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Qingchun Zhao,1,* Song Xu,1,2,* Jinghao Liu,1 Ying Li,2 Yaguang Fan,2 Tao Shi,3 Sen Wei,1 Shou-Ching Tang,4,5 Hongyu Liu,2 Jun Chen1,2 1Department of Lung Cancer Surgery, 2Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, 3Department of Pathology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 4Division of Hematology and Oncology, Georgia Regents University Cancer Center, Augusta, GA, USA; 5Department of Surgery, Tianjin Tumor Hospital and Research Institute, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China *These authors contributed equally to this work Objective: The aim of this retrospective study was to investigate the relationship between thyroid transcription factor-1 (TTF-1) expression and epidermal growth factor receptor (EGFR) gene mutations in lung adenocarcinomas of Chinese patients. Methods: There were 200 lung adenocarcinoma patients who were enrolled in this study. Tumor specimens of these patients were investigated for TTF-1 expression and mutations in EGFR using immunohistochemistry and a liquid chip platform for DNA analysis of slides with sections of formalin-fixed, paraffin-embedded specimens. Results: The rates of TTF-1 expression and EGFR mutations were 81.5% and 45.5%, respectively, in the lung adenocarcinoma specimens of the recruited patients. Among female nonsmokers (n=72), 93.1% of specimens were positive for TTF-1 expression, and 63.9% had EGFR mutations. Of 89 patients with EGFR mutations, 83 (50.9%) specimens were simultaneously positive for TTF-1 expression. Kaplan–Meier analysis of all patient specimens found that postoperative survival time was not significantly associated with TTF-1 expression and the presence of EGFR mutations. However, patients with disease stages III–IV whose tumors were positive for TTF-1 expression and EGFR mutations had better postoperative survival than similar patients whose tumors were negative for TTF-1 expression and EGFR mutations. Conclusion: Our study showed a significant association between TTF-1 positivity and the presence of EGFR mutations (exon 21) in the Chinese lung adenocarcinoma patients. We further identify that patients with disease stages III–IV who were positive for TTF-1 expression and EGFR mutations had a better postoperative survival than those patients who were negative for TTF-1 expression and EGFR mutations. Therefore, TTF-1 might be a potential prognostic biomarker for stages III–IV lung adenocarcinoma patients. In clinical practice, TTF-1 expression may be a marker for planning therapy for certain patients with lung adenocarcinoma, especially for selection of EGFR tyrosine kinase inhibitors. Keywords: EGFR, lung adenocarcinoma, survival, TTF-1

Rui Ma,1 Songchao Tang,2 Honglue Tan,1 Wentao Lin,1 Yugang Wang,1 Jie Wei,2 Liming Zhao,2 Tingting Tang1 1Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 2Key Laboratory for Ultrafine Materials of Ministry of Education and The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, People’s Republic of China Abstract: A bioactive composite was prepared by incorporating 40 wt% nano-­hydroxyapatite (nHA) into polyetheretherketone (PEEK) through a process of compounding, injection, and molding. The mechanical and surface properties of the nHA/PEEK composite were characterized, and the in vitro osteoblast functions in the composite were investigated. The mechanical properties (elastic modulus and compressive strength) of the nHA/PEEK composite increased significantly, while the tensile strength decreased slightly as compared with PEEK. Further, the addition of nHA into PEEK increased the surface roughness and hydrophilicity of the nHA/PEEK composite. In cell tests, compared with PEEK and ultra-high-molecular-weight polyethylene, it was found that the nHA/PEEK composite could promote the functions of MC3T3-E1 cells, including cell attachment, spreading, proliferation, alkaline phosphatase activity, calcium nodule formation, and expression of osteogenic differentiation-related genes. Incorporation of nHA into PEEK greatly improved the bioperformance of PEEK. The nHA/PEEK composite might be a promising orthopedic implant material. Keywords: polyetheretherketone, nano-hydroxyapatite, biocomposite, osteoblast functions, orthopedic implant material

Marked increase in leptin concentration in spent peritoneal dialysate has been reported following continuous ambulatory peritoneal dialysis treatment. The present study was designed to determine whether functional leptin receptor is expressed by human peritoneal mesothelial cells and if so, the possible implication in dialysis. Expression of leptin receptors in cultured mesothelial cells and omental tissue was examined. The effect of leptin on the production of transforming growth factor-beta (TGF-beta) by mesothelial cells in the presence or absence of high glucose was determined using in vitro culture model of human peritoneal mesothelial cells and adipocytes. The signaling mechanism involved in leptin-induced TGF-beta synthesis by mesothelial cells was studied. Both mRNA and protein of the full-length leptin receptor are constitutively expressed in mesothelial cells. The leptin receptor expression in mesothelial cells was upregulated by glucose but not leptin. In adipocytes, glucose increased the mRNA expression and synthesis of leptin. The Janus kinase-signal transducers and activation (JAK-STAT) signal transduction pathway in mesothelial cells was activated by either exogenous or adipocytes-derived leptin. Exogenous leptin induced the release of TGF-beta by mesothelial cells. The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression. Our novel findings reveal that functional leptin receptor is present on human peritoneal mesothelial cells. The leptin-induced TGF-beta synthesis in mesothelial cells is associated with the expression of leptin receptor and the activation of the JAK-STAT signal transduction pathway. [ABSTRACT FROM AUTHOR]

Background: Few studies have quantitatively analyzed the imaging disparities between multiple sclerosis (MS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to compare the imaging characteristics of MS and CADASIL in middle-aged patients., Materials and Methods: This retrospective study used a single-center database and included patients aged 40-60 years with MS and CADASIL who underwent the designated imaging protocol including 3D T1-weighted imaging and fluid attenuated inversion recovery (FLAIR), diffusion tensor imaging and susceptibility-weighted imaging between January 2018 and March 2023. Patients with MRI-detected macrobleeds were excluded., Results: A total of 27 patients with MS (mean age, 46.7 years ± 4.4, 8 men) and 30 patients with CADASIL (mean age, 51.6 years ± 5.8, 14 men) were included. No significant differences were observed in the Fazekas grades of white matter lesions (WMLs). Patients with CADASIL exhibited greater external capsule involvement (56.7% vs.18.5 %; p = 0.006), whereas the MS group had more lesions in the corpus callosum (81.5% vs. 53.3 %, p = 0.02) and brainstem (74.1% vs. 46.7 %, p = 0.04). The CADASIL group exhibited a higher incidence of microbleeds (12.07 vs. 0.11, p = 0.001). The WMLs in the MS group exhibited a lower T1 lesion/cerebrospinal fluid signal index (2.206 vs. 2.882, p < 0.001). A value of ≤2.57 demonstrated a sensitivity of 92.6 % and a specificity of 90.0 % in differentiating MS. Patients with MS had a thinner corpus callosum (7.18 mm vs 7.86 mm, p = 0.04), while patients with CADASIL showed significantly higher mean diffusivity (0.8776 × 10 -3 vs. 0.7637 × 10 -3 mm2/s, p = 0.03) and lower fractional anisotropy (0.7581 vs. 0.8389, p = 0.04) in the splenium of the corpus callosum., Conclusion: Middle-aged patients with MS and CADASIL showed comparable Fazekas grades for WMLs. However, lesion distribution, T1 signal characteristics, and splenic diffusivity changes can help differentiate between MS and CADASIL., Competing Interests: Declaration of competing interest The authors have nothing to disclose. The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Atrial Fibrillation (AF) screening from face videos has become popular with the trend of telemedicine and telehealth in recent years. In this study, the largest facial image database for camera-based AF detection is proposed. There are 657 participants from two clinical sites and each of them is recorded for about 10 minutes of video data, which can be further processed as over 10 000 segments around 30 seconds, where the duration setting is referred to the guideline of AF diagnosis. It is also worth noting that, 2 979 segments are segment-wise labeled, that is, every rhythm is independently labeled with AF or not. Besides, all labels are confirmed by the cardiologist manually. Various environments, talking, facial expressions, and head movements are involved in data collection, which meets the situations in practical usage. Specific to camera-based AF screening, a novel CNN-based architecture equipped with an attention mechanism is proposed. It is capable of fusing heartbeat consistency, heart rate variability derived from remote photoplethysmography, and motion features simultaneously to reliable outputs. With the proposed model, the performance of intra-database evaluation comes up to 96.62% of sensitivity, 90.61% of specificity, and 0.96 of AUC. Furthermore, to check the capability of adaptation of the proposed method thoroughly, the cross-database evaluation is also conducted, and the performance also reaches about 90% on average with the AUCs being over 0.94 in both clinical sites.

Background: Fibrin and platelet (FP)-rich clots have been shown to be associated with cancer-related stroke. This study aims to investigate the prognostic role of thrombus composition in clinical outcomes among cancer patients who experienced stroke and received endovascular thrombectomy (EVT)., Methods: We included acute ischemic stroke patients who underwent EVT between March 2015 and November 2021. These patients were categorized into three groups: those with active cancer, those with non-active cancer, and those without cancer. The percentages of FP in clots were quantified under hematoxylin and eosin staining. The primary outcome was defined as any stroke recurrence or mortality within 90 days following the index stroke event., Results: A total of 420 patients with retrieved clots were included in the study. This cohort comprised 50 patients with active cancer, 23 patients with non-active cancer, and 347 patients without cancer. The percentage of FP was significantly higher in thrombi retrieved from patients with active cancer compared with the other two groups. Patients in the active cancer group exhibited a higher rate of the primary outcome compared with the other groups. After adjusting for clinical variables, a higher percentage of FP in thrombi remained significantly associated with the primary outcome in the active cancer group (adjusted odds ratio (aOR) =1.03 (1.00-1.06), P=0.028), but not in the other two groups., Conclusion: Among stroke patients receiving EVT, thrombi with a higher percentage of FP not only identify individuals with active cancer but also predict stroke recurrence or mortality within 90 days., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite recent findings indicating a paradoxical association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) mortality, the impact of HDL-C on subsequent outcomes after ischemic stroke remains unclear. The study aims to investigate the relationships between HDL-C levels and post-stroke functional outcomes while examining the potential modifying influence of HDL-C-related single nucleotide polymorphisms identified through genome-wide association studies. This cohort study included 1,310 patients diagnosed with acute ischemic stroke (AIS), all of whom had their admission serum lipid profile and genotyping information. Participants were categorized into four groups based on gender and HDL-C level. Prognostic outcomes were assessed using a modified Rankin Scale (mRS) at 1, 3, and 12 months post-admission. Multivariate logistic regression and restricted cubic spline regression analysis were used to assess the associations between HDL-C levels and outcomes. The mean age of patients was 61.17 ± 12.08 years, and 69.31% were men. After adjusting confounders, patients with the highest HDL-C level group had a significantly higher risk of poor functional outcomes at 1, 3, and 12 months following stroke compared to the reference group. Restricted cubic splines depicted a nonlinear association between HDL-C levels and poor prognosis in both men and women. The ABCA1 gene rs2575876 AA genotype combined with abnormal HDL-C levels exhibited a significantly heightened risk of post-stroke adverse outcomes at 1 and 3 months compared to patients with normal HDL-C levels and GG + GA genotype. These findings suggest that the combined effects of ABCA1 genetic variants with either low or high HDL-C levels could further heighten this risk., (© 2024. The Author(s).)

Background: Neurological deterioration within 24 h after intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with poor outcomes in patients with acute ischemic stroke (AIS). This study aimed to elucidate the features of neurological deterioration specifically during tPA infusion in these patients., Methods: We analyzed patients with AIS receiving thrombolysis between January 2018 and December 2021. Very early neurological deterioration (VEND) was defined as an increase of 4 or more points in the National Institutes of Health Stroke Scale (NIHSS) score during tPA infusion. Poor functional outcome was defined as a modified Rankin Scale score of 3-6 at three months., Results: Among the 345 patients with AIS who received tPA, 8.4% had VEND; all of which were caused by ischemic progression. Patients with VEND had a higher prevalence of intracranial atherosclerotic disease (41% vs. 17%, P = 0.005). VEND independently predicted poor functional outcome in both groups with minor (NIHSS score <6) and non-minor (NIHSS score >6) stroke. Among patients with minor stroke, those with VEND were more likely to undergo endovascular thrombectomy (EVT) than those without (38% vs. 5%, P = 0.019). In patients receiving EVT after VEND, the NIHSS scores at 24 h, which were correlated with 3-month functional outcome, were lower in those with successful recanalization than in those without (12 ± 9 vs. 26 ± 7, P = 0.047)., Conclusion: VEND predicted poor functional outcomes in patients with AIS. Timely and successful recanalization using EVT potentially alleviates the negative impact of VEND on long-term outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: Recurrent stroke after revascularization surgeries predicts poor outcome in patients with moyamoya disease (MMD). Early identification of patients with stroke risk paves the way for rescue intervention. This study aimed to investigate the role of ultrasound in identifying patients at risk of post-operative ischemic events (PIEs)., Methods: This prospective study enrolled patients with symptomatic MMD who underwent indirect revascularization surgeries. Ultrasound examinations were performed preoperatively and at 3 mo post-operatively to evaluate the hemodynamic changes in extracranial and intracranial arteries on the operated side. PIE was defined as ischemic stroke or transient ischemic attack in the operated hemisphere within 1 y. The areas under receiver operating characteristic curves were compared between models for prediction of PIE., Results: A total of 56 operated hemispheres from 36 patients (mean age, 23.0 ± 18.5 y) were enrolled in this study, and 27% developed PIE. In multivariate logistic regression models, PIE was associated with lower end-diastolic velocity and flow volume (FV) of the ipsilateral external carotid artery (ECA), and lower FV of ipsilateral superficial temporal artery and occipital artery at 3 mo post-operatively (all p < 0.05). Moreover, the post-operative FV of the ipsilateral ECA was the only one factor that significantly increased the areas under receiver operating characteristic curves from 0.727 to 0.932 when adding to a clinical-angiographic model for prediction of PIE (p = 0.017). This parameter was significantly lower in hemispheres with PIE, both in adult and pediatric patients., Conclusion: After indirect revascularization, surgeries in patients with symptomatic MMD, FV of ipsilateral ECA at 3 mo helps clinicians to identify patients at risk of PIE., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

KRAS gene mutations are common in pancreatic ductal adenocarcinoma (PDAC), but targeting mutant KRAS is still challenging. Here, an endoribonuclease-prepared small interfering RNA (esiRNA) library was used to screen new kinases that play critical roles in PDAC driven by KRAS gene mutations, and serine/threonine kinase 31 (STK31) was identified and characterized as a potential therapeutic target for KRAS-mutant PDAC. Our results showed that STK31 was upregulated in KRAS-mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRAS G12D mutation. Inhibition of STK31 in KRAS-mutant cell lines significantly reduced PDAC cell growth in vitro and hindered tumor growth in vivo. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. A pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c-Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. Through RNA sequencing, we found that the cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Taken together, our results indicate that STK31, which is the downstream target of the KRAS/MAPK/ERK/c-Jun signaling pathway in KRAS-mutant PDAC, promotes PDAC cell growth by modulating the expression of the cell cycle regulators CCNB1 and CDC25C., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment., (© 2024. The Author(s).)

In involuntary distance education, like during epidemics and wars, students often feel heightened learning anxiety, impacting outcomes. Despite innovative teaching methods, many face hurdles in distance learning. We want to propose specific strategies to solve learning difficulties in distance education., Aim: This study explored whether using digital concept maps (DCM) in physiology courses can reduce learning anxiety among nursing students., Design: The study was quasi-experimental, including a pre-and post-test control group., Methods: 71 nursing students aged 16-18 enrolled in a physiology course were recruited in the study. DCM was the intervention as a tool for in-person learning (first 12 weeks) and distant learning (final six weeks). Each student was required to complete the assignments independently to compare learning outcomes. Questionnaires were administered, and an assignment evaluation was completed before and after the course's different formats., Results: DCM using software using mobile vehicles (mobile, notebook, pad) is digital learning to help nursing students learn difficult subjects. DCM improved the students' learning motivation and effectiveness more in distance learning than in-person learning, decreasing learning anxiety in both face-to-face and distance learning., Conclusions: DCM promoted students' self-regulated learning and positively affected learning outcomes by increasing motivation and reducing stress. This study offers a tailored teaching framework for international settings to reduce student anxiety and improve learning effectiveness., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Ambulance-based telestroke may be a promising solution to improving stroke care. We assessed the technical feasibility and reliability of prehospital evaluations using commercial mobile phones with fifth-generation wireless communication technology., Methods: Six standardized patients portrayed scripted stroke scenarios during ambulance transport in an urban city and were remotely evaluated by independent raters using tablets (three neurologists and three emergency physicians) in a hospital, assisted by paramedics (trained in National Institute of Health Stroke Scale [NIHSS] assessment) in the ambulance; commercial cellular networks were utilized for videoconferencing transmission. The primary outcomes were mean difference (MD) and correlation of NIHSS scores between the face-to-face and remote assessments. We also examined the Bland-Altman plot for itemized NIHSS components, and Kaplan-Meier curves were used to compare the differences in the duration of the two evaluations between neurologists and emergency physicians., Results: We conducted 32 ambulance runs and successfully completed all NIHSS examinations. No significant difference was found between the face-to-face and remote evaluations (MD, 0.782; 95% confidence interval [CI], -0.520-0.395). The correlation of NIHSS scores between the two methods was 0.994 (95% CI, 0.945-1.026), and three items exhibited the highest frequency of runs, with score differences between the two methods. There were no significant differences between neurologists and emergency physicians in the mean evaluation duration and NIHSS scores for the two methods., Conclusion: Prehospital evaluation using commercial mobile phones with fifth-generation wireless communication technology is feasible and reliable during ambulance transport in urban areas. Emergency physicians and neurologists performed similarly in stroke evaluations., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated., Methods: From a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns., Results: Preoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both P < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers., Conclusions: AFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Wu, Lin, Chen, Luo, Li, Fu, Zheng, You, You, You, Lin, Zhou, Lin and Zeng.)

Background: The application of Pringle maneuver (PM) during hepatectomy reduces intraoperative blood loss and the need for perioperative transfusion, but its effect on long-term recurrence and survival for patients with hepatocellular carcinoma (HCC) remains controversial. We sought to determine the association between the application of PM and post-hepatectomy oncologic outcomes for patients with HCC., Methods: Patients who underwent curative hepatectomy for HCC at 9 Chinese hospitals from January 2010 to December 2018 were identified. Using two propensity score methods [propensity score matching (PSM) and inverse probability of treatment weight (IPTW)], cumulative recurrence rate and cancer-specific mortality (CSM) were compared between the patients in the PM and non-PM groups. Multivariate competing-risks regression models were performed to adjust for the effect of non-cancer-specific mortality and other prognostic risk factors., Results: Of the 2,798 included patients, 2,404 and 394 did and did not adopt PM (the PM and non-PM groups), respectively. The rates of intraoperative blood transfusion, postoperative 30-day mortality and morbidity were comparable between the two groups (all P>0.05). In the PSM cohort by the 1:3 ratio, compared to 382 patients in the non-PM group, 1,146 patients in the PM group also had the higher cumulative 5-year recurrence rate and CSM (63.9% and 39.1% vs. 55.3% and 31.6%, both P<0.05). Similar results were also yielded in the entire cohort and the IPTW cohort. Multivariate competing-risks regression analyses demonstrated that no application of the PM was independently associated with lower recurrence rate and CSM based on various analytical cohorts [hazard ratio (HR), 0.82 and 0.77 in the adjusted entire cohort, HR 0.80 and 0.73 in the PSM cohort, and HR 0.80 and 0.76 in the IPTW cohort, respectively]., Conclusions: The findings suggested that no application of PM during hepatectomy for patients with HCC reduced the risk of postoperative recurrence and cancer-specific death by approximately 20-25%., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-7/coif). T.M.P. serves as an unpaid Deputy Editor-in-Chief of Hepatobiliary Surgery and Nutrition. T.Y. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Hyperglycemia affects the outcomes of endovascular therapy (EVT) for acute ischemic stroke (AIS). This study compares the predictive ability of diabetes status and glucose measures on EVT outcomes using nationwide registry data., Methods: The study included 1,097 AIS patients who underwent EVT from the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke. The variables analyzed included diabetes status, admission glucose, glycated hemoglobin (HbA1c), admission glucose-to-HbA1c ratio (GAR), and outcomes such as 90-day poor functional outcome (modified Rankin Scale score ≥ 2) and symptomatic intracranial hemorrhage (SICH). Multivariable analyses investigated the independent effects of diabetes status and glucose measures on outcomes. A receiver operating characteristic (ROC) analysis was performed to compare their predictive abilities., Results: The multivariable analysis showed that individuals with known diabetes had a higher likelihood of poor functional outcomes (odds ratios [ORs] 2.10 to 2.58) and SICH (ORs 3.28 to 4.30) compared to those without diabetes. Higher quartiles of admission glucose and GAR were associated with poor functional outcomes and SICH. Higher quartiles of HbA1c were significantly associated with poor functional outcomes. However, patients in the second HbA1c quartile (5.6-5.8%) showed a non-significant tendency toward good functional outcomes compared to those in the lowest quartile (<5.6%). The ROC analysis indicated that diabetes status and admission glucose had higher predictive abilities for poor functional outcomes, while admission glucose and GAR were better predictors for SICH., Conclusion: In AIS patients undergoing EVT, diabetes status, admission glucose, and GAR were associated with 90-day poor functional outcomes and SICH. Admission glucose was likely the most suitable glucose measure for predicting outcomes after EVT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hsieh, Hsieh, Yang, Sung, Hsieh, Lee, Lin, Chen, Lin, Sung, Tang, Chu, Tsai, Chou, Lin, Wei, Chen, Yan, Chen, Hsiao, Chan, Huang, Liu, Tang, Lee, Lien, Chiou, Lee and Jeng.)

Background: The impact of hepatic resection type on long-term oncological prognosis of patients with early-stage hepatocellular carcinoma (HCC) has not been systematically investigated. We sought to determine risk factors, recurrence patterns, and survival outcomes after anatomical resection (AR) versus non-anatomical resection (NAR) for early-stage HCC., Methods: From a prospectively collected multicenter database, consecutive patients undergoing curative hepatectomy for early-stage HCC were identified. Recurrence patterns, overall survival (OS), recurrence-free survival (RFS), and risk factors were investigated in patients undergoing AR versus NAR using propensity score matching (PSM), subgroup analysis, and COX regression analysis., Results: A total of 3585 patients with early-stage HCC were enrolled, including 1287 and 2298 in the AR and NAR groups, respectively. After PSM, the OS and RFS of patients in the AR group were 58.8% and 42.7%, which were higher than those in the NAR group (52.2% and 30.6%, both p < 0.01). The benefits of AR were consistent across most subgroup analyses of OS and RFS. Multivariable COX regression analysis showed that AR was independently associated with better OS and RFS. Notably, although recurrence patterns were comparable, the risk factors for recurrence were not identical for AR versus NAR. Microvascular invasion and narrow resection margin were only associated with a higher recurrence rate after NAR., Conclusions: This study demonstrated that AR decreases the risk of tumor recurrence and improves OS and RFS in patients with early-stage HCC. AR should be adopted as long as such a surgical maneuver is feasible for initial treatment of early-stage HCC., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes., Methods: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated., Results: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis., Conclusion: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment., (© 2024. The Author(s).)

Purpose: Carotid artery web (CaW) is a rare focal fibromuscular dysplasia that can lead to embolic strokes with large vessel occlusion. This condition can be effectively treated with endovascular thrombectomy (EVT). Our study aims to assess the prevalence of CaW among patients with acute ischemic stroke (AIS) who underwent EVT and to compare the clinical characteristics of CaW with other carotid artery pathologies., Methods: We enrolled consecutive patients with AIS who underwent EVT at a single medical center and two regional teaching hospitals in Taiwan from September 2014 to December 2021. We compared CaW with carotid dissection (CaD) and carotid large artery atherosclerosis (CaLAA) in terms of patient demographics and thrombus histological findings., Results: Of the 576 AIS patients who underwent EVT, four (mean age: 50 years) were diagnosed with CaW, resulting in a prevalence of 0.69%. Among these four patients, three experienced successful reperfusion after EVT and achieved functional independence (defined as a modified Rankin Scale score ≤2) three months post-stroke. Importantly, none of the CaW patients suffered a recurrent stroke within one year. Patients with CaW were younger than those with CaD or CaLAA, and exhibited fewer vascular risk factors. Additionally, CaW was associated with distal occlusion sites. The thrombus composition in CaW patients was similar to that in CaD patients., Conclusions: In conclusion, CaW is a rare finding among Asian patients with carotid artery disease who undergo for AIS. It is more prevalent in younger patients with a limited number of vascular risk factors., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated., Methods: This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib., Findings: The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for C max , AUC 0-t , and AUC 0-∞ were within the 0.80 to 1.25 BE limits. In the FE stage, C max , AUC 0-t , and AUC 0-∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified., Implications: Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability., Clinicaltrials: gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc., Competing Interests: Declaration of competing interest This study was funded by GSK (GSK study 213362). GSK contributed to the study design, implementation, data collection, interpretation, and analysis. All authors had full access to the data and had final responsibility for the decision to submit for publication. Medical writing support was provided by Nicholas Thomas, PhD, of Fishawack Indicia Ltd, UK, part of Avalere Health, and funded by GSK., (Copyright © 2024 GSK. Published by Elsevier Inc. All rights reserved.)

Background: Hepatic pedicle clamping (HPC) is frequently utilized during hepatectomy to reduce intraoperative bleeding and diminish the need for intraoperative blood transfusion (IBT). The long-term prognostic implications of HPC following hepatectomy for hepatocellular carcinoma (HCC) remain under debate. This study aims to elucidate the association between HPC and oncologic outcomes after HCC resection, stratified by whether IBT was administered., Patients and Methods: Prospectively collected data on patients with HCC who underwent curative resection from a multicenter database was studied. Patients were stratified into two cohorts on the basis of whether IBT was administered. The impact of HPC on long-term overall survival (OS) and recurrence-free survival (RFS) between the two cohorts was assessed by univariable and multivariable Cox regression analyses., Results: Of 3362 patients, 535 received IBT. In the IBT cohort, using or not using HPC showed no significant difference in OS and RFS outcomes (5-year OS and RFS rates 27.9% vs. 24.6% and 13.8% vs. 12.0%, P = 0.810 and 0.530). However, in the non-IBT cohort of 2827 patients, the HPC subgroup demonstrated significantly decreased OS (5-year 45.9% vs. 56.5%, P < 0.001) and RFS (5-year 24.7% vs. 33.3%, P < 0.001) when compared with the subgroup without HPC. Multivariable Cox regression analysis identified HPC as an independent risk factor of OS and RFS [hazard ratios (HR) 1.16 and 1.12, P = 0.024 and 0.044, respectively] among patients who did not receive IBT., Conclusions: The impact of HPC on the oncological outcomes following hepatectomy for patients with HCC differed significantly whether IBT was administered, and HPC adversely impacted on long-term survival for patients without receiving IBT during hepatectomy., (© 2023. Society of Surgical Oncology.)

Nickel (Ni) is a human carcinogen with genotoxic and epigenotoxic effects. Environmental and occupational exposure to Ni increases the risk of cancer and chronic inflammatory diseases. Our previous findings indicate that Ni alters gene expression through epigenetic regulation, specifically impacting E-cadherin and angiopoietin-like 4 (ANGPTL4), involved in epithelial-mesenchymal transition and migration. GST-M2, a member of the glutathione S-transferase (GST) enzyme family, plays a crucial role in cellular defense against oxidative damage and has been increasingly associated with cancer. GST-M2 overexpression inhibits lung cancer invasion and metastasis in vitro and in vivo. Hypermethylation of its promoter in cancer cells reduces gene expression, correlating with poor prognosis in non-small-cell lung cancer patients. The impact of Ni on GST-M2 remains unclear. We will investigate whether nickel exerts regulatory effects on GST-M2 through epigenetic modifications. Additionally, metformin, an antidiabetic drug, is being studied as a chemopreventive agent against nickel-induced damage. Our findings indicate that nickel chloride (NiCl 2 ) exposure, both short-term and long-term, represses GST-M2 expression. However, the expression can be restored by demethylation agent 5-aza-2'-deoxycytidine and metformin. NiCl 2 promotes hypermethylation of the GST-M2 promoter, as confirmed by methylation-specific PCR and bisulfite sequencing. Additionally, NiCl 2 also influences histone acetylation, and metformin counteracts the suppressive effect of NiCl 2 on histone H3 expression. Metformin reestablishes the binding of specificity protein 1 to the GST-M2 promoter, which is otherwise disrupted by NiCl 2 . These findings elucidate the mechanism by which Ni reduces GST-M2 expression and transcriptional activity, potentially contributing to Ni-induced lung carcinogenesis., (© 2023 Wiley Periodicals LLC.)

Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells ​(ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in vivo and in vitro. The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 ​h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1β (IL-1β) in vitro. Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kuo-Chuan Wang reports financial support was provided by Ministry of Science and Technology, Taiwan. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Direct oral anticoagulant (DOAC)-associated intracerebral hemorrhage (ICH) is a catastrophic complication. The aim of this study was to investigate the association between computed tomography (CT)-based cerebrovascular small vessel disease (SVD) burden and DOAC-ICH as well as the DOAC concentration upon hospital admission and ICH outcome., Patients and Methods: The study included two cohorts: (1) DOAC-ICH: patients who suffered from DOAC-ICH and underwent drug level measurements upon admission; (2) DOAC-non-ICH: stable DOAC users who underwent head CT without ICH during treatment. We categorized the DOAC levels of the DOAC-ICH patients as low (<50 ng/mL), medium (50-300 ng/mL), and high (>300 ng/mL). The CT-based SVD burden (including white matter lesions [WML], lacunes, and cerebral atrophy) was evaluated, and SVD scores (range, 0-3) were used to evaluate SVD severity., Results: A total of 43 DOAC-ICH patients and 177 DOAC-non-ICH patients were enrolled. DOAC-ICH patients were more likely to have WML, lacunes, or cerebral atrophy compared to DOAC-non-ICH patients. After adjustment, the SVD burden was associated with DOAC-ICH, with a higher risk of more severe SVD (SVD score of 2; odds ratio [OR], 10.3 [3.17, 33.3]; score of 3; OR, 16.8 [4.50, 62.6]). The proportions of patients with high, medium, and low drug levels in the DOAC-ICH group were 16.3%, 55.8%, and 27.9%, respectively. Additionally, the high-level group displayed a larger hematoma size and had worse functional outcomes at 3 months than the other two groups., Discussion and Conclusion: The severity of SVD burden was associated with DOAC-ICH. Furthermore, high DOAC levels in ICH were associated with unfavorable clinical outcomes. To address the potential selection bias from these two cohorts, a prospective study to investigate the co-contribution of drug levels and SVD to DOAC-ICH is essential., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase)., Methods: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis., Results: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata., Conclusions: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy., Competing Interests: Disclosures None.

Background: The optimal antithrombotic strategies for patients with atrial fibrillation who experience ischemic stroke (IS) despite direct oral anticoagulant (DOAC) therapy remain inconclusive. This study compared outcomes for patients with DOAC treatment failure who changed or retained their prestroke DOAC., Methods and Results: This retrospective cohort study analyzed data from the National Health Insurance Research Database from 2012 to 2020. Patients with atrial fibrillation who experienced IS during DOAC therapy were assigned to either (1) the DOAC-change group: changing prestroke DOAC or (2) the DOAC-retain group: retaining prestroke DOAC. The primary outcome was a composite of recurrent IS and transient ischemic attack. The secondary outcomes included intracranial hemorrhage, major bleeding, systemic thromboembolism, and all-cause death. Propensity score-based inverse probability of treatment weighting was applied to balance the baseline characteristics between the DOAC-change and DOAC-retain groups. The Cox proportional hazards model compared the risk of outcomes between the 2 groups. In total, 1979 patients were enrolled (609 DOAC-change patients and 1370 DOAC-retain patients). The incidence rates of recurrent IS or transient ischemic attack were 7.20 and 6.56 per 100 person-years in the DOAC-change and DOAC-retain groups, respectively (hazard ratio [HR], 1.07 [95% CI, 0.87-1.30]). A nonsignificantly higher incidence rate of intracranial hemorrhage was observed in the DOAC-change group compared with the DOAC-retain group (0.75 versus 0.53 per 100-person-years; HR, 1.49 [95% CI, 0.78-2.83]). The systemic thromboembolism, major bleeding, and death rates were comparable between the DOAC-change and DOAC-retain groups., Conclusions: Changing prestroke DOAC does not reduce the risk of recurrent cerebral ischemia in patients with atrial fibrillation who develop IS during DOAC therapy. However, future studies should continue to observe the potential trends of increased intracranial hemorrhage risk.

Background: We aimed to clarify comprehensively the safety profiles of anti-IL-5 drugs and pinpoint potential safety concerns that may arise in their post-marketing phase., Methods: Two researchers conducted comprehensive searches of PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to September 2022. Additionally, we investigated the FDA AE Reporting System for post-marketing adverse event (AE) reports related to anti-IL-5 drugs. The outcomes fulfilled the proportional reporting rate criteria and the Bayesian confidence propagation neural network., Results: We included 24 published studies in our analysis. The anti-IL-5 treatment group showed an incidence of AEs comparable to the placebo group, and it exhibited a significantly lower frequency of serious AEs. Common AEs were asthma, nasopharyngitis, headache, upper respiratory tract infection (URTI), and bronchitis. The post-marketing data included 28,478 case reports associated with the suspect drugs and 75 suspect safety observations affecting 16 system organ classes. New suspect observations included incomplete therapeutic product effect, URTIs, and pulmonary mass in reports related to mepolizumab. Reports associated with mepolizumab and benralizumab also indicated issues with incorrect technique in device usage and product issues., Conclusions: Individual anti-IL-5 drugs' safety profiles largely matched their product inserts. We identified issues like improper device usage, product issue, and URTIs as potential concerns for mepolizumab and benralizumab. Additionally, all anti-IL-5 drugs showed signs of incomplete therapeutic effects., (© 2024. The Author(s).)

Background: Hepatectomy is the preferred treatment for solitary hepatocellular carcinoma (HCC) without macrovascular invasion and distant metastasis, but long-term survival remains unsatisfactory in certain patients. We sought to identify whether the grading severity of microscopic vascular invasion (MVI) was associated with recurrence and survival among patients with solitary HCC., Methods: Consecutive patients who underwent hepatectomy for solitary HCC were identified from a multicenter prospectively-collected database. Patients were categorized into three groups according to the MVI grading system proposed by the Liver Cancer Pathology Group of China: M0 (no MVI), M1 (1-5 sites of MVI occurring ≤1.0 cm away from the tumor), and M2 (>5 sites occurring ≤1.0 cm or any site occurring >1 cm away from the tumor). Recurrence-free survival (RFS) and overall survival (OS) were compared among the groups., Results: Among 227 patients, 97 (42.7%), 83 (36.6%), and 47 (20.7%) patients had M0, M1, and M2, respectively. Median RFS rates among patients with M0, M1, and M2 were 38.3, 35.1, 11.6 months, respectively, while OS rates were 66.8, 62.3, 30.6 months, respectively (both P<0.001). Multivariate Cox-regression analyses demonstrated that both M1 and M2 were independent risk factors for RFS (hazard ratio 1.20, 95% CI: 1.03-1.89, P=0.040; and hazard ratio 1.67, 95% CI: 1.06-2.64, P=0.027) and OS (hazard ratio 1.28, 95% CI: 1.05-2.07, P=0.035; and hazard ratio 1.97, 95% CI: 1.15-3.38, P=0.013)., Conclusions: Grading severity of MVI was independently associated with RFS and OS after hepatectomy for solitary HCC. Enhanced surveillance for recurrence and potentially adjuvant therapy may be considered for patients with MVI, especially individuals with more severe MVI grading (M2)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-411/coif). T.M.P. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2024 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP + varicosities in the PGP9.5 + nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1 ) condensed TH + sympathetic nerves in the portal space, 2 ) extension of sympathetic nerves from the portal to the intralobular space, in which the TH + nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3 ) the TH + nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology. NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1 ) sensory nerves in the hepatoportal space; 2 ) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3 ) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Berberine has been demonstrated to alleviate cerebral ischemia/reperfusion injury, but its neuroprotective mechanism has yet to be understood. Studies have indicated that ischemic neuronal damage was frequently driven by autophagic/lysosomal dysfunction, which could be restored by boosting transcription factor EB (TFEB) nuclear translocation. Therefore, this study investigated the pharmacological effects of berberine on TFEB-regulated autophagic/lysosomal signaling in neurons after cerebral stroke. A rat model of ischemic stroke and a neuronal ischemia model in HT22 cells were prepared using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD), respectively. Berberine was pre-administered at a dose of 100[Formula: see text]mg/kg/d for three days in rats and 90[Formula: see text][Formula: see text]M in HT22 neurons for 12[Formula: see text]h. 24[Formula: see text]h after MCAO and 2[Formula: see text]h after OGD, the penumbral tissues and OGD neurons were obtained to detect nuclear and cytoplasmic TFEB, and the key proteins in the autophagic/lysosomal pathway were examined using western blot and immunofluorescence, respectively. Meanwhile, neuron survival, infarct volume, and neurological deficits were assessed to evaluate the therapeutic efficacy. The results showed that berberine prominently facilitated TFEB nuclear translocation, as indicated by increased nuclear expression in penumbral neurons as well as in OGD HT22 cells. Consequently, both autophagic activity and lysosomal capacity were simultaneously augmented to alleviate the ischemic injury. However, berberine-conferred neuroprotection could be greatly counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Meanwhile, autophagy inhibitor 3-Methyladenine (3-MA) also slightly neutralized the pharmacological effect of berberine on ameliorating autophagic/lysosomal dysfunction. Our study suggests that berberine-induced neuroprotection against ischemic stroke is elicited by enhancing autophagic flux via facilitation of TFEB nuclear translocation in neurons.

Introduction: Several early noncontrast CT (NCCT) signs of spontaneous intracerebral hemorrhage (ICH) can predict hematoma expansion (HE). However, the associations of underlying cerebral small vessel disease (SVD) on early NCCT signs and HE have been less explored., Methods: We conducted an analysis of all patients with spontaneous supratentorial ICH and received follow-up imaging between 2016 and 2020 at a stroke center. The early NCCT signs were categorized as shape or density signs. HE was defined as an increase in hematoma volume ≥6 mL or 33% from baseline. The severity of SVD was assessed by both a 3-point CT-based and a 4-point magnetic resonance imaging (MRI)-based SVD score. Regression models were used to examine the associations between SVD score and hematoma volume, NCCT signs, and HE., Results: A total of 328 patients (median age: 64 years; 38% female) were included. The median baseline ICH volume was 8.6 mL, with 38% of the patients had shape signs and 52% had density signs on the initial NCCT. Higher MRI-SVD scores were associated with smaller ICH volumes (p = 0.0006), fewer shape (p = 0.001), or density signs (p = 0.0003). Overall, 16% of patients experienced HE. A higher MRI-SVD score was inversely associated with HE (adjusted odds ratio 0.71, 95% CI: 0.53-0.96). Subgroup analysis revealed that this association was primarily observed in patients who were younger (&lt;65 years), male, had deep hemorrhage, or did not meet the criteria for cerebral amyloid angiopathy diagnosis., Conclusions: In patients with spontaneous ICH, a more severe SVD was associated with smaller hematoma volume, fewer NCCT signs, and a lower risk of HE. Further research is required to investigate why a higher burden of severely diseased cerebral small blood vessels is associated with less bleeding., (© 2023 S. Karger AG, Basel.)

Metabolomics has become a promising method for understanding pathological mechanisms. Plasma (PLS) is the most common sample type used for metabolomics studies, and dried blood spot (DBS) sampling has been regarded as a good strategy due to its unique characteristics. However, how results obtained from DBS can be correlated to results obtained from PLS remains unclear. To bridge the results and to investigate the feasibility of using DBS to study metabolomics, we performed a comparative study using 64 paired PLS and DBS samples. The number of features extracted from the two different sample types was investigated. The concentration correlations of the identified metabolites between the DBS and PLS were individually studied. Approximately 47 % showed a strong correlation, 19 % showed a moderate correlation, and 34 % showed a low or even negligible correlation. Finally, we applied both PLS- and DBS-based metabolomics to explore the dysregulated metabolites in diabetes mellitus (DM) patients. Thirty-two non-DM subjects and 32 DM patients were enrolled, and 2 significant metabolites were found in both PLS and DBS samples. In summary, detailed correlation information between PLS and DBS metabolites was first explored in this study, and it is anticipated that these results could facilitate future applications in DBS-based metabolomics., 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 © 2023 Elsevier B.V. All rights reserved.)

Background and Aim: Previous studies have suggested cardiovascular risk factors increase the risk of not only common sporadic stroke but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the Taiwanese population., Methods: This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke. The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3 R544C in stroke., Results: From the 114,282 participants with both genotype and questionnaire results, 1080 (0.95%) harbored the pathogenic NOTCH3 R544C variant. When compared to the matched controls ( n  = 10,800), the carriers presented with a history of stroke (OR: 2.52, 95% confidence interval (CI) (1.45, 4.37)), dementia (OR: 30.1, 95% CI (3.13, 289.43)), and sibling history of stroke (OR: 2.48, 95% CI (1.85, 3.34)) phenotypes. The risk of stroke increased with every 10-year increase in age ( p  = 0.006, Cochran-Mantel-Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1080 carriers with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI (3.54, 43.3)) and diabetes mellitus (OR: 4.10, 95% CI (1.31, 12.4)) were independently associated with stroke. Harboring the NOTCH3 R544C variant in the Taiwan Biobank is comparable with a 6.74 standard deviations increase in individual's polygenic risk score for stroke., Conclusion: While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also played a role in the occurrence of stroke in Taiwanese community-dwelling individuals carrying the NOTCH3 variant., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Patients with end-stage renal disease (ESRD) are often excluded from clinical trials of endovascular thrombectomy (EVT). This study investigated the outcome in these patients., Methods: From September 2014 to July 2021, all patients undergoing EVT for anterior circulation stroke in two stroke centers in Taiwan were included. They were divided into no renal dysfunction (non-RD, estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 ), RD (eGFR <60 mL/min/1.73 m 2 but no dialysis), and ESRD undergoing dialysis (ESRD-dialysis). The clinical features and outcomes were compared., Results: Of 482 patients included, there were 20 ESRD-dialysis, 110 RD, and 352 non-RD patients. The Alberta Stroke Program Early CT Score (ASPECTS), National Institutes of Health Stroke Scale (NIHSS), use of intravenous thrombolysis, EVT-related time metrics, and successful recanalization rates were comparable among the three groups. However, the ESRD-dialysis patients had more symptomatic intracerebral hemorrhage (ICH, 15% vs 3.6% vs 3.7%), more contrast-induced encephalopathy (15% vs 1.8% vs 0.9%), and a higher mortality at 90 days (35% vs 18% vs 11%) than the other groups. Multivariable analysis revealed that ESRD-dialysis was associated with a less favorable outcome (OR 0.21, 95% CI 0.04 to 0.77) and more severe disability or mortality (modified Rankin Scale 5 or 6; OR 13.1, 95% CI 3.93 to 48.1) at 90 days. In the ESRD-dialysis group, the patients with premorbid functional dependence had a significantly higher mortality than those without (75% vs 8.3%; P=0.004)., Conclusion: ESRD-dialysis patients were associated with symptomatic ICH and less favorable outcome at 90 days. Patients with premorbid functional dependency had an excessively high mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP)., Methods: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging., Results: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages., Conclusion: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system., (© 2023. The Author(s).)

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-Kras G12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA + fibroblasts in both transgenic mice and human specimens. Mechanistically, Kras G12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic Kras G12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Flexor hallucis longus (FHL) transfer is an effective surgery in treating insertional Achilles tendinopathy (IAT). However, limited data exist regarding the post-surgery changes in the transferred FHL. The study aimed to compare the sequential changes and hypertrophy of FHL after isolated FHL transfer (FHLT). We retrospectively enrolled patients who underwent isolated FHLT for insertional Achilles pathology from 2015 to 2020 and divided them into two groups based on whether reattachment of the residue Achilles stump to the FHL was performed or not. We recorded demographic characteristics, MRI parameters, and functional outcome. We also analyzed the correlation between the collected data and FHL hypertrophy. Results revealed no significant differences in most MRI parameters of FHL and functional outcomes between the groups. However, the fat distribution within the FHL showed significant reduction and notable 20.2% hypertrophy after FHLT. Interestingly, the hypertrophy of the FHL was significantly more pronounced in the non-reattached group. Furthermore, we observed a positive correlation between the follow-up period and FHL hypertrophy. In conclusion, the FHL demonstrated significant enlargement over time following FHLT. The compensatory hypertrophy of the transferred FHL was particularly evident and the cumulative incidences of FHL enlargement over time were higher in the non-reattached groupcompared to reattached group. However, both reattachment and non-reattachment of Achilles stump on FHL transfer for insertional Achilles tendinopathy carried similar postoperative functional outcomes., (© 2023. The Author(s).)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 ( NOTCH3 ) variant position to cognitive impairment associated with CADASIL., Methods and Results: Patients with the cysteine-altering NOTCH3 variant were enrolled in a cross-sectional study, including the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B , -4.090 [95% CI, -6.708 to -1.473]; P =0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B , 2.854 [95% CI, 0.603-5.105]; P =0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively., Conclusions: APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment.