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Aim: Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics., Methods: This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX., Results: The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis., Conclusions: A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups., (© 2024 Japan Society of Hepatology.)

Background: We have been able to use molecular targeted agents for unresectable hepatocellular carcinoma since 2009, and immune checkpoint inhibitors have been approved in recent years. We assessed the efficacy of systemic therapy in Hiroshima University Hospital by each era., Methods: A total of 357 patients who were treated with sorafenib, lenvatinib, atezolizumab plus bevacizumab combination therapy, or durvalumab plus tremeliumab combination therapy as first-line systemic therapy in our hospital from November 2009 to December 2023 were enrolled in this retrospective cohort study. We divided the years from 2009 to 2023 into the following three periods: cohort I, 2009-2016, the single-molecular targeted agent era; cohort II, 2017-2020, the multi-molecular targeted agent era; and cohort III, 2020-2023, the immuno-oncology era., Results: The median survival time was 9.5 months in cohort I, 15.8 months in cohort II, and 20.2 months in cohort III. The median survival time in cohort III was significantly (p < 0.01) longer than in the other cohorts. The overall response rate by mRECIST was 4.1% in cohort I, 28.7% in cohort II, and 47.2% in cohort III. The disease control rate was 41.6% in cohort I, 61.2% in cohort II, and 73.6% in cohort III. Both overall response rate and disease control rate significantly increased by era., Conclusions: We consider that advancements in systemic therapy, along with changes in treatment strategies, such as sequential therapy after progression, contribute to the prolonged prognosis across different eras., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

A 58-year-old man visited an orthopedic clinic complaining of pain in his right lower back and numbness in his lower limbs for one month. Imaging tests revealed a tumorous lesion from the left side of the second lumbar vertebra to the paraspinal muscles. CT-guided biopsy of the tumor was performed, and immunostaining results diagnosed hepatocellular carcinoma (HCC). Although the liver showed signs of chronic liver damage, no primary tumor was found within the liver or in other organs. Blood tests showed negative hepatitis virus markers for both HBV and HCV. The tumor markers AFP, AFP-L3, and DCP were high. Because he developed spinal cord compression syndrome due to a lumbar tumor, radiation therapy and denosumab administration were performed. Subsequently, systemic therapy with durvalumab plus tremelimumab was started. In the year following the start of treatment, the tumor has shrunk, and no new lesions have been observed. Tumor markers have also decreased. We have experienced a case of HCC in the lumbar spine without a primary tumor in the liver. This is a very rare case, and the combination therapy with durvalumab and tremelimumab resulted in a complete response, which we consider to be a valuable case., (© 2024. The Author(s).)

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of unknown cause for which no curative treatments have been developed. Cytokines play an important role in the pathogenesis of UC, and therapies targeting specific cytokines have been successful in treating refractory UC. The purpose of this study was to measure mucosal cytokines in UC and identify those that contribute to non-relapsing mucosal healing diagnosed by endoscopy., Methods: This prospective, observational study included 163 patients with UC. The mucosa was evaluated by Mayo Endoscopic Subscore (MES) and linked color imaging (LCI) at the time of endoscopy, and cytokine mRNA expression in biopsy tissue taken from the same site was quantified by real-time PCR and compared with endoscopic findings. The relationship between cytokine mRNA expression and endoscopic findings was investigated., Results: Cytokines such as IFNγ, IL-1β, IL-8, IL-17A, and IL-23 were significantly elevated in proportion to endoscopic severity of MES and LCI classification.Interestingly, we found differences in the expression of cytokines (e.g., IL-22 and IL-33) between MES and LCI classification according to disease severity. Additionally, pathway analysis based on RNA sequencing compared between LCI-A and LCI-B in the patients diagnosed as MES 0 revealed that IL-5 and IL-6 are involved in the finer differences in endoscopic mucosal redness., Conclusions: This study is the first to report the correlation between mucosal cytokine expression and the pathogenesis of mucosal healing (MH) in UC and supports the contribution of specific cytokines as molecular markers of MH or in the pathogenesis of MH in UC., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. 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.)

Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r 2  = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Radiotherapy is one of the definitive treatments for head and neck squamous cell carcinoma, especially early-stage glottic squamous cell carcinoma. Although there are several studies on the initiation weekday of cancer treatment, there are very few studies in the radiotherapy field. Thus, the present study investigated whether the initiation weekday of radiotherapy affects the local control rate for stage 1 glottic squamous cell carcinoma. A total of 105 patients with stage 1 glottic squamous cell carcinoma underwent definitive radiotherapy alone between 2007 and 2021. The group in which radiotherapy was started between Monday and Wednesday was compared with the group in which radiotherapy was started on Thursday or Friday. Sixty-seven patients started radiotherapy between Monday and Wednesday and 38 on Thursday or Friday. The 5-year local control rate was 98% (95% confidence interval: 94-100%) in the Monday-Wednesday group and 83% (95% confidence interval: 71-96%) in the Thursday-Friday group, with a significant difference (P = 0.005). On multivariate analysis including age, overall administration time (days), fractionation, irradiation field size and initiation weekday of radiotherapy, no factors other than initiation weekday affecting local control were identified. Radiotherapy toxicity did not differ between the two groups. For stage 1 glottic squamous cell carcinoma, starting radiotherapy on Thursday or Friday is associated with a lower local control rate; therefore, radiotherapy should be started by Wednesday., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Study Design: Experimental study., Objective: We sought to elucidate the association between ligamentum flavum thickening and tissue buckling, and the clinical and imaging factors related to buckling by comparing the ligamentum flavum thickness on MRI images and within the actual tissue., Summary of Background Data: Ligamentum flavum thickening is a main contributor to lumbar spinal canal stenosis. Buckling of the tissue may contribute to ligamentum flavum thickening along with tissue hypertrophy; however, this association has not been established conclusively., Materials and Methods: Ligamentum flavum samples (135 ligament samples) from 70 patients with lumbar spinal canal stenosis were evaluated. The ligamentum flavum thicknesses on magnetic resonance imaging (MRI) and in the tissue samples were compared to assess for the presence of buckling. The ligamentum flavum samples were divided into groups with or without buckling based on the difference between their thicknesses on MRI and in the tissues. The Pearson correlation coefficient test was used to assess the relationships between the LF thicknesses on MRI and in the tissues, MRI-tissue difference and LF thickness in the tissues, and MRI-tissue difference and LF thickness on MRI. Further, differences between the buckling+ and buckling- groups were compared using the unpaired t-test (LF thickness on MRI, LF thickness in the tissues, age, disc angle, and disc height) and χ2 (disc level, disc degeneration, and receival/nonreceival of dialysis) test., Results: The ligamentum flavum thickness on MRI and in the tissues had a positive linear relationship, although the thickness was estimated to be significantly larger on MRI than in the tissues themselves. The ligamentum flavum with buckling had a larger thickness on MRI, less tissue hypertrophy, more severe disc degeneration, and was present in patients with a higher rate of dialysis. There were no differences in age and disc height, angle, or level between the two groups., Conclusions: Buckling of the ligamentum flavum coexists with tissue hypertrophy and contributes to perceived ligamentum thickening on imaging. Buckling of the ligamentum flavum tends to occur in less hypertrophied tissues and is associated with the grade of disc degeneration and the presence of other characteristics associated with spinal degeneration., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Several predictive factors of immune checkpoint inhibitor response have been reported, but there has not been sufficient exploration of which patients benefit from immune checkpoint inhibitor rechallenge. We report the case of a patient with non-small cell lung cancer who had 6 years of complete response with initial nivolumab treatment. After relapse, however, rechallenge with nivolumab did not result in tumour shrinkage or long-term response. Even in patients who had an exceptional response to the initial immune checkpoint inhibitor, long-term efficacy may not be achieved by immune checkpoint inhibitor rechallenge. Thorough investigation of biomarkers that predict efficacy of immune checkpoint inhibitor rechallenge is warranted., Competing Interests: Dr Takakura, Dr Washioka, Dr Murakami, Dr Koh declare no conflict of interest. Dr Akamatsu: Grants or contracts: Amgen Inc., Chugai Pharmaceutical Co. Ltd. Honoraria: Amgen Inc., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., MSD K.K., Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., AstraZeneca K.K., Bristol‐Myers Squibb., Eli Lilly Japan K.K., Nippon Kayaku. Co. Ltd., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd. Advisory Board: Amgen Inc, Janssen Pharmaceutical K.K., Sandoz, MSD. Committee: WCLC Patient Advocacy Committee. Dr Shibaki: Honoraria: AstraZeneca KK, Chugai Pharmaceutical Co. Ltd, MSD KK, Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co Ltd, Daiichi Sankyo Co., Ltd., Boehringer Ingelheim Japan Inc. Dr Shimizu: Grants: AbbVie, Eli Lilly, LOXO Oncology, Novartis, Daiichi‐Sankyo, Takeda Oncology, Bristol‐Myers Squibb, Eisai, Incyte, AstraZeneca, Pfizer, Chordia Therapeutics, Astellas, Parexel, IQVIA. Consulting fees: AbbVie, Chordia Therapeutics, Chugai, Daiichi‐Sankyo, Kyowa Kirin. Honoraria: Chugai, Taiho, MSD, IQVIA. Advisory Board: AbbVie, Chordia Therapeutics, Chugai, Daiichi‐Sankyo, Kyowa Kirin. Committee: ESMO Targeted Anticancer Therapies (TAT) Scientific Committee, Joint Scientific Committee Review External IRB Member of Phase 1 Trials in Hong Kong, HKSAR, China, Executive Committee of Asia Pacific Oncology Drug Development Consortium (APODDC). Dr Yamamoto: Grants: AstraZeneca, Chugai, MSD, Taiho Pharmaceutical, Boehringer Ingelheim, Novartis, Abbvie, Amgen, Asahi Kasei, Janssen, Bristol‐Myers Squibb Japan, IQvia, EPS Corporation, Amgen, A2 Healthcare, Mebix, Ono Pharmaceutical. Consulting fees: AstraZeneca, Chugai, MSD, Lilly Japan, Amgen, Novartis, Ono Pharmaceutical. Honoraria: AstraZeneca, Chugai, MSD, Takeda, Acuuray, Abbvie, Amgen, Ono Pharmaceutical, Guardant Health, Kyorin, Daiichi Sankyo, Taiho Pharmaceutical, Tsumura & Co., TERUMO, Lilly Japan, Boehringer Ingelheim Japan, Novartis, Pfizer, Miyarisan Pharmaceutical, Merck Biopharma, Janssen. Advisory Board: AstraZeneca., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Portal hypertensive enteropathy (PHE) is a small-bowel lesion observed in patients with portal hypertension. The clinical significance of endoscopic findings in PHE remains unclear. We aimed to clarify the clinical significance and predictive factors of capsule endoscopic findings in patients with PHE based on long-term outcomes., Methods: This retrospective study enrolled 55 patients with PHE (33 males and 22 females; median age, 64 years; range, 23-87) followed for > 3 years using capsule endoscopy (CE) between February 2009 and May 2023. We evaluated the clinical factors affecting PHE exacerbations and the effects of PHE exacerbations on gastrointestinal bleeding by comparing exacerbated and unchanged PHE groups., Results: Overall, 3 (5%) patients showed improvement, 33 (60%) remained unchanged, and 19 (35%) showed exacerbation on follow-up CE. In the exacerbated group, the rates of worsened fibrosis-4 index, exacerbated esophageal varices, and exacerbated portal hypertensive gastropathy were significantly higher than those in the unchanged group (21%, 32%, and 42% vs. 3%, 6%, and 12%, respectively; P < 0.05), and the rate of splenectomy was significantly lower in the exacerbated group than in the unchanged group (5% vs. 39%, respectively; P < 0.01). In multivariate analysis, exacerbation of esophageal varices and absence of splenectomy were significantly associated with PHE exacerbation. The rate of gastrointestinal bleeding after follow-up CE was significantly high in the exacerbated group (log-rank, P = 0.037)., Conclusions: Exacerbation of esophageal varices and splenectomy were significantly associated with exacerbation of PHE. Exacerbated PHE requires specific attention to prevent gastrointestinal bleeding., (© 2024. The Author(s).)

The efficacy and safety of immune-checkpoint inhibitors (ICI) for the treatment of unresectable hepatocellular carcinoma are known. We explored ICI rechallenges with direct switching from 1 ICI regimen to another. This retrospective study included 16 patients who received atezolizumab-bevacizumab (Atezo+Bev) and durvalumab-tremelimumab (Dur+Tre) as the first-line and second-line combination therapy, respectively, at Hiroshima University Hospital. The radiological response and adverse event were evaluated in all patients. Of the 16 patients, 12 were male, and the median age at Atezo+Bev induction was 71 years. The reasons for medication changes were disease progression in 11 patients and adverse events in 5 patients. With Atezo+Bev and Dur+Tre initiation, the Barcelona-Clinic Liver-Cancer stage (A/B/C) progressed in 9/6/3 and 3/4/9 patients and the Child-Pugh classification (A/B/C) progressed in 12/4/0 and 9/6/3 patients, respectively. The disease control rate and overall response rate of Atezo+Bev were 87.5% and 58.3%, respectively, and of Dur+Tre were 62.5% and 0%, respectively. The most common immune-related adverse event in both the Atezo+Bev and Dur+Tre groups was colitis; 3 of the 5 patients with colitis on Atezo+Bev treatment had colitis with Dur+Tre, and 2 had exacerbations. Regarding liver function, ALBI score significantly decreased during Atezo+Bev, but not Dur+Tre, treatment. In patients with colitis following Atezo+Bev, subsequent Dur+Tre treatment may induce colitis recurrence or exacerbation. For immune-related adverse events other than colitis, Dur+Tre could provide relatively safe disease control while maintaining liver function., Competing Interests: This work was supported by JSPS KAKENHI Grant Number 23K07463, Takeda Science Foundation Grant Number 2022043779, 2022 Bristol-Myers Squibb KK Research Grants and by The Hiroshima University Fund “Nozomi H Foundation” subsidy for the promotion of cancer treatment research.TK received honorarium from Astra Zeneca and Chugai Pharma. The other authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: When evaluating response to immune checkpoint inhibitor therapy, the tumor sometimes initially swells before shrinking and ultimately responding, also called pseudo-progression. In this study, we analyzed whether tumor markers were useful for reflecting the treatment response., Methods: Thirty-three patients who were treated with durvalumab plus tremelimumab combination therapy (Dur + Tre) were enrolled. Their functional reserve was Child-Pugh grade A. Their tumor markers α-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), or AFP-Lectin 3 fraction (AFP-L3) were positive. Tumor markers were evaluated before treatment and at 1, 4, and 8 weeks after the start of treatment. The first radiological evaluation was carried out at 4 weeks and the second evaluation at 8-12 weeks. The responders included those with complete response and partial response and the nonresponders included those with stable disease (SD) and progression disease at best response evaluated by Response Evaluation Criteria in Solid Tumors., Results: In the responder group, the change ratio of AFP, DCP, and AFP-L3 specifically decreased at 8 weeks. In the nonresponder group, the change ratio of DCP specifically increased at 4 weeks. The optimal cut-off value to divide responders and nonresponders at 4 weeks was approximately -40%. The ratio of responders was 72.7% in the patients whose AFP or DCP decreased over 40% at 4 weeks., Conclusions: The change in tumor markers is a more useful predicter of tumor response to Dur + Tre than imaging evaluation alone., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 ( 1 ), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C -nucleoside GS-646089 ( 2 ) with broad antiviral activity against RSV (EC 50 = 3-46 nM), human metapneumovirus (EC 50 = 210 nM), human rhinovirus (EC 50 = 54-61 nM), and enterovirus (EC 50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [( S )-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo . 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

Background and Aims: Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease., Approach and Results: We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets., Conclusions: The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study aimed to clarify the population in whom the presence of metabolic dysfunction-associated fatty liver disease (MAFLD) especially contributes to recurrence after liver resection for non-B, non-C hepatocellular carcinoma (NBNC-HCC)., Methods: Of the 199 patients who underwent liver resection for NBNC-HCC, those who exceeded Milan criteria and with pathologically proven vascular invasion, intrahepatic metastasis, and positive resection margins were excluded, and the remaining 94 were eligible for this study. We explored factors contributing to postoperative recurrence in populations with and without advanced liver fibrosis., Results: Independent factors contributing to postoperative recurrence in the study population were male sex ( P  = 0.023) and presence of type 2 diabetes (DM) ( P  = 0.006) and advanced liver fibrosis ( P  < 0.001). Factors in cases with advanced liver fibrosis (n = 43) were non-overweight ( P  = 0.02), type 2 DM ( P  = 0.006), and preoperative alpha-fetoprotein level of 8.2 ng/ml or higher ( P  = 0.021). In cases without advanced liver fibrosis (n = 51), only presence of all three MAFLD criteria was related to recurrence., Conclusion: Liver fibrosis is a strong factor contributing to postoperative recurrence of NBNC-HCC, as previously reported. In patients with advanced liver fibrosis, presence of type 2 DM was the only factor associated with recurrence among MAFLD criteria. On the other hand, in patients without advanced liver fibrosis, the combination of all MAFLD criteria, rather than a specific criterion alone, contributed to recurrence. MAFLD criteria were found to have utility as predictors of postoperative recurrence in NBNC-HCC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment.

This study investigated whether the progression of liver fibrosis affects the prevalence of sarcopenia and incidence of decreased gait speed in older patients with chronic liver disease (CLD). Patients with CLD aged ≥ 60 years were classified into low, intermediate, and high fibrosis 4 (FIB-4) index groups according to the degree of liver fibrosis. The prevalence of sarcopenia and incidence of decreased gait speed (< 1.0 m/s) were compared among the three groups. Logistic regression analysis was performed to investigate factors affecting the risk of decreased gait speed. No significant difference was observed in the prevalence of sarcopenia among the three groups, but the incidence of decreased gait speed significantly differed (p = 0.029). When analyzed individually, a significant difference in decreased gait speed incidence was observed between the high and low FIB-4 index groups (p = 0.014). In logistic regression analysis, the progression of liver fibrosis (odds ratio: 1.32, 95% confidence interval: 1.13-1.55) and lower extremity muscle strength (LEMS) (odds ratio: 0.92, 95% confidence interval: 0.88-0.97) were significantly associated with decreased gait speed. As liver fibrosis progresses in older patients with CLD, it becomes important to focus on not only skeletal muscle mass and grip strength, but also gait speed and LEMS., (© 2024. The Author(s).)

Aim: Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is used as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). Serious adverse events (AEs), including rupture of esophagogastric varices, have been seen during treatment. Therefore, the relationships of efficacy, safety, and portal hypertension (PH) were analyzed., Methods: A total of 146 patients with u-HCC and Child-Pugh Scores of 5-7 received Atezo + Beva. Prophylactic treatment for varices was performed for patients with the risk of rupture of varices before the start of Atezo + Beva. A propensity score-matched cohort was created to minimize the risk of potential confounders. Efficacy was assessed in 41 propensity score-matched pairs. AEs were assessed between patients without PH (n = 80) and with PH (n = 66)., Results: In patients without PH and with PH, median overall survival was 18.4 months and 18.8 months (p = 0.71), and median progression-free survival was 8.6 months and 5.8 months (p = 0.92), respectively. On the best radiological response evaluation for Response Evaluation Criteria in Solid Tumors, the objective response rate was 31.7% and 26.8% (p = 0.81), respectively. Variceal rupture occurred in three patients with PH, but there were no significant differences in the occurrence of variceal rupture (p = 0.090) and Grade 3-4 AEs between patients without and with PH., Conclusions: No significant differences in efficacy and safety were observed with PH. Prophylactic treatment for varices before the start of Atezo + Beva would allow treatment to continue relatively safely., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Context: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation., Objectives: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care., Methods: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738)., Results: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC., Conclusion: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification., Methods: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis., Results: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%)., Conclusions: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Understanding the pharmacokinetics of drug candidates of interest in the brain and evaluating drug delivery to the brain are important for developing drugs targeting the brain. Previously, we demonstrated that a CAG repeat-binding small molecule, naphthyridine-azaquinolone (NA), resulted in repeat contraction in mouse models of dentatorubral-pallidoluysian atrophy and Huntington's disease caused by aberrant expansion of CAG repeats. However, the intracerebral distribution and drug deliverability of NA remain unclear. Here, we report three-dimensional whole-brain imaging of an externally administered small molecule using tissue clearing and light sheet fluorescence microscopy (LSFM). We designed and synthesized an Alexa594-labeled NA derivative with a primary amine for whole-brain imaging (NA-Alexa594-NH 2 ), revealing the intracerebral distribution of NA-Alexa594-NH 2 after intraparenchymal and intracerebroventricular administrations by whole-brain imaging combined with tissue clearing and LSFM. We also clarified that intranasally administered NA-Alexa594-NH 2 was delivered into the brain via multiple nose-to-brain pathways by tracking the time-dependent change in the intracerebral distribution. Whole-brain imaging of small molecules by tissue clearing and LSFM is useful for elucidating not only the intracerebral distribution but also the drug delivery pathways into the brain.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2-12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months-not reached) and 4.0 months (range, 2.5-6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02-0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003-0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.

Background: Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma., Methods: This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration., Results: Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol · Cre ( P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L ( P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch., Conclusion: Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited., Competing Interests: The authors declare no conflict of interest., (©2023 Tottori University Medical Press.)

Background: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma., Methods: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood., Results: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies., Conclusions: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma., (© 2023. Springer Nature Limited.)

Aim: Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors., Methods: Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival., Results: During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months., Conclusion: Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor., (© 2023. Asian Pacific Association for the Study of the Liver.)

The purpose of this study was to evaluate the safety and efficacy of BL 23 (Shenshu) acupuncture on serum cytokine levels. Sixteen healthy adults were randomized into the BL 23 acupuncture group or pseudo-acupuncture group and changes of serum cytokines were analyzed. The changes in IL-13, TNF-α, and GM-CSF levels were different between the BL 23 acupuncture group and pseudo-acupuncture group (P < 0.05). No adverse events associated with acupuncture were observed. In conclusion, BL 23 acupuncture can suppress immune responses via decreases in TNF-α and suppression of increases in IL-13 and GM-CSF. This study elucidated some of the mechanisms of the acupuncture effect., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to disclose in this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aim: The prognosis of acute liver failure (ALF) remains poor, and liver transplantation is an alternative treatment option. Assessing the prognosis of ALF is important in determining treatment strategies. Here, we investigated clinical factors including serum pro-inflammatory cytokine levels that are associated with the prognosis of ALF., Methods: Sixty-six patients who developed ALF were enrolled in this study. Serum concentrations of 12 pro-inflammatory cytokines were measured on admission. The prognosis and factors associated with survival and development of hepatic coma were analyzed., Results: Of 66 patients, 4 patients underwent liver transplantation, and 49 patients were rescued without liver transplantation, while the remaining 13 patients died. Serum concentrations of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-13, TNF, IFN -γ, IP-10, and G-CSF were significantly elevated in ALF patients. IL-4 and IL-8 levels were higher in patients who underwent liver transplantation or died than in rescued patients. Multivariable analysis identified age ≥ 55 years and IL-4 ≥ 1.2 pg/mL on admission as independent factors for mortality. Serum IL-8 levels were higher in patients with hepatic coma, and prothrombin-international normalized ratio ≥ 3.5 and IL-8 ≥ 77.2 pg/mL on admission were associated with development of hepatic coma after admission., Conclusion: Serum levels of several pro-inflammatory cytokines were elevated in ALF patients. IL-4 and IL-8 were correlated with survival and development of hepatic coma after admission, respectively. Measurement of serum pro-inflammatory cytokines seems to be useful for the management of ALF., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aim: Accelerated hyperfractionation (AHF) is used in head and neck cancer to improve the local control (LC) rate, but reports of outcomes for early-stage GC are limited. The outcomes of radiotherapy (RT) for stage 1 glottic carcinoma (GC) were retrospectively analyzed, comparing AHF and once-daily fractionation (ODF) using 2.0-2.4 Gy., Patients and Methods: A total of 102 patients with stage 1 GC underwent RT alone between 2007 and 2021, with 43 in the AHF group and 59 in the ODF group. A p-value less than 0.05 was considered to indicate a significant difference., Results: The 5-year LC rate was 98% in the AHF group and 91% in the ODF group (p=0.19). During RT, significantly more patients in the AHF group required opioids due to mucositis than in the ODF group (74% vs. 25%, p<0.001), and the rate of aspiration pneumonia tended to be higher in the AHF group than in the ODF group (7% vs. 0%, p=0.072)., Conclusion: There was no difference in the LC rate between AHF and ODF for stage 1 GC. Moreover, the AHF group required opioids at a higher rate and tended to have a higher risk of developing aspiration pneumonia., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by excessive lipid accumulation in the liver, and its global incidence is increasing. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are oral antidiabetes drugs that promote glucose excretion into the urine and have been reported to exert therapeutic effects in NAFLD, but liver stiffness measurements (LSMs) determined by transient elastography are inconsistent. In addition, the effects of SGLT2is on the FibroScan-aspartate aminotransferase (FAST) scores have not been reported. We evaluated the effect of SGLT2is on patients with NAFLD complicated by type 2 diabetes using biochemical tests, transient elastography, and FAST scores., Methods: Fifty-two patients with type 2 diabetes complicated by NAFLD who started SGLT2i treatment between 2014 and 2020 at our hospital were selected from the database. Pre- and post-treatment serum parameters, transient elastography, and FAST scores were compared., Results: After 48 weeks of SGLT2i treatment, body weight, fasting blood glucose, hemoglobin A1c, AST, alanine aminotransferase, gamma-glutamyltransferase, uric acid, fibrosis-4 index, and AST to platelet ratio index improved. Median LSM decreased from 7.0 kPa to 6.2 kPa ( P  = 0.023) and the median controlled attenuation parameter decreased from 304 dB/m to 283 dB/m ( P  = 0.022). Median FAST score decreased from 0.40 to 0.22 ( P  < 0.001), and the number of cases with a cutoff value of ≥0.35 decreased from 15 to 6 ( P  = 0.001)., Conclusion: SGLT2i use not only improves weight loss and blood glucose levels but also improves hepatic fibrosis by ameliorating hepatic steatosis and inflammation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting the immune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase.

A human protein heterogeneous ribonucleoprotein U (hnRNP U) also known as Scaffold attachment factor A (SAF-A) and its orthologous rat protein SP120 are abundant and multifunctional nuclear protein that directly binds to both DNA and RNA. The C-terminal region of hnRNP U enriched with arginine and glycine is essential for the interaction with RNA and the N-terminal region of SAF-A termed SAP domain has been ascribed to the DNA binding. We have reported that rat hnRNP U specifically and cooperatively binds to AT-rich DNA called nuclear scaffold/matrix-associated region (S/MAR) although its detailed mechanism remained unclear. In the present study analysis of hnRNP U deletion mutants revealed for the first time that a C-terminal domain enriched with Arg-Gly (defined here as 'RG domain') is predominantly important for the S/MAR-selective DNA binding activities. RG domain alone directly bound to S/MAR and coexistence with the SAP domain exerted a synergistic effect. The binding was inhibited by netropsin, a minor groove binder with preference to AT pairs that are enriched in S/MAR, suggesting that RG domain interacts with minor groove of S/MAR DNA. Interestingly, excess amounts of RNA attenuated the RG domain-dependent S/MAR-binding of hnRNP U. Taken together, hnRNP U may be the key element for the RNA-regulated recognition of S/MAR DNA and thus contributing to the dynamic structural changes of chromatin compartments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Miyaji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new classification system for fatty liver disease. In this study, we investigated the clinical characteristics of patients with MAFLD-hepatocellular carcinoma (HCC) in comparison with those with nonalcoholic fatty liver disease (NAFLD) and considered the validity and challenges of the new criteria., Methods: This study included 237 untreated non-B, non-C HCC patients with hepatic steatosis. We examined the profile and laboratory findings of patients with MAFLD-HCC and NAFLD-HCC. We also classified MAFLD-HCC patients according to the factors on which the diagnosis was based and compared their clinical characteristics., Results: A total of 222 (94%) and 101 (43%) patients were diagnosed with MAFLD and NAFLD, respectively. MAFLD-HCC patients were more likely to be male than NAFLD-HCC, but there were no significant differences in metabolic indices, noninvasive liver fibrosis score or HCC status. In a study of MAFLD-HCC patients by diagnostic factor, those with overweight only were younger and had advanced liver fibrosis histologically, and when limited to patients younger than 70 years, the majority were overweight. Redefinition of overweight as BMI ≥ 25 reduced the number of MAFLD-HCC patients by only 5, from 222 to 217., Conclusions: MAFLD accounted for the majority of non-B, non-C HCC cases with hepatic steatosis. Examination of additional cases and revision of the detailed criteria is needed so that it can be used to efficiently select patients with fatty liver who are at high risk of developing HCC., (© 2023. The Author(s).)

To our knowledge, there have been no reports of first-line lenvatinib (LEN) and LEN re-challenge following atezolizumab/bevacizumab (Atezo-Bev) failure in the same patient. We herein report a patient with advanced hepatocellular carcinoma who failed either 1st line LEN and 2nd line Atezo-Bev, and successfully achieved complete response to LEN rechallenge with sequencial transcatheter arterial chemoembolization (TACE). This patient had a poor response to TACE before immunotherapy and introduction of molecular-targeted drugs but showed a good response to selective TACE after LEN rechallenge. Our findings suggest the need to reconsider the use of molecular-targeted drugs and TACE with advances in immunotherapy.

Competing Interests: Conflict of interest: the authors declare no conflict of interest.

Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is currently positioned as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). It may be difficult to decide whether to continue this treatment if radiological response is assessed as stable disease (SD). Therefore, the relationship between radiological response and prognosis was analyzed. A total of 109 patients with u-HCC and Child-Pugh Score of 5-7 received this treatment. Radiological response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at the first and second evaluations. Of SD patients (n = 71) at the first RECIST evaluation, partial response, SD, and progressive disease (PD) were seen in 10, 55, and 6 patients, respectively, at the second evaluation. On multivariate analysis, in patients with SD at the first RECIST evaluation, a 25% or greater increase in the alpha-fetoprotein (AFP) value from initiation of treatment (odds ratio, 7.38; p = 0.037) was the independent factor for PD at the second evaluation. In patients with SD (n = 59) at the second RECIST evaluation, decreased AFP from initiation of treatment (hazard ratio, 0.46; p = 0.022) was the independent factor related to progression-free survival on multivariate analysis. AFP trends could help decide the Atezo + Beva treatment strategy.

We report a rare case of acute liver injury by daily exposure to small amounts of chloroform in non-alcoholic fatty liver disease (NAFLD) patient. The patient had been followed up in our hospital every 3 months. Although his alanine aminotransferase (ALT) levels were steady around 30 ~ 60 U/L until August 2014, ALT level was spontaneously increased to more than 1,000 U/L at the follow-up point in late August 2014. As he was diagnosed as acute liver injury by chloroform exposure, we withdrew him from the exposure of chloroform and treated him with 600 mg/day of ursodeoxycholic acid. Afterwards, his ALT level rapidly improved and normalized within 1 month. To verify the influences of chloroform exposure, we measured plasma chloroform levels by gas chromatography. Although plasma chloroform concentration was 7.1 ng/ml (normal range: < 0.2 ng/ml) at the time of liver injury, the concentration had decreased to 0.7 ng/ml by 1 month later. Despite the fact that he had put on a face mask to protect from aspiration of chloroform, liver injury still occurred in the present case. Chloroform has a high solubility for lipids and accumulation of lipids in the liver might become a risk factor for liver injury by chloroform., (© 2023. Japanese Society of Gastroenterology.)

Background: Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) may alter mitochondrial function and energy production in immune cells in HIV (+) patients., Methods: Cellular bioenergetics were determined in PBMCs from HIV-1 (-) participants exposed to TAF versus TDF in vitro, at a comparable concentration to a clinically relevant plasma exposure. A decrease in cellular oxygen consumption rate (OCR) at baseline (basal-OCR) and under cellular stress (max-OCR) may suggest mitochondrial dysfunction. We also assessed the in vivo impact of TAF vs TDF on OCR in PBMCs from 26 people with HIV (PWH) interchanged from TDF-based to TAF-based antiretroviral therapy (ART) over a 9-month period in the setting of an open label clinical trial. The Wilcoxon and Mann Whitney tests were used for comparison of continuous variables., Results: PBMCs from HIV-1 (-) participants exposed in vitro to a concentration of 0.12-3.3 μM for TAF and TDF at 2 and 24 h, reduced basal and maximal OCR compared to vehicle control. Switch studies of antivirals (TAF vs TDF) within the same PWH showed that TAF-based ART was associated with reduced OCR compared to TDF-based ART in PBMCs. We observed that TAF-treated PBMCs selectively relied more on glucose/pyruvate supply rather than fatty acid to fuel their mitochondria., Conclusions: Compared to TDF, TAF may alter bioenergetics in immune cells from PWH in vitro and in vivo. The clinical significance in terms of the differential impact caused by TAF versus TDF on mitochondrial function and energy production in immune cells, a regulator of immune function, requires further studied in HIV, preexposure prophylaxis and hepatitis B., Competing Interests: Declaration of competing interest Eisuke Murakami was an employee of Gilead during this research and performed the measurement of intracellular drug levels in PBMCs. All other authors have declared no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Hepatitis B virus (HBV) evades host immunity by regulating intracellular signals. To clarify this immune tolerance mechanism, we performed gene expression analysis using HBV-infected humanized mouse livers., Methods: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 3 (TRAIL-R3) was significantly upregulated in livers of HBV-infected human hepatocyte transplanted mice by cDNA microarray and next-generation sequencing. We analyzed the significance of TRAIL-R3 upregulation in HBV infection using human hepatocyte transplanted mice and HepG2 cell lines., Results: TRAIL-R3 induction by HBV infection was verified by in vitro and in vivo HBV replication models, and induction was inhibited by antiviral nucleot(s)ide analogue treatment. TRAIL-R3 transcription was regulated by the TRAIL-R3 promoter at -969 to -479 nucleotides upstream from the transcription start site, and by hepatitis B x (HBx) via activation of nuclear factor-κB (NF-κB) signal. TRAIL not only induced cell apoptosis but also inhibited HBV replication. TRAIL-R3 upregulation could inhibit both TRAIL-dependent apoptosis in HBV-infected hepatocytes and TRAIL-mediated suppression of HBV replication., Conclusions: These results suggest a mechanism by which HBV persists by escaping host immunity through upregulation of TRAIL-R3. Development of novel drugs to inhibit this escape system might lead to complete HBV elimination from human hepatocytes., Competing Interests: Potential conflicts of interest. M. I. has received research funding from AbbVie. H. A. has received honoraria from Eisai and Bayer. K. C. has received honoraria from Bristol-Myers Squibb, MSD K.K., AbbVie, Gilead Science, Dainippon Sumitomo Pharma, and Mitsubishi Tanabe Pharma; and research funding from Gilead Science, Dainippon Sumitomo Pharma, MSD K.K., AbbVie, Eisai, TORAY, Otsuka Pharma, Chugai Pharma, Takeda Pharma, and Roche. 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) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The present study retrospectively evaluated the efficacy of stereotactic body radiation therapy (SBRT), including repeated SBRT, for hepatocellular carcinoma. Participants comprised 220 HCC patients treated with SBRT in Hiroshima University Hospital between December 2008 and December 2021. Median overall survival (OS) and disease-free survival were 52 months (range, 45-64 months) and 17 months (range, 14-23 months), respectively. The 5-year local tumor recurrence rate was 3.4% (95% confidence interval (CI), 1.3-6.9%). Fifty-three patients underwent repeated SBRT (twice, 53 cases; three times, 10 cases; four times, 4 cases; five times, 1 case). Median interval between first and second SBRT was 20 months. Median OS from first SBRT was 76 months (95% CI, 50-102 months). Among patients with repeated SBRT, only one case showed local recurrence after second SBRT. Albumin-bilirubin score increased significantly from 6 to 12 months after repeated SBRT, both in the same segment and in remote segments, but the increase was not significant in the same segment. Only one case of grade 3 bile duct stricture was observed in patients who were treated with repeated SBRT. In conclusion, repeated SBRT provides good local control and a low risk of side effects.

Purpose: This study aimed to reveal the clinical features requiring sacroiliac joint (SIJ) arthrodesis, which was performed for patients who complain of severe SIJ pain., Methods: The differences in clinical features between a surgical treatment group (n=20) and a conservative treatment group (n=66) were investigated. All patients were definitively diagnosed with SIJ pain by the use of SIJ injections., Results: Six significant features were identified in the surgical treatment group, namely, sitting tolerance (<15 minutes), walking with a cane, pain in the supine position, pain while lying on the painful side, numbness in the lower limbs, and any accident that induced SIJ pain (P<0.01). Univariate logistic regression analysis revealed that sitting tolerance <15 minutes (odds ratio : 31.73), pain in the supine position (13.07), and pain while lying on the painful side (18.30) showed a high odds ratio., Conclusions: Sitting tolerance (<15 minutes), walking with a cane, pain in the supine position, pain while lying on the painful side, numbness in the lower limbs, and a history of any accident that induced SIJ pain may be considered as indicators for surgery after >?6 months of continued substantial conservative treatment. J. Med. Invest. 70 : 123-128, February, 2023.

Introduction: Measurements of body composition, such as the skeletal muscle index (SMI), are useful for predicting prognosis in hepatocellular carcinoma (HCC). This study aimed to analyze the relationship between skeletal muscle changes during therapy with atezolizumab plus bevacizumab (Atezo + Beva) or lenvatinib (Len) and the association between SMI and prognosis., Methods: Patients with advanced HCC and Child-Pugh A status received Atezo + Beva or Len as first-line systemic chemotherapy. We assessed prognosis and body composition obtained by bioelectrical impedance analysis., Results: A total of 109 patients received treatment (Atezo + Beva, n = 47; Len, n = 62). During treatment, the arm SMI was reduced in the Len group and maintained in the Atezo + Beva group. The extracellular water to total body water ratio (ECW/TBW) increased significantly in both groups during treatment. In the Atezo + Beva group, no factor was associated with prognosis. Multivariate analysis showed that in the Len group, the arm SMI (hazard ratio [HR], 0.5; 95% CI: 0.26-0.89; p = 0.02), ECW/TBW (HR: 2.7; 95% CI: 1.21-6.01; p = 0.01), and Child-Pugh score (HR: 2.3; 95% CI: 1.31-6.13; p = 0.004) were associated with progression-free survival., Conclusion: Assessing body composition with BIA before Atezo + Beva and Len treatment may be useful., (© 2023 S. Karger AG, Basel.)

Purpose: Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev., Methods: A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included., Results: Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3., Conclusion: The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3., (© 2022. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)