has received honoraria from Nipponrinshosha Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., CHUGAI PHARMACEUTICAL CO.,LTD., and Takeda Pharmaceutical Company Limited, Dr. Samejima has received honoraria from Johnson & Johnson, TAIHO PHARMACEUTICAL CO., LTD., Shizenkagakusha, B. Braun Melsungen AG, Stryker JapanK.K., Olympus Corporation, MiRXES, Shinoharasyuppansha, ishiyakusyuoppansha, nihonketuekiseizaikikou, and Ziosoft. Dr. Aokage has received honoraria from Johnson & Johnson, CHUGAI PHARMACEUTICAL CO.,LTD., AstraZeneca plc, COVIDIEN JAPAN INC., Kyowa Kirin Co.,Ltd., and CSL Behring K.K. Dr. Tsuboi has received honoraria from Johnson & Johnson, CHUGAI PHARMACEUTICAL CO.,LTD., AstraZeneca plc, COVIDIEN JAPAN INC., MSD, Novartis Pharma K.K., Bristol Myers Squibb, ONO PHARMACEUTICAL CO., LTD., and Eli Lilly Japan K.K. Dr. Ishii has received grants from DAIICHI SANKYO, INC., ONO PHARMACEUTICAL CO.,LTD., Noile-Immune Biotech, Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co.,Ltd., Indivumed GmbH, H.U. Group Research Institute, and Nihon Medi-Physics Co.,Ltd., and consulting fees from Takeda Pharmaceutical Company Limited, and honoraria from Roche Diagnostics K.K., CHUGAI PHARMACEUTICAL CO., LTD.,Novartis Pharma K.K., Eli Lilly Japan K.K., AstraZeneca., RIKEN GENESIS CO., LTD., Merck Biopharma Japan., and Takeda Pharmaceutical Company Limited. The remaining authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A 53-year-old woman with a history of recurrent right lower quadrant pain presented with slightly bloody stools in April 2023. She was initially diagnosed with acute diverticulitis using an abdominal computed tomography (CT) scan and was treated conservatively. On the second day, however, she reported significant hematochezia. A subsequent contrast-enhanced CT scan revealed an extravasation in the ascending colon, which was promptly managed with colonoscopy. Despite initial hemostasis, she experienced recurrent bleeding. Another contrast-enhanced CT scan revealed a pseudoaneurysm with ongoing extravasation in the same area. Angiography confirmed a pseudoaneurysm in a branch of the ileocolic artery, which was successfully treated by embolization. She was discharged after an 18 day hospital stay. This case highlights a pseudoaneurysm caused by diverticulitis., (© 2024. Japanese Society of Gastroenterology.)

Background: Endoscopic retrograde cholangiography (ERC)-related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC-related procedures and sarcopenia/skeletal muscle mass loss., Methods: Patients with BTC who underwent radical surgical resection following ERC-related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre-ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated., Results: The study cohort included 90 patients with a median age of 72 (interquartile range, 65-75) years. The median PMI pre-ERC and surgery was 4.40 and 4.15 cm 2 /m 2 , respectively (p < .01). The median ΔPMI was -6.2% (interquartile range, -10.9% to 0.5%). By multivariate analysis, post-ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively)., Conclusions: Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post-ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Background and Objective: The identification of factors associated with long-term prognosis after community-onset pneumonia in elderly patients should be considered when initiating advance care planning (ACP). We aimed to identify these factors and develop a prediction score model., Methods: Patients aged 65 years and older, who were hospitalized for pneumonia at nine collaborating institutions, were included. The prognosis of patients 180 days after the completion of antimicrobial treatment for pneumonia was prospectively collected., Results: The total number of analysable cases was 399, excluding 7 outliers and 42 cases with missing data or unknown prognosis. These cases were randomly divided in an 8:2 ratio for score development and testing. The median age was 82 years, and there were 68 (17%) deaths. A multivariate analysis showed that significant factors were performance status (PS) ≥2 (Odds ratio [OR], 11.78), hypoalbuminemia ≤2.5 g/dL (OR, 5.28) and dementia (OR, 3.15), while age and detection of antimicrobial-resistant bacteria were not associated with prognosis. A scoring model was then developed with PS ≥2, Alb ≤2.5, and dementia providing scores of 2, 1 and 1 each, respectively, for a total of 4. The area under the curve was 0.8504, and the sensitivity and specificity were 94.6% and 61.7% at the cutoff of 2, respectively. In the test cases, the sensitivity and specificity were 91.7% and 63.1%, respectively, at a cutoff value of 2., Conclusion: Patients meeting this score should be considered near the end of life, and the initiation of ACP practices should be considered., (© 2024 Asian Pacific Society of Respirology.)

Tumor budding in the cancer stroma has been reported to be a prognostic factor in non-small cell lung cancer. Micronest in cancer stroma (MICS) is often observed as a formation that is larger and more conspicuous than budding, but its clinicopathologic significance is unclear. In this study, we aimed to examine the clinicopathological significance of MICS in lung squamous cell carcinoma (LSqCC). A total of 198 consecutive patients with pathologically diagnosed LSqCC (anyT N0-1M0) were enrolled in this study. MICS were defined as those that met the following criteria: (1) consisting of 5-200 tumor cells or less than 200 μm in diameter and (2) more than 200 μm away from the adjacent main lesion. The prognostic impact of the presence or absence of MICS and the characteristics of MICS-forming cancer cells were evaluated by immunohistochemistry (IHC). MICS was observed in 57 patients (28.8%), and overall survival (OS) and recurrence-free survival (RFS) were significantly shorter in the MICS-positive group (OS: 44.4% vs. 84.4%, p < 0.001; RFS: 30.0% vs. 82.6%, p < 0.001). Univariate and multivariate analyses revealed that the presence of MICS was an independent poor prognostic factor for OS (hazard ratio [HR] 3.54, p < 0.001) and RFS (HR 4.99, p < 0.001). Immunohistochemistry showed that the expression levels of the cell-cell adhesion molecule E-cadherin and hypoxia-induced protein GLUT-1 were significantly decreased in cancer cells forming MICS lesions compared to the tumor component excluding MICS within the same tumor (non-MICS lesions). Our data show that MICS is a distinct morphological feature with important biological and prognostic significance., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to the present study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cellular traction forces are contractile forces that depend on the material/substrate stiffness and play essential roles in sensing mechanical environments and regulating cell morphology and function. Traction forces are primarily generated by the actin cytoskeleton and transmitted to the substrate through focal adhesions. The cell nucleus is also believed to be involved in the regulation of this type of force; however, the role of the nucleus in cellular traction forces remains unclear. In this study, we explored the effects of nucleus-actin filament coupling on cellular traction forces in human dermal fibroblasts cultured on substrates with varying stiffness (5, 15, and 48 kPa). To investigate these effects, we transfected the cells with a dominant-negative Klarsicht/ANC-1/Syne homology (DN-KASH) protein that was designed to displace endogenous linker proteins and disrupt nucleus-actin cytoskeleton connections. The force that exists between the cytoskeleton and the nucleus (nuclear tension) was also evaluated with a fluorescence resonance energy transfer (FRET)-based tension sensor. We observed a biphasic change in cellular traction forces with a peak at 15 kPa, regardless of DN-KASH expression, that was inversely correlated with the nuclear tension. In addition, the relative magnitude and distribution of traction forces in nontreated wild-type cells were similar across different stiffness conditions, while DN-KASH-transfected cells exhibited a different distribution pattern that was impacted by the substrate stiffness. These results suggest that the nucleus-actin filament coupling play a homeostatic role by maintaining the relative magnitude of cellular traction forces in fibroblasts under different stiffness conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).

The direct conversion of CO2 in flue gas to value-added chemicals is a potentially important cost-effective solar-driven CO2 reduction technology. The present work demonstrates the solar-powered conversion of CO2 to CO with greater than 10% efficiency using a Mn complex cathode and an Fe-Ni anode in a single-compartment reactor without an ion exchange membrane in conjunction with a Si solar cell. Reactors separated by ion exchange membranes are typically used to prevent any effects of oxygen generated by the counter electrode. However, the present Mn complex catalyst maintained its activity even in the presence of 15% O2. Operando surface-enhanced Raman spectroscopy established that the present Mn catalyst preferentially reacted with CO2 without adsorbing O2. This unique characteristic enabled solar-driven CO2 reduction using a single-compartment reactor. In contrast, catalytic metals such as Ag tend to lose activity in such systems as a consequence of reaction with oxygen produced at the anode., (© 2024 Wiley‐VCH GmbH.)

Purpose: The causes of epidural catheter migration beneath the skin have not been previously investigated. We hypothesized that greater subcutaneous fat thickness might be associated with increased catheter migration beneath the skin., Methods: We conducted a retrospective cross-sectional study of patients who had undergone combined general and epidural anesthesia, selecting individuals who received thoracic and abdominal CT scans within the first 5 postoperative days. Needle depth was defined as the distance from the needle tip to the skin surface when the anesthesiologist determined that the needle tip had reached the epidural space. We measured the length of the epidural catheter from the skin surface to the epidural space (catheter length), and subcutaneous fat thickness (fat thickness) using CT imaging. Migration distance was calculated by subtracting needle depth from catheter length., Results: We analyzed 127 patients (72 males), all undergoing epidural catheter insertion in the left lateral decubitus position via a paramedian approach. The median age of the patients was 71 years. Epidural catheters were postoperatively found to substantially curve beneath the skin. Regression analysis revealed no significant influence of fat thickness on catheter length (regression coefficient 0.10, 95% confidence interval [CI]: - 0.17, 0.38). However, it indicated a positive correlation between fat thickness and needle depth (regression coefficient 0.50, 95% CI: 0.30, 0.70), and a negative correlation between fat thickness and migration distance (regression coefficient - 0.40, 95% CI: - 0.65, - 0.14)., Conclusion: We found a negative correlation between epidural catheter migration beneath the skin and subcutaneous fat thickness. Anesthesiologists should be aware of the possibility of substantial subcutaneous curving of the catheter, especially in patients with scant subcutaneous fat., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Aim: In autism spectrum disorder (ASD), abnormal sensory processing patterns are observed in various sensory modalities, including visual, auditory, touch, olfactory, taste, vestibular, and proprioceptive senses. Few studies have examined the relationship between sensory processing patterns and emotions, or their effects on daily life. We investigated the relationship between sensory processing patterns and emotional/behavioral problems in children with ASD., Participants and Methods: A retrospective chart review was conducted. Forty-three children with ASD (33 boys, 10 girls, median age 9 years) in the outpatient clinic of a psychiatric hospital participated; their parent (s) were invited to complete the Sensory Profile 2 (SP2) and the Child Behavior Checklist (CBCL) questionnaires. The participants' teachers were invited to complete the Teacher's Report Form (TRF)., Results: In the correlation analyses, each of the four quadrants of the SP2 (low registration, sensory seeking, hypersensitivity, and sensory avoiding) had significant positive correlations with different types of emotional and behavioral problems measured by the CBCL. Focusing on emotion, 'anxious/depressed' was correlated with low registration (r = 0.41) and sensory avoiding (r = 0.60), while 'withdrawal/depressed' was correlated with sensory avoiding (r = 0.46). Only one significant correlation was revealed between the SP2 and the TRF., Conclusion: Our results suggest a link between sensory processing patterns and emotional/behavioral problems. In school settings, the relationship between sensory processing patterns and emotional/behavioral problems may be easily overlooked.

Purpose: We investigated whether the quality of high-resolution computed tomography (CT) images of the temporal bone improves with deep learning reconstruction (DLR) compared with hybrid iterative reconstruction (HIR)., Methods: This retrospective study enrolled 36 patients (15 men, 21 women; age, 53.9 ± 19.5 years) who had undergone high-resolution CT of the temporal bone. Axial and coronal images were reconstructed using DLR, HIR, and filtered back projection (FBP). In qualitative image analyses, two radiologists independently compared the DLR and HIR images with FBP in terms of depiction of structures, image noise, and overall quality, using a 5-point scale (5 = better than FBP, 1 = poorer than FBP) to evaluate image quality. The other two radiologists placed regions of interest on the tympanic cavity and measured the standard deviation of CT attenuation (i.e., quantitative image noise). Scores from the qualitative and quantitative analyses of the DLR and HIR images were compared using, respectively, the Wilcoxon signed-rank test and the paired t-test., Results: Qualitative and quantitative image noise was significantly reduced in DLR images compared with HIR images (all comparisons, p ≤ 0.016). Depiction of the otic capsule, auditory ossicles, and tympanic membrane was significantly improved in DLR images compared with HIR images (both readers, p ≤ 0.003). Overall image quality was significantly superior in DLR images compared with HIR images (both readers, p < 0.001)., Conclusion: Compared with HIR, DLR provided significantly better-quality high-resolution CT images of the temporal bone., (© 2024. The Author(s).)

Background: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors., Objective: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting., Patients and Methods: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea)., Results: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival., Conclusions: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab., (© 2024. The Author(s).)

Background: Cryobiopsy use is anticipated to become more common in diagnosing lung diseases. In Japan, inserting a Fogarty catheter through a suction channel above the endotracheal tube's cuff for hemostasis is common practice. However, the rigid nature of the endotracheal tube poses challenges to tracheal intubation using a bronchoscope. The endotracheal tube cuff must be removed to prevent interference during Fogarty catheter insertion. To simplify the procedure and enhance safety, we devised and implemented a method of inserting a hemostatic Fogarty catheter with a suction tube externally attached to a softer endotracheal tube. This study aimed to evaluate the sustainability of this Fogarty catheter insertion method using suction tubes., Methods: The hemostatic Fogarty catheter insertion method was retrospectively validated. We compared outcomes between 60 patients who underwent the conventional method with a suction channel above the cuff and 50 patients who underwent the novel approach with an externally attached suction tube., Results: The physicians performing bronchoscopy and inserting the Fogarty catheter in the group in which the suction tube was externally attached for Fogarty catheter insertion had little experience. However, the overall bronchoscopy time was shorter; the two groups showed no significant differences in complications., Conclusion: Regarding cryobiopsy procedures, using an externally attached suction tube for Fogarty catheter insertion was practical and comparable to the conventional method of using a suction channel above the cuff. This method made the procedure more simple and safe., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Background: We quantified the pathological spatial intratumor heterogeneity of programmed death-ligand 1 (PD-L1) expression and investigated its relevance to patient outcomes in surgically resected non-small cell lung carcinoma (NSCLC)., Methods: This study enrolled 239 consecutive surgically resected NSCLC specimens of pathological stage IIA-IIIB. To characterize the spatial intratumor heterogeneity of PD-L1 expression in NSCLC tissues, we developed a mathematical model based on texture image analysis and determined the spatial heterogeneity index of PD-L1 for each tumor. The correlation between the spatial heterogeneity index of PD-L1 values and clinicopathological characteristics, including prognosis, was analyzed. Furthermore, an independent cohort of 70 cases was analyzed for model validation., Results: Clinicopathological analysis showed correlations between high spatial heterogeneity index of PD-L1 values and histological subtype (squamous cell carcinoma; P < .001) and vascular invasion (P = .004). Survival analysis revealed that patients with high spatial heterogeneity index of PD-L1 values presented a significantly worse recurrence-free rate than those with low spatial heterogeneity index of PD-L1 values (5-year recurrence-free survival [RFS] = 26.3% vs 47.1%, P < .005). The impact of spatial heterogeneity index of PD-L1 on cancer survival rates was verified through validation in an independent cohort. Additionally, high spatial heterogeneity index of PD-L1 values were associated with tumor recurrence in squamous cell carcinoma (5-year RFS = 29.2% vs 52.8%, P < .05) and adenocarcinoma (5-year RFS = 19.6% vs 43.0%, P < .01). Moreover, we demonstrated that a high spatial heterogeneity index of PD-L1 value was an independent risk factor for tumor recurrence., Conclusions: We presented an image analysis model to quantify the spatial intratumor heterogeneity of protein expression in tumor tissues. This model demonstrated that the spatial intratumor heterogeneity of PD-L1 expression in surgically resected NSCLC predicts poor patient outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: New nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We investigated clustering analyses to decipher the complex landscape of SLD pathologies including the former nomenclature of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: Japanese individuals who received annual health checkups including abdominal ultrasonography (n = 15 788, men/women: 10 250/5538, mean age: 49 years) were recruited., Results: The numbers of individuals with SLD, MASLD, MetALD, ALD, NAFLD, and MAFLD were 5603 (35.5%), 4227 (26.8%), 795 (5.0%), 324 (2.1%), 3982 (25.8%), and 4946 (31.3%), respectively. Clustering analyses using t-distributed stochastic neighbor embedding and K-means to visually represent interconnections in SLDs uncovered five cluster formations. MASLD and NAFLD mainly shared three clusters including (i) low alcohol intake with relatively low-grade obesity; (ii) obesity with dyslipidemia; and (iii) dysfunction of glucose metabolism. Both MetALD and ALD displayed one distinct cluster intertwined with alcohol consumption. MAFLD widely shared all of the five clusters. In machine learning-based analyses using algorithms of random forest and extreme gradient boosting and receiver operating characteristic curve analyses, fatty liver index (FLI), calculated by body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides, was selected as a useful feature for SLDs., Conclusions: The new nomenclature of SLDs is useful for obtaining a better understanding of liver pathologies and for providing valuable insights into predictive factors and the dynamic interplay of diseases. FLI may be a noninvasive predictive marker for detection of SLDs., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion., Methods: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas., Results: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K + channel inhibitors and prostaglandin D 2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels., Conclusions: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K + channels to dilate the nasal mucosal vasculature., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: There are limited data regarding whether anemia is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI)., Methods: Patients with AF undergoing PCI at 15 institutions between January 2015 and March 2021 were included in this analysis. Based on the baseline hemoglobin levels, moderate to severe anemia was defined as hemoglobin levels <11 g/dL, and mild anemia was defined as hemoglobin levels 11-12.9 g/dL for men and 11-11.9 g/dL for women. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, stent thrombosis, and stroke) and major bleeding events (BARC 3 or 5), were compared among patients with moderate/severe anemia, mild anemia, and no anemia., Results: In a total of 746 enrolled patients, 119 (16.0%) and 168 (22.5%) patients presented with moderate/severe and mild anemia. The incidence of MACE (22.5%, 11.0%, and 9.1%, log-rank p < 0.001), all-cause death (20.0%, 7.2%, and 4.8%, log-rank p < 0.001), and major bleeding events (10.7%, 6.5%, and 2.7%, log-rank p < 0.001) were the highest in the moderate/severe anemia group compared with the mild and no anemia groups. Multivariable Cox regression analyses determined moderate/severe anemia as an independent predictor for MACE (p = 0.008), all-cause death (p = 0.005), and major bleeding events (p = 0.031) at 1 year after PCI., Conclusion: Moderate/severe anemia was significantly associated with the higher incidence of MACE and all-cause death as well as major bleeding events compared with mild and no anemia in AF patients undergoing PCI., Competing Interests: Declaration of competing interest All authors report no conflict of interest related to this study., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear., Case Presentation: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy., Conclusion: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment., (© 2024 S. Karger AG, Basel.)

We report a case of an 87 year-old woman who was admitted with jaundice, but had no pain or fever. Contrast-enhanced computed tomography revealed a tumor in the head of the pancreas, which caused distal malignant biliary obstruction. Initial transpupillary drainage by endoscopic retrograde cholangiopancreatography (ERCP) was difficult due to severe biliary stricture caused by the tumor, but cannulation of the pancreatic duct was successful. Pancreatic ductal adenocarcinoma was revealed through cytologic examination of pancreatic juice and the patient underwent percutaneous transhepatic biliary drainage (PTBD). 16 days after the jaundice was resolved, an uncovered Zilver® metallic stent was successfully deployed using a guidewire from the PTBD route, and the patient was discharged with palliative care due to advanced age. However, 54 days after discharge, the patient presented with black vomiting and recurrent jaundice. ERCP revealed an obstructed stent with black debris, and further evaluation revealed a ruptured pseudoaneurysm that branched off the gastroduodenal artery within the metallic biliary stent. Angiography revealed that embolization was successful. The patient recovered and was discharged without further episodes., (© 2024. Japanese Society of Gastroenterology.)

Due to fungal diseases that threaten immunocompromised patients, along with the limited availability of antifungal agents, there is an urgent need for new antifungal compounds to treat fungal infections. Here, we aimed to identify potential antifungal drugs from natural products using the fission yeast Schizosaccharomyces pombe as a model organism since it shares many features with some pathogenic fungi. Here, we identified tubeimoside I (TBMS1), an extract from Chinese herbal medicine, that showed strong antifungal activity against S. pombe . To gain insight into the underlying mechanism, we performed transcriptomics analyses of S. pombe cells exposed to TBMS1. A significant proportion of the differential expressed genes were involved in cell wall organization or biogenesis. Additionally, TBMS1 treatment of S. pombe cells resulted in pleiotropic phenotypes, including increased sensitivity to β-glucanase, enhanced calcineurin activity, translocation of GFP-Prz1 to the nucleus, as well as enhanced dephosphorylation of Prz1, suggesting that TBMS1 disrupted cell wall integrity of S. pombe cells. Notably, calcofluor staining showed that abnormal deposits of cell wall materials were observed in the septum and cell wall of the TBMS1-treated cells, which were further corroborated by electron microscopy analysis. We also found that oxidative stress might be involved in the antifungal action of TBMS1. Moreover, we confirmed the antifungal activities of TBMS1 against several clinical isolates of pathogenic fungi. Collectively, our findings suggest that TBMS1, a novel antifungal compound, exerts its antifungal activity by targeting cell walls, which may pave the way for the development of a new class of antifungals., Importance: Fungal infections pose a serious threat to public health and have become an emerging crisis worldwide. The development of new antifungal agents is urgently needed. Here, we identified compound tubeimoside I (TBMS1) for the first time showing strong antifungal activity, and explored the underlying mechanisms of its antifungal action by using the model yeast Schizosaccharomyces pombe . Notably, we presented multiple evidence that TBMS1 exerts its antifungal activity through targeting fungal cell walls. Moreover, we verified the antifungal activities of TBMS1 against several pathogenic fungi. Our work indicated that TBMS1 may serve as a novel antifungal candidate, which provides an important foundation for designing and developing new cell wall-targeting agents for combating life-threatening fungal infections., Competing Interests: The authors declare no conflict of interest.

Background: There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events., Methods: We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy., Results: Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events., Conclusions: Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aim: There has been no report on a direct comparison between linked color imaging (LCI) and second-generation narrow-band imaging (2G-NBI) for surveillance of epithelial neoplasms in the upper gastrointestinal tract (UGIT). The aim of this study was to verify the superiority of LCI to 2G-NBI for surveillance esophagogastroduodenoscopy and to clarify how each endoscopic system should be used., Methods: This study was conducted as an open-label, two-arm-parallel (1:1), multicenter, randomized controlled trial at six institutions. Patients aged 20-85 years with a treatment history of epithelial neoplasms in the UGIT were recruited. Patients were assigned to a 2G-NBI group and an LCI group, and esophagogastroduodenoscopy was performed with primary image-enhanced endoscopy followed by white light imaging (WLI). The primary endpoint was the detection rate of one or more epithelial neoplasms in the primary image-enhanced endoscopy. A WLI-detected epithelial neoplasm was defined as a lesion that was detected in only WLI., Results: A total of 372 patients in the 2G-NBI group and 378 patients in the LCI group were analyzed. Epithelial neoplasms in the UGIT were detected by 2G-NBI in 18 patients (4.6%) and were detected by LCI in 20 patients (5.3%) (P = 0.87). WLI-detected epithelial neoplasms were in 11 patients in the 2G-NBI group (3.0%) and in 1 patient in the LCI group (0.27%) (P = 0.003)., Conclusions: Linked color imaging did not show superiority to 2G-NBI for the detection of epithelial neoplasms. Also, the percentage of WLI-detected epithelial neoplasms in primary NBI was significantly higher than that in primary LCI., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype., Methods: This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA)., Results: Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01)., Conclusions: The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effectiveness and safety of pre-emptive transcatheter arterial embolization (P-TAE) for aortic side branches (ASBs) to prevent Type 2 endoleaks (EL2) before endovascular aneurysm repair (EVAR) using the Excluder stent-graft system (Excluder)., Materials and Methods: In this prospective, multicenter study, 80 patients (mean age, 79.1 years [SD ± 6.7]; 85.0% were men; mean aneurysmal sac diameter, 48.4 mm [SD ± 7.4]) meeting the eligibility criteria were prospectively enrolled from 9 hospitals. Before EVAR, P-TAE was performed to embolize the patent ASBs originating from the abdominal aortic aneurysm. Contrast-enhanced computed tomography (CT) was performed at 1 month and 6 months after EVAR. The primary endpoint was EL2 incidence at 6 months, and the secondary endpoints were aneurysmal sac diameter changes at 6 and 12 months, P-TAE outcomes, adverse events related to P-TAE, reintervention, and aneurysm-related mortality., Results: All patients successfully underwent P-TAE without serious. Coil embolization was successful in 81.6% of ASBs. EL2 incidence at 6 months was identified in 18 of 70 (25.7%) patients. Aneurysmal sac diameter shrinkage (≥5 mm) was observed in 30.0% of patients at 6 months and in 40.9% at 12 months. Only 1 patient required reintervention for EL2 within 1 year of EVAR; aneurysm-related deaths were not observed., Conclusions: P-TAE for ASBs before EVAR using Excluder is a safe and effective strategy. It aids in achieving early aneurysmal sac shrinkage and reduces EL2 reintervention at 1 year after EVAR., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP., (© 2024. The Author(s).)

Aim: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use., Methods: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment., Results: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05)., Conclusion: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors., (© 2024 Japan Society of Hepatology.)

Purpose: To investigate the midterm stent patency and patient prognosis after stenting for superior mesenteric artery malperfusion complicating with acute aortic dissection., Material and Methods: Thirteen patients who underwent branch vessel stenting for superior mesenteric artery malperfusion between 2011 and 2021 in six institutions were retrospectively reviewed. By comparing pre- and postoperative computed tomography scans in the same plane, the length of the stent implanted in the superior mesenteric artery and the stent-to-vessel diameter ratio were measured. The technical and clinical success of stenting, midterm patient prognosis, and stent patency were evaluated., Results: Superior mesenteric artery stenting was technically successful in 12 patients (92.3%). The mean length of the stents implanted in the superior mesenteric artery was 61.3 ± 39.4 mm (range, 14-127 mm). The mean proximal and distal stent-to-vessel diameter ratios were 1.02 ± 0.16 and 1.30 ± 0.42, respectively. A weak correlation was found between the length of the stents implanted in the superior mesenteric artery and the distal stent-to-vessel diameter ratio (R 2 = 0.34). Two major complications occurred, one of which resulted in death within 30 days, and 12 (92.3%) were clinically successful. Of these 12 patients, no recurrent intestinal ischemia occurred during the follow-up duration (mean, 45.2 months). Partial occlusion of the stent distal edge without intestinal ischemia was observed in one patient (distal stent-to-vessel diameter ratio = 2.33) 42 months after stenting. The overall survival rate and primary stent patency rate were 84.6% and 91.7%, respectively., Conclusions: Midterm stent patency and survival after superior mesenteric artery stenting for malperfusion were acceptable., Competing Interests: None, (© 2024 Japanese Society of Interventional Radiology.)

Introduction: Histological outcome of the targeted focal therapy is in principle confirmed by targeted needle biopsy from the treated area in clinical trial. Herein, we report a rare case in which the MFT was followed by RARP., Case Presentation: A 68-year-old man with PSA 9.6 ng/mL and PI-RADS 4 lesion in the right transition zone on multi-parametric MRI underwent MR/ultrasound fusion-guided targeted biopsy, which revealed grade-group 1 cancer. Targeted focal therapy with microwave ablation was performed, resulting in disappearance of the PI-RADS 4 lesion at post-operative 4 months. However, PSA rose to 11.5 ng/mL, and a new PI-RADS 4 lesion, was identified in the left peripheral zone. RARP was performed to reveal new grade-group 3 cancer, and no viable cells in the previously treated area with MFT., Conclusion: RARP was safely performed even after MFT and proved the pathological complete response of microwave ablation., Competing Interests: The authors declare conflict of interest for Alfresa Pharma K.K. about support our clinical trial., (© 2024 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

The update of the draft genome assembly of sea urchin, Hemicentrotus pulcherrimus, which is widely studied in East Asia as a model organism of early development, was performed using Oxford nanopore long-read sequencing. The updated assembly provided ~600-Mb genome sequences divided into 2,163 contigs with N50 = 516 kb. BUSCO completeness score and transcriptome model mapping ratio (TMMR) of the present assembly were obtained as 96.5% and 77.8%, respectively. These results were more continuous with higher resolution than those by the previous version of H. pulcherrimus draft genome, HpulGenome&#95;v1, where the number of scaffolds = 16,251 with a total of ~100 Mb, N50 = 143 kb, BUSCO completeness score = 86.1%, and TMMR = 55.4%. The obtained genome contained 36,055 gene models that were consistent with those in other echinoderms. Additionally, two tandem repeat sequences of early histone gene locus containing 47 copies and 34 copies of all histone genes, and 185 of the homologous sequences of the interspecifically conserved region of the Ars insulator, ArsInsC, were obtained. These results provide further advance for genome-wide research of development, gene regulation, and intranuclear structural dynamics of multicellular organisms using H. pulcherrimus., (© 2024 The Authors. Development, Growth & Differentiation published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental Biologists.)

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Evidence regarding the association of the usage of biologic agents (Etanercept, Tocilizumab, adalimumab and so on), such as anti-tumor necrosis factor α, with the incidence and risk factors of non-tuberculous Mycobacteria (NTM) infection is limited. Therefore, this study aimed to investigate the incidence and risk factors of NTM and their associations with biologic agents' usage, and also investigated the potential of Mycobacterium avium complex (MAC) antibodies as a predictor of NTM infection development., Methods: This retrospective study included 672 patients with autoimmune diseases from four hospitals in Nagasaki, Japan, from January 1, 2011, to June 30, 2019, who fulfilled the inclusion criteria., Results: Of the 672 patients, 9 (1.3%) developed complicated NTM infection, including two with disseminated infection, after the introduction of biologic agents. Of the nine patients, two died due to NTM infection but none tested positive for MAC antibodies prior to initiation of biologic agents. The mortality rate was higher in patients complicated with NTM than without NTM (22.2% vs 2.6%, P = 0.024). The corticosteroids dosage at the time of initiating the biologic agents was significantly higher in the NTM group than in the non-NTM group (median, 17 mg vs 3 mg, P = 0.0038)., Conclusion: In the patients undergoing therapy with biologic agents, although NTM complication was rare, it could be fatal. In particular, for patients on a relatively high dose corticosteroids, careful observation is essential for identifying NTM complication, even if the MAC antibody test is negative., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment., Methods and Material: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests., Results: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis., Conclusion: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 38-year-old woman was admitted to our university hospital with loss of muscle strength. She was diagnosed with dermatomyositis and underwent contrast-enhanced computed tomography of the entire body to check for malignant tumors. Computed tomography revealed multiple enhanced hepatic nodules and an extrahepatic portosystemic shunt. Although a needle biopsy of the nodule could not diagnose definitive hepatocellular carcinoma, some nodules increased in size after three months. Because of the inconclusive results of the second biopsy, we performed shunt embolization using a vascular plug. After another three months, the hepatic nodules shrank markedly, as expected.

Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus ( Af293 ) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae , and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus , indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus . The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus . Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis., Importance: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA., Competing Interests: Y.T. is a co-inventor of JP2014-257451 (on the method for expanding γδ T cells using PTA) and JP2014-73475 (on the method for a nonradioactive cellular cytotoxicity assay). The other authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.