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Objectives: This study aimed to determine the prevalence of knee pain among high school volleyball attackers, identify associated factors, and explore the relationship between knee pain and lower back pain (LBP)., Methods: A cross-sectional study involving 82 high school volleyball attackers (15-17 years) used questionnaires, interviews, and field-based assessments to collect data on demographics, volleyball-specific factors, flexibility, and jumping ability. Logistic regression analysis was used to identify factors associated with knee pain., Results: The prevalence of knee pain was 19.5%. Factors significantly associated with knee pain were a history of LBP (OR, 4.64; 95% CI, 1.28 to 16.8; p  = 0.019) and flexibility determined by the absolute difference in heel-buttock distance (OR, 1.37; 95% CI, 1.02 to 1.83; p  = 0.037). Participants with knee pain had more volleyball experience and a higher proportion of players who competed as starters in the previous year. Both groups reported approximately 18 hours of practice per week during the school year and around 27 hours during school holidays, with no significant difference observed., Conclusion: Factors associated with knee pain include a history of LBP and reduced flexibility on the heel-buttock distance test. The study highlights the need for a comprehensive approach, considering the coexistence of LBP and focusing on improving anterior thigh flexibility.

Background Context: Orthotic treatment is a common option for the conservative treatment of osteoporotic vertebral fractures (OVF). However, there is insufficient evidence of its clinical benefit., Purpose: To investigate the effectiveness of orthotic treatment for OVF., Study Design/setting: Retrospective cohort study with data from two prospective studies., Patient Sample: This study included 160 patients with fresh OVF enrolled in 2012 and 2020 prospective cohort studies., Outcome Measures: The visual analog scale (VAS) score for low back pain was used for clinical outcomes, and radiographic parameters included the percent height of the vertebra and angular change of the vertebral body. Moreover, the occurrence of secondary vertebral fractures was followed-up over time., Methods: The patients were divided into brace and no-brace groups and were matched according to propensity score for age, sex, anterior percent height at the initial examination, and presence of old OVFs. Hazard ratio for the cumulative incidence of secondary vertebral fractures with and without bracing were calculated and analyzed using the generalized Wilcoxon test. In addition, the brace group was divided into soft and rigid brace groups and compared with the no-brace group., Results: Each group had 61 cases after propensity score matching. There were no significant differences in the VAS improvement for low back pain and the change in percent height of the anterior and posterior walls from initial examination to 6 months after injury (p=.87, p=.39 and p=.14, respectively, mixed-effect models). Meanwhile, the mean angular change of fractured vertebrae was 4.3° / 3.2° initially and 1.2° / 2.5° at 6 months (the brace group / no-brace group, respectively; p=.007, mixed-effect models). A significant difference was also observed between the rigid brace group and the no-brace group (p=.008, mixed effect models). The incidence of secondary vertebral fractures was 1.6% / 11.4% at 1 month, indicating a significant difference (the brace group / no-brace group, respectively; p=.028). The hazard ratio for the cumulative incidence of secondary fractures due to orthotic treatment was 0.47 (95% confidence interval 0.20-1.09, p=.054)., Conclusions: Although orthotic treatment for fresh OVF did not relieve pain, it might contribute to the stabilization of the fractured vertebra, especially using a rigid brace. Moreover, it might influence a reduction of the imminent vertebral fracture risk immediately after the onset of OVF., Classifications: Clinical study., 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 Inc. All rights reserved.)

We herein report a case of IgA nephropathy in a 20-year-old male who maintained a complete remission of minimal change nephrotic syndrome (MCNS) through the administration of rituximab (RTX). He was diagnosed with nephrotic syndrome at 4 years of age. After he relapsed frequently, he was diagnosed with MCNS at 8 years of age based on the findings of a kidney biopsy. At 13 years of age, RTX therapy was initiated to maintain a complete remission after steroid treatment. MCNS recurred twice, including the time in which the interval between the RTX administrations was long. Whenever he relapsed, remission induction was achieved using steroids, and remission maintenance was achieved using RTX. Five months after the 7th RTX administration, the serum IgA level started to increase. After the 9th RTX administration, he demonstrated microhematuria despite the urinary protein level indicating complete remission. At the 10th administration, the urinary protein and the red-blood cell casts were also observed. A renal biopsy was performed 84 months after the initial administration of RTX, and the patient was diagnosed with complications of IgA nephropathy. RTX is not considered to be a useful treatment for IgA nephropathy. The reasons for this are due to the fact that IgA1 does not decrease even following the administration of RTX, because B cells residing in the mucosa may not be deleted by RTX, and IgA production may also continue due to the presence of CD20 - long-lived plasma cells. Even when administering RTX, if there are findings of glomerulonephritis on urine testing, the possibility of IgA nephropathy must be considered., Competing Interests: Declarations. Conflict of interest: All the authors have declared no competing interest. Informed consent: Informed consent was obtained from the patient in the present study. Human and animal rights: This article does not contain any studies with human participants or animals performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objectives: This study aimed to investigate the characteristics of patients with recurrent or advanced non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune-checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer., Materials and Methods: This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April 1, 2013, and March 31, 2020, and achieved long-term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation., Results: Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non-significant trend towards a higher incidence of secondary malignancies in smokers compared to non-smokers., Conclusion: This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

The mechanism of chronic knee osteoarthritis (OA) pain and postoperative pain due to knee arthroplasty has not been elucidated. This could be involved neuroplasticity in brain connectivity. To clarify the mechanism of chronic knee OA pain and postoperative pain, we examined the relationship between resting-state functional connectivity (rs-FC) and clinical measurements in knee OA before and after knee arthroplasty, focusing on rs-FCs with the anterior insular cortex (aIC) as the key region. Fifteen patients with knee OA underwent resting-state functional magnetic resonance imaging and clinical measurements shortly before and 6 months after knee arthroplasty, and 15 age- and sex-matched control patients underwent an identical protocol. Seed-to-voxel analysis was performed to compare the clinical measurements and changed rs-FCs, using the aIC as a seed region, between the preoperative and postoperative patients, as well as between the operative and control patients. In preoperative patients, rs-FCs of the aIC to the OFC, frontal pole, subcallosal area, and medial frontal cortex increased compared with those of the control patients. The strength of rs-FC between the left aIC and right OFC decreased before and after knee arthroplasty. The decrease in rs-FC between the left aIC and right OFC was associated with decreased subjective pain score. Our study showed a correlation between longitudinally changed rs-FC and clinical measurement before and after knee arthroplasty. Rs-FC between the aIC and OFC have the potential to elucidate the mechanisms of knee OA pain and postoperative pain due to knee arthroplasty., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The most frequently used first-line treatment in patients with advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab. Upon progression after this treatment, the standard of care in many countries is sorafenib, due to the lack of reimbursement for other drugs. Several randomized trials are currently underway to clarify the best second-line therapy in patients with HCC. This real-world study aimed to compare outcomes reached by lenvatinib and sorafenib second-line therapy in this setting., Methods: The overall cohort included 891 patients with HCC from 5 countries treated with atezolizumab plus bevacizumab in first-line setting between October 2018 and April 2022. At the data cut-off (May 2022), 41.5% of patients were continuing a first-line treatment, 5.5% were lost at follow-up, and 53.0% of patients had progressive disease after first-line therapy. 51.5% of patients with progressive disease received a second-line treatment, while 48.5% did not receive any subsequent therapy. Between patients receiving second-line treatment, 11.1% of patients underwent transarterial chemoembolization, 21.0% received sorafenib, 35.4% underwent lenvatinib, and 32.5% were treated with other drugs., Results: Lenvatinib second-line subgroup achieved a median overall survival (mOS) of 18.9 months, significative longer (p = 0.01; hazard ratio [HR]: 2.24) compared to sorafenib subgroup that reached a mOS of 14.3 months. The multivariate analysis highlighted albumin-bilirubin 1 grade (p < 0.01; HR: 5.23) and lenvatinib second-line therapy (p = 0.01; HR: 2.18) as positive prognostic factors for OS. The forest plot highlighted a positive trend in terms of OS in favor of patients treated with lenvatinib second-line regardless of baseline characteristics before first-line therapy., Conclusion: These results suggest that, in patients with HCC progressed to first-line atezolizumab plus bevacizumab, lenvatinib second-line therapy is associated to an improved survival compared to sorafenib., (© 2024 S. Karger AG, Basel.)

Amides and peptides are ubiquitous functional groups found in several natural and artificial materials, and they are essential for the advancement of life and material sciences. In particular, their relevance in clinical medicine and drug discovery has increased in recent years. Dehydrative condensation of readily available carboxylic acids with amines is the most "direct" method for amide synthesis; however, this methodology generally requires a stoichiometric amount of condensation agent (coupling reagent). Catalytic direct dehydrative amidation has become an "ideal" methodology for synthesizing amides from the perspective of green chemistry, with water as the only byproduct in principle, high atom efficiency, environmentally friendly, energy saving, and safety. Conversely, organoboron compounds, such as boronic acids, which are widely used in various industries as coupling reagents for Suzuki-Miyaura cross-coupling reactions or pharmaceutical structures, are environmentally friendly molecules that have low toxicity and are easy to handle. Based on the chemical properties of organoboron compounds, they have potential Lewis acidity and the ability to form reversible covalent bonds with dehydration, making them attractive as catalysts. This review explores studies on the development of direct dehydrative amide/peptide bond formation reactions from carboxylic acids using organoboron catalysis, classifying them based on chemical bonding and catalysis over approximately 25 years, from the early developmental days to 2023.

We previously found that "albumin grade", formerly called the "ALBS grade," demonstrated significant capability for prognostic stratification in hepatocellular carcinoma (HCC) patients treated with lenvatinib. The purpose of the present study was to compare the performance of the albumin grade with that of the modified albumin-bilirubin (mALBI) grade in predicting overall survival of HCC patients with different BCLC stages and treatment types. We enrolled 7,645 Japanese patients newly diagnosed with HCC using the Akaike information criteria (AIC), likelihood ratio, and C-index in different Barcelona Clinic Liver Cancer (BCLC) stages and treatments. The albumin grade showed similar and slightly better performance than the mALBI grade for BCLC stage 0 and A and especially for patients who underwent curative surgery and ablation. In patients treated with transcatheter arterial chemoembolization, molecular targeted agents, and the best supportive care, the mALBI grade had better performance than the albumin grade. However, the differences of the indices were very small in all scenarios. Overall, the albumin grade was comparable in efficacy to the mALBI grade, showing particular benefit for patients with early-stage HCC., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified., Methods: Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined., Results: A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation., Conclusion: In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Previous studies have shown that rapid on-site evaluation (ROSE) improves the diagnostic yield of bronchoscopy using endobronchial ultrasound with a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPL). While ROSE of imprint cytology from forceps biopsy has been widely discussed, there are few reports on ROSE of brush cytology. This study investigated the utility of ROSE of brush cytology during bronchoscopy. We retrospectively analyzed data from 214 patients who underwent bronchoscopy with EBUS-GS for PPL. The patients in the ROSE group had significantly higher diagnostic sensitivity through the entire bronchoscopy process than in the non-ROSE group (96.8% vs. 83.3%, P = 0.002). The use of ROSE significantly increased the sensitivity of brush cytology with Papanicolaou staining (92.9% vs. 75.0%, P < 0.001). When ROSE was sequentially repeated on brushing specimens, initially negative ROSE results converted to positive in 79.5% of cases, and the proportion of specimens with high tumor cell counts increased from 42.1 to 69.0%. This study concludes that ROSE of brush cytology improves the diagnostic accuracy of bronchoscopy and enhances specimen quality through repeated brushing., (© 2024. The Author(s).)

C3 glomerulopathy is a rare disease that results in nephritis due to complement dysregulation and is characterized by C3 deposition in the glomerulus. Dysregulation of the alternative pathway underlies the pathogenesis, but activation of the terminal pathway is also common. The disease is often caused by acquired rather than genetic factors, i.e., autoantibodies against C3 or C5 converting enzyme (convertase) and other complement-related proteins. We report a case of C3 glomerulopathy diagnosed by renal biopsy that responded well to corticosteroids and went into complete remission within two months. Analysis of complements and complement-related proteins revealed a low level of C3 and a high level of soluble terminal pathway protein complex (sC5b-9). Under genetic analysis about complement-related genes, no pathogenic variant was observed. Based on these findings, we diagnosed this patient with C3 glomerulopathy with autoantibodies. Corticosteroids had a marked effect, which also supports this speculation. Analyses of complements and complement-related proteins, and genetic variants may be useful in understanding the pathogenesis of C3 glomerulopathy and in selecting treatment options., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Purpose: By imaging dopamine transporter (DAT) uptake in the striatum, 123 I-FP-CIT SPECT can differentiate dopaminergic neurodegenerative disease (dNDD) and non-dNDD, which differ in pathophysiology and clinical management. Our aim was to compare and validate the diagnostic abilities of various 123 I-FP-CIT SPECT quantitative indices for dNDD., Materials and Methods: Distribution volume ratio (DVR) and binding ratio (BR), measures of DAT uptake capacity, were measured by analyzing clinical 123 I-FP-CIT SPECT images of 29 patients with dNDD, including dementia with Lewy bodies and Parkinson's disease, and 18 patients with non-dNDD, using Montreal Neurological Institute space-based anatomical standardization and an atlas template, which utilizes statistical parametric mapping. Additionally, we computed the specific binding ratio (SBR) based on Bolt's method and the maximum and mean standardized uptake values (SUVmax and SUVmean, respectively)., Results: The caudate-to-occipital lobe, putamen-to-occipital lobe, and striatum-to-occipital lobe ratios (COR, POR, and SOR, respectively) on DVR and POR and SOR on BR were significantly lower in dNDD than in non-dNDD, with areas under the ROC curve (AUCs) of 0.941-0.960, showing high diagnostic accuracy for dNDD. However, the AUC of COR on BR was 0.839, indicating lower diagnostic performance. SBR had an AUC of 0.921, while SUVmax and SUVmean had AUCs of 0.906 and 0.900, respectively. Although striatal asymmetry on both DVR and BR exhibited AUCs of 0.728 and 0.734 and asymmetry on SBR showed an AUC of 0.757, the ratio-based DAT quantitative indices were superior. There were strong positive correlations of DVR with BR, DVR with SBR or SUVmax, BR with SBR or SUVmax, and SBR with SUVmax., Conclusion: COR, POR, and SOR on DVR and POR and SOR on BR were the most useful DAT quantitative indices. These indices can be compared with SBR and SUV, suggesting that comprehensive evaluation improves the diagnostic accuracy of dNDD., (© 2024. The Author(s).)

Xyloglucan in plant cell walls has complex side-chain structures; Aspergillus oryzae produces various enzymes to degrade and assimilate xyloglucan. In this study, we identified and characterized α-1,2-l-fucosidase (AfcA) which is involved in xyloglucan degradation in A. oryzae. AfcA expression was induced in the presence of xyloglucan oligosaccharides. AfcA showed specific activity toward α-(1→2)-linked l-fucopyranosyl residues attached to the side chains of xyloglucan oligosaccharides and milk oligosaccharides, but not toward α-(1→3)-, α-(1→4)-, and α-(1→6)-linked l-fucopyranosyl residues. As fucopyranosyl residues in the side chains of xyloglucan oligosaccharides prevent the degradation of xyloglucan oligosaccharides by isoprimeverose-producing oligoxyloglucan hydrolase and β-galactosidase, the cooperative action of AfcA, isoprimeverose-producing oligoxyloglucan hydrolase, and β-galactosidase play a key role in degrading fucosylated xyloglucan in A. oryzae., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years., Methods: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies., Results: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCF SKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells., Conclusion: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC., Competing Interests: Declaration of competing interest Ken Tajima received research funding from Novartis. Kazuhisa Takahashi received research funding from Chugai Pharm, MSD, Ono Pharm, and Bristol-Myers Squibb. Additionally, Kazuhisa Takahashi acknowledges donations from Eli Lilly Japan, Teijin Pharm, Chugai Pharm, Nippon Boehringer Ingelheim, Kyorin Pharm, Taiho Pharm, and Sanofi. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease., Methods: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available., Results: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS., Conclusion: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM., (© 2024 Asian Pacific Society of Respirology.)

Scrotal and penile edema is a noninfectious complication of peritoneal dialysis (PD). A tear in the Spigelian fascia is occasionally recognized as a Spigelian hernia. However, there is no documented evidence that this is a contributing factor for scrotal edema in individuals undergoing PD. We encountered a case of scrotal edema in a patient undergoing PD due to bilateral metachronous tears in the Spigelian fascia, which was successfully treated through surgical repair. A 20-year-old man with end-stage kidney disease due to Alport syndrome underwent PD. Eight months after induction of PD, he heard a rupture sound in the left inguinal region after coughing and developed genital edema. A computed tomography scan showed a tear in the left Spigelian fascia. Surgical repair was successful and there was no recurrence after PD was resumed. Seven months after surgery, he heard a rupture sound in the right inguinal region after coughing and developed genital edema. A computed tomography scan showed a tear in the right Spigelian fascia. Surgical repair was successful and there has been no recurrence since. It is important to recognize that the development of scrotal edema in a patient undergoing PD may be indicative of a tear in the Spigelian fascia., Competing Interests: AcknowledgementsNone. Author contributionsKW wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript. Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of MPO-ANCA-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.

Background: Posthepatectomy liver failure (PHLF) is a serious complication associated with high mortality rates. Machine learning (ML) has rapidly developed and may outperform traditional models in predicting PHLF in patients who have undergone hepatectomy. This study aimed to predict PHLF using ML and compare its performance with that of traditional scoring systems., Methods: The clinicopathological data of 334 patients who underwent liver resection were retrospectively collected. The Pycaret library, a simple, open-source machine learning library, was used to compare multiple classification models for PHLF prediction. The predictive performance of 15 ML algorithms was compared using the mean area under the receiver operating characteristic curve (AUROC) and accuracy, and the best-fit model was selected among 15 ML algorithms. Next, the predictive performance of the selected ML-PHLF model was compared with that of routine scoring systems, the albumin-bilirubin score (ALBI) and the fibrosis-4 (FIB-4) index, using AUROC., Results: The best model was extreme gradient boosting (accuracy:93.1%; AUROC:0.863) among the 15 ML algorithms. As compared with ALBI and FIB-4, the ML PHLF model had higher AUROC for predicting PHLF., Conclusion: The novel ML model for predicting PHLF outperformed routine scoring systems., Competing Interests: The authors have no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements) that might pose a conflict of interest related to the submitted manuscript., (© 2024 Tashiro et al.)

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

Background: Our investigation focused whether infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before or after receiving the mRNA COVID-19 vaccine can increase immune protection. And we also investigated relationship of infection acquired., Methods: Three shots of the mRNA coronavirus disease 2019 (COVID-19) vaccine BNT162b2 were administered to 736 healthcare workers at Tokyo Shinagawa Hospital. Serum samples were collected before the first shot (P1), at one month (P2), and at six months (P3) after the second shot and at one month after the third shot (P4). The presence of infection was assessed using IgG against the nucleocapsid (IgG (N) and RBD in the spike protein of SARS-CoV-2. We defined infection before P2 as natural infection (NI) and infection between P2 and P3 as breakthrough infection (BI) and compared susceptibility to further infection between the NI (-) and NI (+) groups and between BI (-) and BI (+) groups. Events in 485 participants who had a complete dataset of IgG (N) and IgG (RBD) from P1 to P4 were analyzed., Results: The presence of SARS-CoV-2 infection before P2 were examined by examining the titers of IgG (N)P1, IgG (N) P2, and IgG (RBD) P1 that exceeded the cutoff values. Consequently, 35 participants (7.22 %) were categorized into the NI (+) group, whereas 450 (92.8 %) were categorized into the NI (-) group. Between P2 and P3, the NI (-) group showed a higher rate of SARS-CoV-2 infection than the NI (+) group; however, there was no significant difference in the infection rate between P3 and P4. The infection rate was significantly lower in the BI (+) group than in the BI (-) group. Pre-primary vaccination infection significantly increased IgG (RBD) levels between P1 and P3. Post-primary vaccination infection significantly increased IgG (RBD) levels between P3 and P4., Conclusions: Infection with SARS-CoV-2 before or after receiving the mRNA COVID-19 vaccine can increase immune protection; however, the duration of this effect may be limited., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Masahiro Shinoda reports financial support was provided by Abbott Japan Co Ltd. Satoshi Murakami reports a relationship with Abbott Japan Co Ltd that includes: employment. Satoshi Sugawa reports a relationship with Abbott Japan Co Ltd that includes: employment. Authors without Satoshi Sugawa and Satoshi Murakami received joint research funding from Abbott Japan Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (© 2024 The Author(s).)

Objective: Radium-223 is a first alpha-emitting radionuclide treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with bone metastases. Although the spread-based bone scan index (BSI) and novel index of the intensity-based two-dimensional total bone uptake (2D-TBU) from bone scintigraphy may provide useful input in radium-223 treatment, they have not been evaluated in detail yet. This study aimed to fill this gap by evaluating BSI and 2D-TBU in patients treated with radium-223., Methods: Twenty-seven Japanese patients with mCRPC treated with radium-223 were retrospectively analyzed. The patients were evaluated via blood tests and bone scans at baseline and 3 cycles intervals of treatment. BSI and 2D-TBU were analyzed via VSBONE BSI in terms of correlations, response to radium-223 treatment, association with treatment completion, and the Kaplan-Meier survival analysis was performed., Results: Nineteen patients (70.4%) completed six cycles of radium-223 treatment, whereas eight patients (29.6%) did not complete the treatment regimen. A significant difference in baseline BSI and 2D-TBU was observed between these groups of patients. Both BSI and 2D-TBU were highly correlated (r = 0.96, p < 0.001). Univariate analysis showed an association between radium-223 completion in median BSI and 2D-TBU values (p = 0.015) and completion percentage differences (91.7% vs. 45.5%; p = 0.027). The Kaplan-Meier product limit estimator showed that the median overall survival was 25.2 months (95% CI 14.0-33.6 months) in the completion group and 7.5 months (95% CI 3.3-14.2 months) in the without completion group (p < 0.001). The overall survival based on median cutoff levels showed a significant difference in 2D-TBU (p = 0.007), but not in BSI (p = 0.15)., Conclusions: The 2D-TBU may offer advantages over BSI in classifying patients towards radium-223 treatment based on the degree of progression of bone metastases. This study supports the importance of preliminary assessment of bone metastasis status using BSI and 2D-TBU extracted from VSBONE BSI for radium-223 treatment decisions., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma., Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University., Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p  = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival., Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma., Competing Interests: Dr. Asao reports honoraria from AstraZeneca K.K., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K, Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K, Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited outside of the submitted work. Dr. Shukuya reports grants and honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., and Merck Sharp & Dohme K.K. and honoraria from Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company, Pfizer Inc., and Eisai Co., Ltd. outside of the submitted work. Dr. Fumiyuki Takahashi reports grants from 10.13039/100004325AstraZeneca, 10.13039/100017346Nippon Boehringer Ingelheim, 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004336Novartis, and Lilly Japan outside of the submitted work. Dr. Kazuhisa Takahashi reports grants and honoraria from Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company Limited, and grants from 10.13039/100018036Nippon Shinyaku Co., Ltd., Tsumura & Co., Teijin Pharma Limited, 10.13039/100015990Sanofi K.K., Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., 10.13039/501100002973Daiichi Sankyo Co., Ltd., Nipro Pharma Corporation, 10.13039/100010740Asahi Kasei Pharma Corporation, Kyowa Kirin Co., Ltd., and honoraria from Merck Sharp & Dohme K.K., AstraZeneca K.K., Merck Biopharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Bristol-Myers K.K., Meiji Seika Pharma Co., Ltd., Viatris Inc., Janssen Pharmaceutical K.K., Abbott Japan LLC, and Thermo Fisher Scientific Inc. outside the submitted work. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Radiation therapy (RT) for head and neck cancer, which has made remarkable progress in recent years, is one of the main treatment modalities because it can preserve organ function and morphology after treatment. However, while RT is widely used, complications have been reported, especially laryngeal edema, which can be an airway management problem during general anesthesia. Of the 3 cases of RT-induced laryngeal edema presented here, the first developed 4 days post-RT, the second manifested signs and symptoms associated with laryngeal edema after RT performed 4 years and 4 months previously, and the third exhibited severe laryngeal edema over a decade post-RT despite the absence of clinical signs and symptoms. Patients with a previous history of RT involving the head and neck region may encounter challenges in airway management due to laryngeal edema. Therefore, it is crucial to assess the airway preoperatively and devise a comprehensive airway management plan that encompasses various devices and techniques.

Background: Tissue-based comprehensive genomic profiling (CGP) is increasingly being employed for genotype-directed therapies in patients with advanced cancer. However, tissue availability may limit their potential applications. In Japan, the cost of cancer gene panel tests is covered by public insurance for patients diagnosed with advanced solid tumors once in their lifetime. Therefore, it is essential to improve the success rate (reportability) and accuracy of CGP tests. The purpose of this study was to identify the factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data., Methods: This study included 159 samples analyzed using tumor-only panel FoundationOne® CDx cancer genome profiling (F1CDx) and 85 samples analyzed using matched-pair panel OncoGuide™ NCC Oncopanel system (NCCOP) at St. Marianna University Hospital. Sample characteristics (fixation conditions, storage period, histology, tumor cell ratio, and genomic tumor cell content), CGP performance, and quality control status were evaluated across all 244 tested samples., Results: In 237/244 samples (97.1%), CGP testing results were successfully obtained [F1CDx, 99.4% (158/159) and NCCOP, 92.9% (79/85)]. An increased number of fibroblasts, inflammatory cells, and necrotic tumor cells, long-term storage, and/or prolonged fixation of tissue sections were involved in the unreported results and/or qualified CGP results. In addition, a negative correlation between median insert size values and ΔΔCq was observed in the NCCOP system., Conclusion: We identified various factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data, suggesting that thorough selection and preparation of tissue sections could optimize CGP and maximize useful information., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background and Aim: While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post-SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common., Methods: A total of 6048 patients with no history of HCC who achieved SVR by oral direct-acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post-SVR HCC was compared between risk groups using the aMAP score, FIB-4 index, Tahata model, GAF4 criteria, GES score, and ADRES score., Results: During the observation period with a median duration of 4.0 years after SVR, post-SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C-index was below 0.8 for all models (range, 0.660-0.748), indicating insufficient stratification ability., Conclusion: Although all six proposed models demonstrated a good ability to predict the development of post-SVR HCC, their ability to stratify the risk of post-SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post-SVR HCC in regions where early detection of HCC is common., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Postoperative infection and subsequent device loss are serious complications in the use of titanium dental implants and plates for jawbone reconstruction. We have previously reported that NaOH-CaCl 2 -thermal-ICl 3 -treated titanium (NaCaThIo) has a nano-scale surface and exhibits antibacterial activity against Staphylococcus aureus. The present study examined the surface properties of mixed-acid treated and then iodine-treated titanium (MA-NaCaThIo), and evaluated oral antibacterial activity and cytotoxicity compared with the results obtained with NaCaThIo. MA-NaCaThIo formed a surface layer with a nano-scale network structure having microscale irregularities, and both the thickness of the surface layer (1.49 ± 0.16 μm) and the average surface roughness (0.35 ± 0.03 μm) were significantly higher than those of NaCaThIo. Furthermore, MA-NaCaThIo maintained high hydrophilicity with a contact angle of 7.5 ± 1.7° even after 4 weeks, as well as improved apatite formation, iodine ion release, and antibacterial activity against Prevotella intermedia compared to NaCaThIo. Cell culture test revealed that MA-NaCaThIo exhibited no cytotoxicity against MG-63 and Vero cells, while increased cell proliferation, ALP activity and mineralization of MG-63 compared to NaCaThIo. This treated titanium is expected to be useful for the development of next-generation titanium devices having both bone-bonding and antibacterial properties., (© 2023 Wiley Periodicals LLC.)

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

Chylothorax after cardiac surgery is a rare complication associated with severe morbidity and mortality. This report documents successful treatment with percutaneous thoracic duct embolization for chylothorax after total arch replacement. A 69-year-old man underwent replacement of the aortic arch to treat a ruptured aortic aneurysm. After surgery, the left thoracic drain discharged 2,000 to 3,000 mL serosanguineous fluid per day, even though the patient took nothing orally and was administered subcutaneous octreotide therapy. On postoperative day 9, percutaneous thoracic duct embolization was performed, and the drain could be removed. The chylothorax did not recur, and the patient was discharged on postoperative day 17., (© 2024 The Authors. Published by The Texas Heart Institute®.)

Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients., Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies., Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups., Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice., Competing Interests: Andrea Casadei-Gardini has received grants and personal fees from MSD, Eisai, Bayer and is an advisor for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. Atsushi Hiraoka received lecture’s fees from Chugai, Lilly, AstraZeneca. Fabian Finkelmeier has received travel support from Ipsen, and speaker’s fees from AbbVie, MSD, Ipsen, Eisai and Fresenius. Gianluca Masi is an advisor for Roche, MSD, Eisai. Giuseppe Cabibbo is a consultant for Roche, AstraZeneca, Eisai, MSD. Hidenori Toyoda has received grants and personal fees from Gilead, AbbVie, Eisai, Fujifilm, Teruma, Kowa, Takeda. Ho Yeong Lim is an advisor for Roche, Eisai, AstraZeneca, Bayer. Hong Jae Chon has advisory role for Roche, Eisai, Bayer, ONO, MDS, BMS, Sanofi, Servier, AstraZeneca, Silajen, Menarini, GreenCross Cell; received speaker’s fee and research grants from Roche, Eisai, Bayer, BMS, Sanofi, Dong-A ST, BORYUNG, Inno.N, Hanmi, YUHAN. Josè Presa is an advisor for Gilead, AbbVie, Roche, AstraZeneca, Giszi, Advaus. Mario Scartozzi received grants and personal fees from MSD, Merck, Servier, Novartis, AstraZeneca. Masatoshi Kudo received lecture’s fees from Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Takeda Pharmaceutical; is an advisor for F. Hoffmann-La Roche, AstraZeneca, Chugai Pharmaceutical, Eisai; and received grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, GE Healthcare Japan Corporation, Eisai, AbbVie, EA Pharma. Massimo Iavarone received grants and personal fees from MSD, Gilead, AstraZeneca, Bayer, Roche, Ipsen, Eisai. Takeshi Hatanaka received lecture’s fees from Eisai. The other coauthors have no conflict of interest to disclose., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The social amoeba Dictyostelium discoideum switches between solitary growth and social fruitification depending on nutrient availability. Under starvation, cells aggregate and form fruiting bodies consisting of spores and altruistic stalk cells. Once cells socially committed, they complete fruitification, even if a new source of nutrients becomes available. This social commitment is puzzling because it hinders individual cells from resuming solitary growth quickly. One idea posits that traits that facilitate premature de-commitment are hindered from being selected. We studied outcomes of the premature de-commitment through forced refeeding. Our results show that when refed cells interacted with non-refed cells, some of them became solitary, whereas a fraction was redirected to the altruistic stalk, regardless of their original fate. The refed cells exhibited reduced cohesiveness and were sorted out during morphogenesis. Our findings provide an insight into a division of labor of the social amoeba, in which less cohesive individuals become altruists., (© 2024. The Author(s).)

Aim: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older., Methods: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed., Results: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression-free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group., Conclusions: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients., (© 2023 Japan Society of Hepatology.)

[Purpose] This study aimed to investigate whether modification of vastus medialis activity can delay the varus thrust. [Participants and Methods] Ten participants (Kellgren-Laurence grades I: n=2, II: n=6, and III: n=2) diagnosed with knee osteoarthritis were enrolled. The intervention involved free walking on a 10-m walkway at any speed after donning a functional electrical stimulation set to contract the vastus medialis before heel contact. Using a Vicon Nexus ground reaction force meter and a wireless electromyograph DELSYS, varus thrust, maximal knee extension angle, maximal knee adduction moment, and vastus medialis onset time were assessed both before and after intervention. [Results] A significant difference in varus thrust was detected from before to after the intervention (2.7 ± 1.1° vs. 2.2 ± 1.3°). Both the vastus medialis activation time (-0.06 ± 0.09 vs. -0.21 ± 0.1) and the knee-joint extension angle (8.7 ± 5.1° vs. 5.5 ± 5.9°) decreased following intervention, whereas the knee adduction moment significantly increased (0.50 ± 0.20° vs 0.56 ± 0.18°). [Conclusion] Wearing the functional electrical stimulation set caused the vastus medialis to act earlier in response to heel strike, thereby improving the knee-joint extension angle and suppressing varus thrust., Competing Interests: None., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Aims: The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment., Methods: A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c-index) and Akaike information criterion (AIC) results., Results: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring system. For IMABALI-De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS., Conclusion: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB., (© 2023 UICC.)

Inside cells, proteins complex with nucleic acids to form liquid droplets resulting from liquid-liquid phase separation. The presence of mutated proteins can change the state of these liquid droplets to solids or gels, triggering neurodegenerative diseases. The mechanism of the liquid to solid or gel transition is still unclear. Solutions of poly(l-ornithine- co -l-citrulline) (P L OC) copolymers, which exhibit upper critical solution temperature-type behavior, change state upon cooling. In this study, we evaluated the effect of nucleic acids complexed with P L OC on phase changes. In the presence of nucleic acids, such as polyC and polyU, P L OC formed liquid droplets at low temperatures. The droplets dissolved at temperatures above the phase separation temperature. The phase separation temperature depended on the chemical structure of the nucleobase, implying that electrostatic and hydrogen bonding interactions between the nucleic acid and P L OC influenced phase separation. Furthermore, the liquid droplets spontaneously changed to gel-like precipitates due to spontaneous release of nucleic acids from the complex. The rate of the liquid droplet-to-gel transition depended on the magnitude of electrostatic and hydrogen bonding interactions between P L OC and nucleic acid. P L OC complexed with mRNA also underwent a liquid droplet-to-gel transition upon the release of mRNA. This work provides insights into the mechanism of pathogenic transitions of the cellular droplets.

Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration., (© 2024. The Author(s).)

Background: Medial meniscus extrusion (MME) is associated with knee osteoarthritis (OA) progression because of increased loading stress in the medial compartment of the knee. Using a lateral wedge insole (LWI) decreases loading stress and immediately reduces MME., Objective: To investigate whether the wearing duration of LWI affects the midterm response to MME and is associated with knee OA progression., Study Design: Cohort study., Methods: Twenty-three patients with knee OA who were conservatively treated with LWI were classified according to the duration of the LWI wear per day: less than 5 h (short-duration group) or over 5 h (long-duration group). MME was evaluated in the single-leg standing position by ultrasound. Knee OA progression and limb alignment were evaluated radiographically. These evaluations were performed thrice: at the initial office visit as a baseline without LWI (time 0), with LWI (LWI-time 0), and 1 year after intervention with LWI (LWI-1 year)., Results: In both groups, the MMEs at LWI time 0 were significantly decreased compared with those at time 0. In the long-duration group, this reduction in MME was maintained 1 year after the intervention compared with time 0 (time 0: 3.9 ± 0.9, LWI-1 year: 2.6 ± 1.1), but this improvement was not observed in the short-duration group (time 0: 3.8 ± 1.7, LWI-1 year: 3.6 ± 1.7). In addition, three of four patients demonstrated OA progression, and varus alignment had significantly progressed compared with that at time 0 in the short-duration group. However, the long-duration group showed OA progression only in one patient and maintained limb alignment., Conclusions: The duration of wearing LWI affects the midterm reduction of MME and knee OA progression while maintaining limb alignment., (Copyright © 2024 International Society for Prosthetics and Orthotics.)

Objectives: It is unclear whether improvements in knee pain or physical function lead to improvements in activities of daily living (ADL) and quality of life (QOL) in patients with moderate to severe knee osteoarthritis (KOA). This study aimed to investigate whether improvements in knee pain and physical function, achieved through exercise therapy, lead to improvements in ADL and QOL in patients with moderate to severe KOA., Methods: This case-control study included 18 patients with KOA. We evaluated knee range of motion, knee extension muscle strength (KEM), gait speed, knee pain, Knee Injury and Osteoarthritis Outcome Score (KOOS)-ADL, and KOOS-QOL at the first visit and after 3 months of exercise therapy. Patients were classified into the ADL and QOL improvement or no-improvement groups. Statistical analysis used split factorial analysis of variance with time and group as the main effects. When interactions were observed, post-hoc analysis was performed with two-sample t -tests., Results: For ADL improvement, the improvements in KEM of the affected side and gait speed were statistically significant. At 3 months, the gait speed of the improvement group was significantly higher than that of the no-improvement group. For QOL improvement, there was no significant interaction for any of the factors evaluated., Conclusions: No factor showed significant contribution to improved QOL in patients with moderate to severe KOA. However, increased gait speed may improve ADL and contribute to the development of efficient rehabilitation programs for patients with moderate to severe KOA., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (2024 The Japanese Association of Rehabilitation Medicine.)

Novel imidazole-containing boronic acid and palladium hybrid catalysis for regioselective O -allylation of carbohydrates has been developed. This catalytic process enables the introduction of a useful allyl functional group into the equatorial hydroxy group of cis -1,2-diols of various carbohydrates with low catalyst loading and excellent regioselectivities. This is the first report on hybrid catalysis in combination with a Lewis base-containing boronic acid and a transition metal complex.

Background: Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis., Methods: The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed., Results: Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p <  0.001) were independent poor prognostic factors. Multivariate analysis revealed that preoperative BFM < 12 kg and preoperative albumin < 3.5 g/dL were independently associated with BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021 and p = 0.047, respectively)., Conclusions: Loss of BFM in the early postoperative period may have a poor prognosis in radical resection of PDAC., (© 2024. The Author(s).)

A boronic acid-catalyzed peptide bond formation from α-amino acid methyl esters is described. The catalysis showed high chemoselectivity for β-hydroxy-α-amino esters, affording the peptides in high to excellent yields with high functional group tolerance. This hydroxy-directed peptide bond formation could be applicable to oligopeptide syntheses. This is the first successful example of organoboron-catalyzed peptide bond formation from α-amino acid-derived inert esters.

Background & Aims: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy., Methods: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included., Results: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044)., Conclusions: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing., Objective: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC., Patients and Methods: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years)., Results: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115)., Conclusions: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background & Aims: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC., Methods: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis., Results: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46)., Conclusions: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose a new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%); 1) isolated thrombocytopenia with no morphological evidence of dysplasia in any blood cell type in a blood smear, 2) normal or slightly increased plasma TPO level (< cutoff), 3) elevated RP% or IPF% (> upper limit of normal), and 4) absence of other conditions that potentially cause thrombocytopenia including secondary ITP. A diagnosis of ITP is made if conditions 1-4 are all met. Cases in which criterion 2 or 3 is not met or unavailable are defined as "possible ITP," and diagnosis of ITP can be made mainly by typical clinical course. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments., (© 2023. The Author(s).)