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Moon Hee Lee,1 Seok-Kyu Yoon,1 Hyungsub Kim,2 Yong-Soon Cho,3 Sungpil Han,4 Shi Hyang Lee,1 Kyun-Seop Bae,1 Jina Jung,5 Sung Hee Hong,5 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; 2Department of Emergency Medical Services, College of Health Sciences, Eulji University, Seongnam, Republic of Korea; 3Department of Pharmacology and Clinical Pharmacology, Inje University College of Medicine, Busan, Republic of Korea; 4Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of KoreaCorrespondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea, Tel +82-2-3010-4613, Fax +82-2-3010-4623, Email mdlhs@amc.seoul.krPurpose: The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects.Patients and Methods: Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs).Results: For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263– 1.1765) for Cmax and 1.1329 (1.0232– 1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005– 0.9117) for Cmax and 0.8056 (0.7445– 0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases.Conclusion: A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.Keywords: bazedoxifene, cholecalciferol, drug-drug interaction, pharmacokinetics, tolerability

Seok Kyu Yoon,1 Kyun-Seop Bae,1 Dong Hyun Hong,2 Seong Su Kim,2 Young Kweon Choi,2 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2Department of Pharmaceutical Research, iCure Pharmaceutical Incorporated, Seoul, Republic of KoreaCorrespondence: Hyeong-Seok LimDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul Tel +82-2-3010-4623Fax +82-2-3010-4622Email mdlhs@amc.seoul.krIntroduction: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation.Methods: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software.Results: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application.Conclusion: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.Keywords: clinical trial(s), clinical trial simulation(s), pharmacokinetics, pharmacometrics, analysis

The purpose of this study was to determine the therapeutic efficacy of radiofrequency ablation for treating renal VX2 tumors with and without renal artery occlusion in a rabbit model. Twenty-four New Zealand White rabbits were percutaneously implanted with renal VX2 tumors. Fifteen days after implantation, both kidneys were surgically exposed, and radiofrequency ablation was conducted. Group A (n=12) was treated with renal artery occlusion, and group B (n=12) was treated without occlusion. In each rabbit, the serum creatinine was measured to evaluate renal damage after arterial occlusion. Two days after radiofrequency ablation, computed tomography was performed to evaluate the difference in therapeutic results between the two groups. We also compared histopathologic findings after radiofrequency ablation. The mean tumor size was 2.4 cm (range, 1.2-3.1 cm). Radiofrequency ablation of renal tumors was technically feasible in all cases. Complete ablation was achieved in 11 of the 12 rabbits (92%) in group A but in only eight of the 12 rabbits (67%) in group B (P<0.05). The average time of radiofrequency application was shorter in group A (mean, 547 s) than in group B (mean, 826 s) (P<0.05). After radiofrequency ablation, the serum creatinine increased from 1.54 to 1.82 mg/dl in group A and from 1.46 to 1.78 mg/dl in group B. However, there was no significant difference between the two groups (P>0.05). In conclusion, radiofrequency ablation with renal artery occlusion can decrease the duration of treatment and increase the therapeutic efficacy for renal VX2 tumors. [ABSTRACT FROM AUTHOR]

Background: The objectives of this retrospective study was to evaluate the efficacy of stereotactic body radiation therapy (SBRT) for small non-resectable hepatocellular carcinoma (HCC) and SBRT combined with transarterial chemoembolization (TACE) for advanced HCC with portal vein tumor thrombosis (PVTT).Methods: Thirty one patients with HCC who were treated with SBRT were used for the study. We studied 32 HCC lesions, where 23 lesions (22 patients) were treated targeting small non-resectable primary HCC, and 9 lesions (9 patients) targeting PVTT using the Cyberknife. All the 9 patients targeting PVTT received TACE for the advanced HCC. Tumor volume was 3.6-57.3 cc (median, 25.2 cc) and SBRT dose was 30-39 Gy (median, 36 Gy) in 3 fractions for consecutive days for 70-85% of the planned target volume.Results: The median follow up was 10.5 months. The overall response rate was 71.9% [small HCC: 82.6% (19/23), advanced HCC with PVTT: 44.4% (4/9)], with the complete and partial response rates of 31.3% [small HCC: 26.1% (6/23), advanced HCC with PVTT: 11.1% (1/9)], and 50.0% [small HCC: 56.5% (13/23), advanced HCC with PVTT: 33.3% (3/9)], respectively. The median survival period of small HCC and advanced HCC with PVTT patients was 12 months and 8 months, respectively. No patient experienced Grade 4 toxicity.Conclusion: SBRT for small HCC and SBRT combined with TACE for advanced HCC with PVTT showed feasible treatment modalities with minimal side effects in selected patients with primary HCC. [ABSTRACT FROM AUTHOR]

CD133 is a cancer stem-cell (CSC) marker associated with radioresistance and chemoresistance in various cancers. In the present study, CD133-expressing liver cancer cells following radiation exposure showed higher activation of MAPK/PI3K signaling pathway and reduction in reactive oxygen species levels compared to CD133- cells. The in vivo study with a xenograft model showed increased tumor formation in irradiated CD133+ cell-injected nude mice compared to the CD133- group, suggesting that CD133 contributes to radioresistance in HCC. Therefore, CD133-expressing liver cancer cells have anti-apoptotic and radioresistance properties that may be useful to improve anti-cancer treatments, including chemotherapy/radiotherapy of HCC. [ABSTRACT FROM AUTHOR]

Background: While there is evidence that COVID-19 vaccination protects against development of post-COVID conditions (PCC) after severe infection data are limited on whether vaccination reduces the risk after cases of less-severe non-hospitalized COVID-19 disease with more recent SARS-CoV-2 variant viruses. This study assessed whether COVID-19 vaccination was protective against subsequent development of PCC in persons with predominantly mild initial infections during both Delta and Omicron variant predominance., Methods: This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with PCR-confirmed SARS-CoV-2 infection between 6/28/2021 and 9/14/2022 were surveyed for PCC, defined by symptoms lasting >1 month after initial infection Cases were participants self-reporting PCC and controls were participants that did not self-report PCC. The exposure was mRNA COVID-19 vaccination (2 or 3 monovalent doses) versus no COVID-19 vaccination. Logistic regression was used to compare the odds of PCC among vaccinated and unvaccinated persons; additional analyses evaluating PCC subtypes were also performed., Results: A total of 936 participants with documented SARS-CoV-2 infection were included; of these 23.6% (221) reported PCC and 83.3% (779) were vaccinated. Participants who received a 3rd COVID-19 monovalent mRNA dose prior to infection had lower odds of PCC-related gastrointestinal, neurological, and other symptoms compared to unvaccinated participants (aOR: 0.37; 95% CI: 0.16-0.85; aOR: 0.56; 95% CI: 0.32-0.97; aOR:0.48; 95% CI: 0.25-0.91)., Conclusions: COVID-19 vaccination protected against development of PCC among persons with mild infection during both Delta and Omicron variant predominance, supporting vaccination as an important tool for PCC prevention., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background and Aims: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC., Approach and Results: CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels ( p <0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68 + cells from patients with high serum IgA levels ( p <0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs ( p <0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8 + T cells. Interestingly, activated CD8 + T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs ( p <0.05)., Conclusions: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Previous estimates of vaccine effectiveness (VE) against asymptomatic influenza virus infection based on seroconversion have varied widely and may be biased. We estimated 2022-2023 influenza VE against illness and asymptomatic infection in a prospective cohort., Methods: In the HEROES-RECOVER cohort, adults at increased occupational risk of influenza exposure across 7 US sites provided weekly symptom reports and nasal swabs for reverse transcription-polymerase chain reaction (RT-PCR) influenza testing. Laboratory-confirmed influenza virus infections were classified as symptomatic (≥1 symptom) or asymptomatic during the week of testing. Participants reported demographic information and vaccination through surveys; most sites verified vaccination through medical record and immunization registry review. Person-time was calculated as days from the site-specific influenza season start (September-October 2022) through date of infection, study withdrawal, or season end (May 2023). We compared influenza incidence among vaccinated versus unvaccinated participants overall, by symptom status, and by influenza A subtype, using Cox proportional hazards regression adjusted for site and occupation. We estimated VE as (1 - adjusted hazard ratio) × 100%., Results: In total, 269 of 3785 (7.1%) participants had laboratory-confirmed influenza, including 263 (98%) influenza A virus infections and 201 (75%) symptomatic illnesses. Incidence of laboratory-confirmed influenza illness among vaccinated versus unvaccinated participants was 23.7 and 33.2 episodes per 100 000 person-days, respectively (VE: 38%; 95% CI: 15%-55%). Incidence of asymptomatic influenza virus infection was 8.0 versus 11.6 per 100 000 (VE: 13%; 95% CI: -47%, 49%)., Conclusions: Vaccination reduced incidence of symptomatic but not asymptomatic influenza virus infection, suggesting that influenza vaccination attenuates progression from infection to illness., Competing Interests: Potential conflicts of interest . A. N., L. J. E., J. D., H. T., G. N.-A., K. D. E., K. L., J. L. B., A. L. P., A. C.-M., and L. O. report funding from the CDC, Westat, or Abt Associates related to the current manuscript. M. G. reports grants from CDC, Westat, and Vanderbilt University Medical Center and participation on the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics Infectious Diseases and Immunization Committee as co-chair. S. K. Y. and A. L. P. report a contract from Novavax, Inc, for unrelated studies. M. T. has consulted for Novavax and CSL Seqirus. A. C.-M. reports funding from the state of Florida for the Firefighter Cancer Initiative and a leadership role in the International Commission on Occupational Health. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Data availability . For questions about data availability, please contact the corresponding author., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4+ regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: This study aimed to identify the risk factors for chronic kidney disease (CKD) and end-stage renal disease (ESRD) following liver transplantation (LT), with a specific focus on tacrolimus levels and intrapatient variability (IPV)., Methods: Among the 1,076 patients who underwent LT between 2000 and 2018, 952 were included in the analysis. The tacrolimus doses and levels were recorded every 3 months, and the IPV was calculated using the coefficient of variability. The cumulative incidence rates of CKD and ESRD were calculated based on baseline kidney function at the time of LT. The impact of tacrolimus levels and their IPV on the development of CKD and ESRD was evaluated, and the significant risk factors were identified., Results: Within a median follow-up of 97.3 months, the 5-year cumulative incidence rates of CKD (0.58 vs. 0.24) and ESRD (0.07 vs. 0.01) were significantly higher in the acute kidney injury (AKI) group than in the normal glomerular filtration rate (GFR) group. In the normal GFR group, the tacrolimus levels were identified as a risk factor for CKD, with a level of ≤4.5 ng/mL suggested as optimal for minimizing the risk of CKD. Furthermore, the IPV of tacrolimus levels and doses emerged as a significant risk factor for CKD development in both groups (P<0.05), with tenofovir disoproxil fumarate also being a risk factor in HBV-infected patients. The IPV of tacrolimus levels was also a significant factor in ESRD development (P<0.05)., Conclusions: This study elucidated the optimal tacrolimus through level and highlighted the impact of IPV on the CKD and ESRD development post-LT.

Background and Aims: Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg., Methods: This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed., Results: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients., Conclusions: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Immunogenicity studies suggest that recombinant influenza vaccine (RIV) may provide better protection against influenza than standard-dose inactivated influenza vaccines (SD IIV). This randomized trial evaluated the relative vaccine effectiveness (VE) and immunogenicity of RIV versus SD IIV in frontline workers and students aged 18-64 years., Methods: Participants were randomized to receive RIV or SD IIV and followed for reverse-transcription polymerase chain reaction (RT-PCR)-confirmed influenza during the 2022-2023 influenza season. Sera were collected from a subset of participants before and at 1 and 6 months postvaccination and tested by hemagglutination inhibition for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria and against cell-grown vaccine reference viruses for A/H1N1 and A/H3N2., Results: Overall, 3988 participants were enrolled and vaccinated (25% of the trial sample size goal); RT-PCR-confirmed influenza occurred in 20 of 1963 RIV recipients and 28 of 1964 SD IIV recipients. Relative VE was 29% (95% confidence interval [CI], -26% to 60%). In the immunogenicity substudy (n = 118), the geometric mean titer ratio (GMTR) comparing RIV to SD IIV at 1 month was 2.3 (95% CI, 1.4-3.7) for cell-grown A/H1N1, 2.1 (95% CI, 1.3-3.4) for cell-grown A/H3N2, 1.1 (95% CI, .7-1.6) for B/Victoria, and 1.4 (95% CI, .9-2.0) for B/Yamagata. At 6 months, GMTRs were >1 against A/H1N1, A/H3N2, and B/Yamagata., Conclusions: Relative VE of RIV compared to SD IIV did not reach statistical significance, but RIV elicited more robust humoral immune responses to 2 of 4 vaccine viruses at 1 month and 3 of 4 viruses at 6 months after vaccination, suggesting possible improved and sustained immune protection from RIV. Clinical Trials Registration. NCT05514002., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by persistent inflammatory cascades, with macrophage activation playing a pivotal role. Chitinase 1 (CHIT1), produced by activated macrophages, is a key player in this cascade. In this study, we aimed to explore the role of CHIT1 in MASH with progressive liver fibrosis., Methods: Fibrotic liver tissue and serum from distinct patient groups were analyzed using nCounter MAX, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. A MASH mouse model was constructed to evaluate the effectiveness of OATD-01, a chitinase inhibitor. Macrophage profiling was performed using single-nuclei RNA sequencing and flow cytometry., Results: CHIT1 expression in fibrotic liver tissues was significantly correlated with the extent of liver fibrosis, macrophages, and inflammation. Single-nuclei RNA sequencing demonstrated a notable increase in macrophages numbers, particularly of lipid-associated macrophages, in MASH mice. Treatment with OATD-01 reduced non-alcoholic fatty liver disease activity score and Sirius red-positive area. Additionally, OATD-01-treated mice had lower CHIT1, F4/80, and α-smooth muscle actin positivity, as well as significantly lower levels of inflammatory markers, pro-fibrotic genes, and matrix remodeling-related mRNAs than vehicle-treated mice. Although the population of F4/80 + CD11b + intrahepatic mononuclear phagocytes remained unchanged, their infiltration and activation (CHIT1 + MerTK + ) significantly decreased in OATD-01-treated mice, compared with that observed in vehicle-treated mice., Conclusions: Our study underscores the pivotal role of CHIT1 in MASH. The observed significant improvement in inflammation and hepatic fibrosis, particularly at higher doses of the CHIT1 inhibitor, strongly suggests the potential of CHIT1 as a therapeutic target in MASH accompanied by progressive liver fibrosis., 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 Cha, Park, Cho, Nam, Yang, Jung, Jang, Choi, Yoon, Sung and Bae.)

Background/aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients., Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted., Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching., Conclusions: Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes.

Purpose: Atezolizumab/bevacizumab (atezo-bev) is the first-line chemotherapy for patients with unresectable hepatocellular carcinoma (HCC). However, hepatic artery infusion chemotherapy (HAIC) can be used as an alternative. Our aim was to compare the prognosis of HAIC treatment between newly diagnosed patients and patients treated after failure of atezo-bev., Methods: We retrospectively assessed 73 patients with HCC treated with HAIC between January 2022 and September 2023. Fifty-seven patients were treated with HAIC at initial diagnosis, while 16 were treated with HAIC after first-line atezo-bev combination chemotherapy. We evaluated tumor responses, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR)., Results: No significant difference was observed in either OS or PFS between patients with HCC treated with HAIC at the initial diagnosis and those treated after atezo-bev treatment failure. However, the ORR of the initial HAIC group was 19.6% and that of the HAIC group after atezo-bev therapy failure was 43.6%, which was a statistically significantly difference., Conclusion: Although no significant difference was observed for OS and PFS, the ORR of patients in the HAIC group after the failure of atezo-bev therapy was superior to that of newly diagnosed patients. HAIC may prolong survival in patients with HCC after atezo-bev treatment failure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

While steroid therapy is the preferred treatment for severe alcohol-associated hepatitis, the role of effector regulatory T (eTreg) cells and their association with steroid response and clinical outcomes in these patients remains to be elucidated. We prospectively enrolled 47 consecutive patients with alcohol-associated hepatitis, consisting of severe alcohol-associated hepatitis treated with steroids (n=18; steroid-treated group) and mild alcohol-associated hepatitis (n=29; nontreated group). After isolating peripheral blood mononuclear cells from the patients at enrollment and again 7 days later, the frequency of eTreg cells was examined using flow cytometry. Single-cell RNA sequencing analysis was conducted using paired peripheral blood mononuclear cells. In vitro experiments were also performed to assess phenotype changes and the suppressive function of Treg cells following steroid treatment. The steroid-treated group exhibited significantly higher Model for End-Stage Liver Disease scores than the nontreated group ( p < 0.01). Within the steroid-treated group, the proportion of eTreg cells significantly expanded in the steroid responders (n=13; p = 0.01). Furthermore, a significant positive correlation was observed between the decrease in the Model for End-Stage Liver Disease score and the increase in eTreg cells ( p < 0.05). Single-cell RNA sequencing using paired peripheral blood mononuclear cells (pre-steroid and post-steroid therapy) from a steroid responder revealed gene expression changes in T cells and monocytes, suggesting enhancement of Treg cell function. In vitro results showed an elevation in the proportion of eTreg cells after steroid therapy. In conclusion, our findings suggest that the efficacy of steroid therapy in patients with severe alcohol-associated hepatitis is mediated by an increase in the number of eTreg cells., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Bile duct resection and reconstruction for bile duct cancer (BDC) is a complex surgical and oncologic procedure that requires extensive resection and reconstruction of the biliary tract. Hepaticojejunostomy is commonly performed for biliary reconstruction after extrahepatic mid-bile duct resection, while hepaticoduodenostomy (HD) is performed only rarely due to the risk of ascending cholangitis. However, the efficacy of HD has not been well-established in extrahepatic mid-BDC surgery. In this study, we aimed to analyze the outcomes of HD in patients who underwent bile duct resection for extrahepatic mid-BDC., Methods: We retrospectively analyzed 38 extrahepatic mid-BDC patients who underwent bile duct resection in our center between January 2018 and June 2023. We compared postoperative outcomes, cancer recurrence, and patient survival between hepaticojejunostomy (n=20) and HD (n=18) groups., Results: Operation time for the HD group was significantly shorter than that of the hepaticojejunostomy group (188 vs. 206 min, P=0.044) with no significant differences in postoperative outcomes. Regression analysis showed that a HD was not associated with a significantly high risk of cancer recurrence or decrease in patient survival., Conclusions: HD appears to have comparable operative benefits, postoperative complications, and oncologic outcomes to hepaticojejunostomy in extrahepatic mid-BDC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-155/coif). The authors have no conflicts of interest to declare., (2024 Gland Surgery. All rights reserved.)

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD ( n = 38) or autoimmune liver disease ( n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8-12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant ( n = 19) showed greater CD3 + T-cell infiltration than the cholestatic variant ( n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20 + , CD38 + , or CD68 + cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants ( p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

Hybrid immunity, as a result of infection and vaccination to SARS-CoV-2, has been well studied in adults but limited evidence is available in children. We evaluated the antibody responses to primary SARS-CoV-2 infection among vaccinated and unvaccinated children aged ≥ 5 years., Methods: A longitudinal cohort study of children aged ≥ 5 was conducted during August 2021-August 2022, at sites in Arizona, Texas, Utah, and Florida. Children submitted weekly nasal swabs for PCR testing and provided sera 14-59 days after PCR-confirmed SARS-CoV-2 infection. Antibodies were measured by ELISA against the receptor-binding domain (RBD) and S2 domain of ancestral Spike (WA1), in addition to Omicron (BA.2) RBD, following infection in children, with and without prior monovalent ancestral mRNA COVID-19 vaccination., Results: Among the 257 participants aged 5 to 18 years, 166 (65%) had received at least two mRNA COVID-19 vaccine doses ≥ 14 days prior to infection. Of these, 53 occurred during Delta predominance, with 37 (70%) unvaccinated at the time of infection. The remaining 204 infections occurred during Omicron predominance, with 53 (26%) participants unvaccinated. After adjusting for weight, age, symptomatic infection, and gender, significantly higher mean RBD AUC values were observed among the vaccinated group compared to the unvaccinated group for both WA1 and Omicron ( p < 0.0001). A smaller percentage of vaccinated children reported fever during illness, with 55 (33%) reporting fever compared to 44 (48%) unvaccinated children reporting fever ( p = 0.021)., Conclusions: Children with vaccine-induced immunity at the time of SARS-CoV-2 infection had higher antibody levels during convalescence and experienced less fever compared to unvaccinated children during infection.

Background and Aim: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD)., Methods: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021., Results: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m 2 ; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m 2 ), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m 2 ; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m 2 ; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively., Conclusion: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Lymph node (LN) metastasis is an established prognostic factor for patients with surgically resected ampulla of Vater (AoV) cancer. The standard procedure for radical resection, including removal of regional LNs, is pancreaticoduodenectomy (PD); however, local excision has been considered as an alternative option for patients in the early stage cancer with significant comorbidities. In the present study, we elucidated the preoperative factors associated with LN metastasis to determine the appropriate surgical extent for T1 AoV cancer., Methods: We included patients who underwent surgery for T1 AoV cancer at Samsung Medical Center and Severance Hospital between 2000 and 2019. Risk factors were analyzed to identify the preoperative parameters associated with LN metastasis or regional LN recurrence during follow-up. Finally, using the identified risk factors, a prediction model was constructed., Results: Among 342 patients, 311 patients underwent PD, whereas 31 patients underwent transduodenal ampullectomy. Fourty-eight patients had LN metastasis according to pathology report, and two patients presented with regional LN recurrence. Age, carbohydrate antigen 19 - 9 (CA 19 - 9), and tumor differentiation were identified as factors associated with the increased risk of LN metastasis or regional LN recurrence. The area under the curve of the prediction model with these three factors was 0.728., Conclusion: Our newly developed prediction model using age, CA 19 - 9, and tumor differentiation can help select patients who require PD over local excision. Nevertheless, additional in-depth analysis is warranted to select appropriate surgical extent for patients with presumed T1 AoV cancer., (© 2024. The Author(s).)

Background: Computed tomography (CT)-guided transthoracic needle biopsy (TNB) could damage lung structures and may disseminate tumor cells into the airway, blood vessels, and pleural cavity, affecting post-operative outcomes. Several studies have investigated the effects of TNB on the prognosis of patients, but the effects remain unclear. This study aimed to investigate whether TNB increases the risk of recurrence of resected stage IA non-small cell lung cancer (NSCLC)., Methods: In this retrospective study, we enrolled 1,077 patients with stage IA NSCLC who underwent curative resection from 2010 to 2020. Recurrence risk factors were evaluated using Cox regression analyses. A multiple logistic regression model, including age, sex, smoking history, total tumor size, invasive tumor size, histology, histologic differentiation, lymphatic invasion, vascular invasion, perineural invasion, and the number of harvested lymph nodes (LNs), was used to calculate the propensity score., Results: According to the pre-operative TNB, patients were classified into the no-TNB (n=823) and TNB (n=190) groups. After propensity score matching analysis, 380 patients were included in the no-TNB group (1:2 matching). Multivariable Cox analysis revealed that pre-operative TNB was a negative prognostic factor in patients with surgically resected stage IA NSCLC [hazard ratio (HR), 3.15; 95% confidence interval (CI): 1.49-6.67; P=0.003]. The 5-year locoregional and overall recurrence-free survival (RFS) rates were significantly lower in the TNB group than in the no-TNB group (88.3% vs . 96.8%, P=0.001; and 84.2% vs . 93.7%, P=0.02, respectively)., Conclusions: For patients with stage IA NSCLC, pre-operative TNB was a negative prognostic factor for recurrence. Surgical diagnosis and treatment without pre-operative tissue diagnosis may be considered first in patients with clinically early lung cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-419/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or vaccination against coronavirus disease 2019 [COVID-19]). From a multi-site cohort of frontline workers, we examined the heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels., Methods: Exposures included event count and event order, categorized into 7 permutations. Outcome was level of serum antibodies against receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding immunoglobulin). Means were examined up to 365 days after each of the first to seventh events., Results: Analysis included 5793 participants measured from 7 August 2020 to 15 April 2023. Hybrid immunity from infection before 1 or 2 vaccine doses elicited modestly superior antibody responses after the second and third events (compared with infections or vaccine doses alone). This superiority was not repeated after additional events. Among adults infected before vaccination, adjusted geometric mean ratios (95% confidence interval [CI]) of anti-RBD early response (versus vaccinated only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (.81-.94), and 0.99 (.85-1.15) after the second to fifth events, respectively. Post-vaccination infections elicited superior responses; adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated only) were 0.93 (.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the second to fifth events, respectively., Conclusions: Evidence of heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy., Competing Interests: Potential conflicts of interest. A. L. N. reports research funding from Pfizer and Vir Biotechnology for unrelated studies. M. G. reports grants from CDC, Abt Associates, Westat, and Vanderbilt University Medical Center and participation on the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics Infectious Diseases and Immunization Committee as co-chair. J. L. U. reports patent 16/900 798. R. S. reports consulting fees for the California legal case Ebers v. Castle Park, payment for lectures and presentations from the American Council of Life Insurers and 360 Dx/Beckman Coulter, patents 17/269 092 and 706843, and stock options for Geneticture, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

HCC (Hepatocellular carcinoma) is the most common malignant tumor; however, the molecular pathogenesis of these tumors is not well understood. Sorafenib, an approved treatment for HCC, inhibits angiogenesis and tumor cell proliferation. However, only ~30% of patients are sensitive to sorafenib and most show disease progression, indicating resistance to sorafenib. The present study used machine learning to investigate several mechanisms related to sorafenib resistance in liver cancer cells. This revealed that unphosphorylated interferon-stimulated genes (U-ISGs) were upregulated in sorafenib-resistant liver cancer cells, and the unphosphorylated ISGF3 (U-ISGF3; unphosphorylated STAT1, unphosphorylated STAT2 and IRF9) complex was increased in sorafenib-resistant liver cancer cells. Further study revealed that the knockdown of the U-ISGF3 complex downregulated U-ISGs. In addition, inhibition of the U-ISGF3 complex downregulated cell viability in sorafenib-resistant liver cancer cells. These results suggest that U-ISGF3 induced sorafenib resistance in liver cancer cells. Also, this mechanism may also be relevant to patients with sorafenib resistance., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Seo et al.)

While many studies have explored dietary substitutes and mobile apps separately, a combined approach to metabolic dysfunction-associated steatotic liver disease (MASLD) has not been investigated. This study evaluated short-term mobile interventions coupled with partial meal replacement in patients with MASLD. Sixty adults with MASLD and a body mass index ≥25 kg/m 2 from a health examination center were randomized into an intervention group using a mobile app with partial meal replacements or a control group receiving standard educational materials. Liver enzyme levels, lipid profiles, and anthropometric measurements were assessed at baseline and after 4 weeks. Twenty-five participants in the intervention group and 24 in the control group completed the trial. Significant reductions were observed in the intervention group for alanine aminotransferase (-28.32 versus [vs.] -10.67, p = 0.006) and gamma-glutamyl transferase (-27.76 vs. 2.79, p = 0.014). No significant changes in aspartate aminotransferase, body weight, or waist circumference were noted in the intervention group. Four weeks of mobile lifestyle intervention incorporating partial meal replacements improved liver enzyme profiles in patients with MASLD. This strategy demonstrated the potential for mitigating elevated liver enzyme levels without altering body weight or waist circumference. Comprehensive and longer-term research is needed to substantiate and elaborate these preliminary outcomes.

Purpose: Given its heterogeneity and diverse clinical outcomes, precise subclassification of Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment., Experimental Design: We recruited 2,626 patients with BCLC-C HCC from multiple centers, comprising training/test (n = 1,693) and validation cohorts (n = 933). The XGBoost model was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-, intermediate-, high-, and very high-risk subgroups based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C)., Results: The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-, 12-, and 24-month survival of patients with BCLC-C were 0.800, 0.831, and 0.715, respectively-significantly higher than those of the conventional models, which were consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKI) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy, particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high- to very high-risk subgroup., Conclusions: ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC., (©2024 American Association for Cancer Research.)

Background/aims: Four high-genetic barrier nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB), namely entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and besifovir dipivoxil maleate (BSV), have been established. The aim of this study is to investigate the efficacy of four high-genetic barrier NAs using a network meta-analysis of randomized trials and propensity score-matched cohorts., Methods: Systematic search was performed using PubMed, Cochrane library, and EMBASE and included randomized controlled trials and cohort studies that used propensity score matching. Studies on treatment-naïve CHB patients treated with ETV, TDF, TAF, or BSV were included. Outcomes included alanine aminotransferase normalization and hepatitis B e antigen seroclearance at week 48 and undetectable hepatitis B virus DNA at weeks 48 and 96. Network meta-analysis was performed to synthesize the results., Results: In total, 15,000 patients from 16 studies were included. In terms of 48- and 96-week virologic response (VR), TDF outperformed ETV with statistical significance (48 weeks: odds ratio [OR], 1.38; p < 0.001; 96 weeks: OR, 1.57; p = 0.004). ETV was ranked first for 48-week biochemical response (BR) and outperformed TDF (OR, 0.76; p = 0.028). In the sensitivity analyses, 48-week VR from randomized-controlled trials were compiled, and the same trend toward the superiority of TDF over ETV was found (OR, 1.51; p = 0.030)., Conclusion: Four high-genetic barrier NAs were compared, and TDF was more likely to achieve a VR after 48 weeks, while ETV provided a superior BR after 48 weeks.

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Kim et al.)

Background: Unexpected conversion to thoracotomy during planned video-assisted thoracoscopic surgery (VATS) can lead to poor outcomes and comparatively high morbidity. This study was conducted to assess preoperative risk factors associated with unexpected thoracotomy conversion and to develop a risk scoring model for preoperative use, aimed at identifying patients with an elevated risk of conversion., Methods: A retrospective analysis was conducted of 1,506 patients who underwent surgical resection for non-small cell lung cancer. To evaluate the risk factors, univariate analysis and logistic regression were performed. A risk scoring model was established to predict unexpected thoracotomy conversion during VATS of the lung, based on preoperative factors. To validate the model, an additional cohort of 878 patients was analyzed., Results: Among the potentially significant clinical variables, male sex, previous ipsilateral lung surgery, preoperative detection of calcified lymph nodes, and clinical T stage were identified as independent risk factors for unplanned conversion to thoracotomy. A 6-point risk scoring model was developed to predict conversion based on the assessed risk, with patients categorized into 4 groups. The results indicated an area under the receiver operating characteristic curve of 0.747, with a sensitivity of 80.5%, specificity of 56.4%, positive predictive value of 1.8%, and negative predictive value of 91.0%. When applied to the validation cohort, the model exhibited good predictive accuracy., Conclusion: We successfully developed and validated a risk scoring model for preoperative use that can predict the likelihood of unplanned conversion to thoracotomy during VATS of the lung.

Background: The assessment of long-term humoral and cellular immunity post-vaccination is crucial for establishing an optimal vaccination strategy., Methods: This prospective cohort study evaluated adults (≥18 years) who received a BA.4/5 bivalent vaccine. We measured the anti-receptor binding domain immunoglobulin G antibody and neutralizing antibodies (NAb) against wild-type and Omicron subvariants (BA.5, BQ.1.1, BN.1, XBB.1 and EG.5) up to 9 months post-vaccination. T-cell immune responses were measured before and 4 weeks after vaccination., Results: A total of 108 (28 SARS-CoV-2-naïve and 80 previously infected) participants were enrolled. Anti-receptor binding domain immunoglobulin G (U/mL) levels were higher at 9 months post-vaccination than baseline in SAR-CoV-2-naïve individuals (8,339 vs. 1,834, p<0.001). NAb titers against BQ.1.1, BN.1, and XBB.1 were significantly higher at 9 months post-vaccination than baseline in both groups, whereas NAb against EG.5 was negligible at all time points. The T-cell immune response (median spot forming unit/10 6 cells) was highly cross-reactive at both baseline (wild-type/BA.5/XBB.1.5, 38.3/52.5/45.0 in SARS-CoV-2-naïve individuals; 51.6/54.9/54.9 in SARS-CoV-2-infected individuals) and 4 weeks post-vaccination, with insignificant boosting post-vaccination., Conclusion: Remarkable cross-reactive neutralization was observed against BQ.1.1, BN.1, and XBB.1 up to 9 months after BA.4/5 bivalent vaccination, but not against EG.5. The T-cell immune response was highly cross-reactive., 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 Hyun, Nham, Seong, Yoon, Noh, Cheong, Kim, Yoon, Park, Gwak, Lee, Kim and Song.)

Objectives: Concomitant COVID-19 and influenza vaccination would be an efficient strategy. Although the co-administration of monovalent COVID-19 and influenza vaccinations showed acceptable immunogenicity, it remains unknown whether the bivalent COVID-19 vaccine could intensify immune interference. We aimed to evaluate the immunogenicity and safety of concomitant BA.5-based bivalent COVID-19 and influenza vaccination., Methods: An open-label, nonrandomized clinical trial was conducted for 154 age-matched and sex-matched healthy adults between October 2022 and December 2022. Participants received either a concomitant bivalent COVID-19 mRNA booster and quadrivalent influenza vaccination (group C) or separate vaccinations (group S) at least 4 weeks apart. Solicited and unsolicited adverse events were reported up to 6 months postvaccination. Immunogenicity was evaluated by anti-spike (S) IgG electrochemiluminescence immunoassay, focus reduction neutralization test, and hemagglutination inhibition assay., Results: Group C did not meet the noninferiority criteria for the seroconversion rates of anti-S IgG and neutralizing antibodies against the wild-type SARS-CoV-2 strain compared with group S (44.2% vs. 46.8%, difference of -2.6% [95% CI, -18 to 13.4]; 44.2% vs. 57.1%, difference of -13.0% [95% CI to -28.9 to 2.9]). However, group C showed a stronger postvaccination neutralizing antibody response against Omicron BA.5 (72.7% vs. 64.9%). Postvaccination geometric mean titers for SARS-CoV-2 and influenza strains were similar between groups, except for influenza B/Victoria. Most adverse events were mild and comparable between the study groups., Discussion: Concomitant administration of bivalent COVID-19 mRNA and quadrivalent influenza vaccines showed tolerable safety profiles and sufficient immunogenicity, particularly attenuating immune imprinting induced by previous ancestral vaccine strains., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: When performing laparoscopic spleen-preserving distal pancreatectomy (LSPDP), sometimes, anatomically challenging patients are encountered, where the pancreatic tail is deep in the splenic hilum. The purpose of this study was to discuss the experience with the surgical technique of leaving the deep pancreatic tail of the splenic hilum in these patients., Methods: Eleven patients who underwent LSPDP with remnant pancreatic tails between November 2019 and August 2021 at Samsung Medical Center in Seoul, Korea were included in the study. Their short-term postoperative outcomes were analyzed retrospectively., Results: The mean operative time was 168.6 ± 26.0 minutes, the estimated blood loss was 172.7 ± 95.8 mL, and the postoperative length of stay was 6.1 ± 1.0 days. All 11 lesions were in the body or tail of the pancreas and included 2 intraductal papillary mucinous neoplasms, 6 neuroendocrine tumors, 2 cystic neoplasms, and 1 patient with chronic pancreatitis. In 10 of the 11 patients, only the pancreatic tail was left inside the distal portion of the splenic hilum of the branching splenic vessel, and there was a collection of intraabdominal fluid, which was naturally resolved. One patient with a remnant pancreatic tail above the hilar vessels was readmitted due to a postoperative pancreatic fistula with fever and underwent internal drainage., Conclusion: In spleen preservation, leaving a small pancreatic tail inside the splenic hilum is feasible and more beneficial to the patient than performing splenectomy in anatomically challenging patients., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2024, the Korean Surgical Society.)

Objectives: Genetic factors are a major cause of osteoporosis. The present study evaluated the association of the apolipoprotein E (ApoE) genotype with bone mineral density (BMD) and its response to menopausal hormone therapy (MHT) in postmenopausal Korean women., Methods: This retrospective cohort study included 172 postmenopausal women with no endocrine diseases, medications, or lifestyles that would affect bone metabolism and who were continuously treated with MHT for at least 2 years. BMDs were measured at baseline and periodically., Results: Linear regression analysis demonstrated similar baseline BMDs at the lumbar spine, but significantly lower at the femur neck and total hip in the ApoE ε4 carrier than in the noncarrier group, after controlling for age, body mass index, and history of MHT usage. Overall, the Wilcoxon signed rank test demonstrated that MHT increased the BMD percentage change at all three regions, and the Generalized Estimating Equation (GEE) demonstrated significant time trends at the lumbar spine and femur neck. ApoE ε4 noncarriers exhibited a significant time trend in BMD changes at the femur neck, whereas ε4 carriers exhibited a time trend at the lumbar spine. However, BMD changes at each time point were comparable at all regions between the groups. Notably, GEE adjusted for baseline characteristics and BMD revealed a significant interaction effect of time and ApoE ε4 allele in BMD changes at the femur neck., Conclusions: Postmenopausal Korean women carrying the ApoE ε4 allele demonstrated a lower hip BMD compared with ε4 noncarriers. Furthermore, the ε4 allele may modulate hip BMD responses to MHT., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © by The Korean Society of Menopause.)

Purpose: The most recent procedure for pectus excavatum repair involves crane-powered entire chest wall remodeling, which employs crane lifting, multiple-bar approach, bridge stabilization, and sandwich techniques. This resulted in a paradigm shift in pectus deformity repair from merely lifting the sunken bone to remodeling the chest wall into normal anatomy., Methods: We analyzed 649 patients who underwent surgery for pectus excavatum or complex combined deformities between March 2018 and January 2022. A crane with sternal wiring or screwing was used to lift the chest wall without using the pectus bar turning power. Multiple bars with bridge connections were placed to eliminate bar displacement. Modified sandwich techniques were applied to relieve the lower coastal flare (flare-buster) and focal protuberance (magic string)., Results: The mean age of the patients included in the study was 12.2 years (range: 3-45 years). A single bar was used for 202 patients until 2021. For the multiple-bar technique, parallel bars (n = 142), crossbars (n = 166), and crossbars plus upper horizontal bars (XI pattern; n = 139) were used. The overall complication rate was 6.2 %. There was no cases of bar displacement were observed, but other minor complications such as pneumothorax (n = 20, 3.1 %), pleural effusion (n = 7, 1.1 %), and wound infection (n = 5, 0.8 %) were detected. Three patients required reoperation (infection, two: hemorrhage, one)., Conclusions: The crane-powered entire chest wall remodeling technique improved the safety and comprehensiveness of the repair procedure. By incorporating bridge stabilization and the use of multiple bars, we effectively resolved the issues related to bar displacement and incomplete repair., Type of Study: Retrospective Cohort Study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to evaluate whether deep learning-based detection and quantification of brain metastasis (BM) may suggest treatment options for patients with BMs., Methods: The deep learning system (DLS) for detection and quantification of BM was developed in 193 patients and applied to 112 patients that were newly detected on black-blood contrast-enhanced T1-weighted imaging. Patients were assigned to one of 3 treatment suggestion groups according to the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) recommendations using number and volume of the BMs detected by the DLS: short-term imaging follow-up without treatment (group A), surgery or stereotactic radiosurgery (limited BM, group B), or whole-brain radiotherapy or systemic chemotherapy (extensive BM, group C). The concordance between the DLS-based groups and clinical decisions was analyzed with or without consideration of targeted agents. The performance of distinguishing high-risk (B + C) was calculated., Results: Among 112 patients (mean age 64.3 years, 63 men), group C had the largest number and volume of BM, followed by group B (4.4 and 851.6 mm 3 ) and A (1.5 and 15.5 mm 3 ). The DLS-based groups were concordant with the actual clinical decisions, with an accuracy of 76.8% (86 of 112). Modified accuracy considering targeted agents was 81.3% (91 of 112). The DLS showed 95% (82/86) sensitivity and 81% (21/26) specificity for distinguishing the high risk., Conclusion: DLS-based detection and quantification of BM have the potential to be helpful in the determination of treatment options for both low- and high-risk groups of limited and extensive BMs., Clinical Relevance Statement: For patients with newly diagnosed brain metastasis, deep learning-based detection and quantification may be used in clinical settings where prompt and accurate treatment decisions are required, which can lead to better patient outcomes., Key Points: • Deep learning-based brain metastasis detection and quantification showed excellent agreement with ground-truth classifications. • By setting an algorithm to suggest treatment based on the number and volume of brain metastases detected by the deep learning system, the concordance was 81.3%. • When dividing patients into low- and high-risk groups, the sensitivity for detecting the latter was 95%., (© 2023. The Author(s).)

Purpose: This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1 cells and prostatitis-induced by 17β-estradiol and dihydrotestosterone in a rat model, focusing on its therapeutic potential for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)., Materials and Methods: RWPE-1 cells were stratified in vitro into three groups: (1) controls, (2) cells with LPS-induced inflammation, and (3) cells with LPS-induced inflammation and treated with CBD. Enzyme-linked immunosorbent assays and western blots were performed on cellular components and supernatants after administration of CBD. Five groups of six Sprague-Dawley male rats were assigned: (1) control, (2) CP/CPPS, (3) CP/CPPS and treated with 50 mg/kg CBD, (4) CP/CPPS and treated with 100 mg/kg CBD, and (5) CP/CPPS and treated with 150 mg/kg CBD. Prostatitis was induced through administration of 17β-estradiol and dihydrotestosterone. After four weeks of CBD treatment, a pain index was evaluated, and prostate tissue was collected for subsequent histologic examination and western blot analysis., Results: CBD demonstrated efficacy in vivo for CP/CPPS and in vitro for inflammation. It inhibited the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway by activating the CB2 receptor, reducing expression of interleukin-6, tumor necrosis factor-alpha, and cyclooxygenase-2 (COX2) (p<0.01). CBD exhibited analgesic effects by activating and desensitizing the TRPV1 receptor., Conclusions: CBD inhibits the TLR4/NF-κB pathway by activating the CB2 receptor, desensitizes the TRPV1 receptor, and decreases the release of COX2. This results in relief of inflammation and pain in patients with CP/CPPS, indicating CBD as a potential treatment for CP/CPPS., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Background: Atezolizumab+bevacizumab (AB) and lenvatinib have been proposed as first-line treatment options for patients with advanced hepatocellular carcinoma (HCC), but comparative efficacy and associated factors are controversial., Materials and Methods: This real-world multicenter study analysed patients with HCC who received AB (n=169) or lenvatinib (n=177)., Results: First, 1:1 propensity score matching (PSM) was performed, resulting in 141 patients in both the AB and lenvatinib groups. After PSM, overall survival (OS) was better in the AB group than in the lenvatinib group [hazard ratio (HR)=0.642, P=0.009], but progression-free survival (PFS) did not vary between the two groups (HR=0.817, P=0.132). Objective response rate (ORR) was also similar between AB and lenvatinib (34.8% vs. 30.8%, P=0.581). In a subgroup of patients with objective responses (OR, n=78), OS (HR=0.364, P=0.012) and PFS (HR=0.536, P=0.019) were better in the AB group (n=41) than in the lenvatinib group (n=37). Time-to-progression from time of OR was also better in the AB group (HR=0.465, P=0.012). Importantly, residual liver function was a significant factor related to OS in both treatments. Child-Pugh score following cessation of the respective treatments was better in the AB group (n=105) than in the lenvatinib group (n=126) (median 6 versus 7, P=0.008), and proportion of salvage treatment was also higher in the AB group (52.4% versus 38.9%, P=0.047). When we adjusted for residual liver function or salvage treatment, there was no difference in OS between the two treatments., Conclusion: Our study suggests that residual liver function and subsequent salvage treatments are major determinants of clinical outcomes in patients treated with AB and lenvatinib; these factors should be considered in future comparative studies., 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 Han, Sung, Yoo, Cho, Lee, Yang, Kim, Nam, Lee, Kim, Lee, Song, Song, Kwon, Kim, Bae, Jang, Choi and Yoon.)

Introduction: Patients with hematological diseases experience complications related to portal hypertension, including life-threatening complications such as variceal bleeding., Methods: We analyzed the prognosis of patients with hematological diseases and portal hypertension treated with transjugular intrahepatic portosystemic shunts (TIPS) or portal vein stents. We retrospectively assessed patients with hematological diseases and portal hypertension who had variceal bleeding. We evaluated the characteristics and prognosis of the enrolled patients. A total of 11 patients with hematological diseases who underwent TIPS, or portal vein stenting, were evaluated., Results: The median follow-up period was 420 days. Of the 11 patients, eight showed resolution of portal hypertension and its complications following TIPS, or stent insertion. One patient experienced rebleeding due to incomplete resolution of portal hypertension, and two other patients also experienced rebleeding because they underwent TIPS closure or revision due to repetitive hepatic encephalopathy., Conclusion: Portosystemic shunt and stent installation are effective treatment options for portal hypertension due to hematological diseases., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Kim et al.)

Importance: Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited., Objective: To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents., Design, Setting, and Participants: Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms., Exposure: Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records., Main Outcome and Measures: Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence., Results: Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose., Conclusion and Relevance: The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Background/aim: Metastasis to the pancreas is rare, and the benefit of resection for secondary pancreatic cancer is poorly defined. Furthermore, there are no guidelines for pancreatic metastasectomy in such patients. The purpose of this study was to discuss our experience with the operative management of secondary pancreatic cancer., Patients and Methods: This retrospective study included 76 patients who underwent pancreatic metastasectomy for secondary pancreatic cancer between January 2000 and December 2020 at Samsung Medical Center, Seoul, Republic of Korea., Results: Among the study subjects, 44 underwent distal pancreatectomy, 21 pancreaticoduodenectomy, 5 total pancreatectomy, and 6 enucleation or wedge resection for metastasis. The overall survival (OS) and recurrence-free survival (RFS) were higher in the patients with RCC than in patients with other malignancies (p=0.004 and p=0.051, respectively). Statistically significant differences were not observed in OS and RFS between patients with right RCC (rRCC) or left RCC (lRCC; p=0.523 and p=0.586, respectively)., Conclusion: Pancreatic metastasectomy may offer promising outcomes regarding curative intent in instances of secondary pancreatic metastasis, particularly in the context of RCC. However, regarding the side of primary RCC, no statistically significant differences were found in OS and RFS between rRCC and lRCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Continuous administration of oxaliplatin, the most widely used first-line chemotherapy drug for colorectal cancer (CRC), eventually leads to drug resistance. Increasing the sensitivity of CRC cells to oxaliplatin is a key strategy to overcome this issue. Impairment of mitochondrial function is a pivotal mechanism determining the sensitivity of CRC to oxaliplatin. We discovered an inverse correlation between Translocase of Outer Mitochondrial Membrane 20 (TOMM20) and oxaliplatin sensitivity as well as an inverse relationship between TOMM20 and HECT, UBA, and WWE domain containing E3 ligase 1 (HUWE1) expression in CRC. For the first time, we demonstrated that HUWE1 ubiquitinates TOMM20 directly and also regulates TOMM20 degradation via the PARKIN-mediated pathway. Furthermore, we showed that overexpression of HUWE1 in CRC cells has a negative effect on mitochondrial function, including the generation of ATP and maintenance of mitochondrial membrane potential, leading to increased production of ROS and apoptosis. This effect was amplified when cells were treated simultaneously with oxaliplatin. Our study conclusively shows that TOMM20 is a novel target of HUWE1. Our findings indicate that HUWE1 plays a critical role in regulating oxaliplatin sensitivity by degrading TOMM20 and inducing mitochondrial damage in CRC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Reverse transcription real-time PCR (rRT-PCR) has been a gold-standard method to detect SARS-CoV-2, for which quality assessment of nucleic acids (NAs) is not needed. In order to prepare for future use, we evaluated NA quality from archived SARS-CoV-2 rRT-PCR samples., Methods: NA samples were collected in February 2021 and extracted using the QIAamp DSP Virus Spin Kit, (53 SARS-CoV-2-positive and 100 SARS-CoV-2-negative). Quality, quantity, and purity of NA were measured spectrophotometrically or fluorescently. Droplet digital PCR was used to characterize the double strand DNA (dsDNA) origin and composition by quantifying 16S rDNA and RPP30., Results: The RIN and purity were not significantly different between groups (p = 0.3828). RNA quantity was significantly higher than dsDNA in both groups (p < 0.0001); both dsDNA and RNA quantity were significantly higher in positive samples (dsDNA, RNA p = 0.021). For dsDNA, 16S rDNA copies were significantly greater than RPP30 in both groups (p < 0.0001), and RPP30 were significantly higher in positive samples (p < 0.0001)., Conclusions: Archived NA quality after SARS-CoV-2 rRT-PCR was guaranteed for subsequent molecular research using human or bacterial DNA, especially for short targets., 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.)