Background/AimOcrelizumab, a CD20-targeting monoclonal antibody, is used for treatment of multiple sclerosis. The aim of this study was to explore the utility of peripheral blood cell subsets in prediction of treatment response to ocrelizumab in relapsing remitting multiple sclerosis (RRMS).Patients and MethodsThirty-one patients with RRMS resistant to first-line immunomodulating agents were enrolled and followed-up for 12 months under ocrelizumab treatment. Disease activity was monitored by 6-monthly assessments of Expanded Disability Status Scale and cranial-spinal magnetic resonance imaging. No evidence of disease activity (NEDA-3) status was determined, and peripheral blood mononuclear cells were immunophenotyped by flow cytometry.ResultsPeripheral blood populations of CD19+ B-cells, plasma cells and CD3+ CD20+ T-cells decreased under ocrelizumab therapy, whereas populations of switched memory B-cells, CD4+ T-cells, naïve T-cells and regulatory B-1a and CD49d+ T-cells were increased. NEDA-3 status was achieved by 19 patients, who exhibited elevated baseline populations of regulatory CD49d+ T- and B-1a-cells, reduced post-treatment (month 6 or 12) populations of switched memory B-cells, and increased post-treatment populations of naïve T-cells. Month 12 Expanded Disability Status Scale scores correlated positively with plasmablast and naïve T-cell populations.ConclusionResponse to ocrelizumab is linked to baseline regulatory and post-treatment effector B- and T-cell subset populations. Memory B-cells appear to be a marker of treatment efficacy for ocrelizumab.

Background/AimThe aim of this study was to examine the effects of diode laser irradiation (910 nm) on bone formation in tibiae with bone defects in estrogen-deficient rats. Micro-computed tomography (micro-CT) was performed for 3-dimensional (3D) morphological evaluation of newly formed bone tissues.Materials and MethodsRats underwent sham operation (Sham) or ovariectomy (OVX), and bone defects were created in the tibiae, which were then subjected to diode laser irradiation for seven days in the laser groups (Sham-laser or OVX-laser groups). Tibiae with bone defects from Sham or OVX groups were irradiated with a guide light instead of a laser, serving as control groups (Sham-Cont or OVX-Cont groups). The tibiae were exposed to laser irradiation every day over a period of seven days. After irradiation, the tibiae underwent micro-CT, and then 3D reconstruction was performed for analysis of new bone formation.ResultsEstrogen deficiency induced osteoporosis in the tibiae of OVX rats. Laser irradiation induced greater new bone formation in the region of bone defects in both Sham- and OVX-laser groups compared to the Sham- and OVX-Cont groups, respectively. No significant difference in the volume of new bone formation was seen between Sham- and OVX-laser groups.ConclusionLaser irradiation could induce new bone formation in the region of bone defects in both Sham and OVX rats. This suggests that laser irradiation has potential for bone regeneration therapy in cases of postmenopausal osteoporosis.

Background/AimGastroesophageal varices (GEV) hemorrhage is a serious complication that can lead to unfavorable outcomes in cirrhotic patients. However, the clinical impact of HCV elimination [sustained viral response (SVR)] by direct-acting antivirals (DAAs), particularly on the long-term effects on the endoscopic findings of GEV have not been sufficiently evaluated. This study aimed to investigate whether HCV elimination with DAA treatment suppresses the progression of GEV.Patients and MethodsThe clinical courses of the endoscopic findings of GEV were retrospectively compared between patients without an SVR (non-SVR group: n=71) and those who achieved an SVR with DAAs (DAA-SVR group: n=38).ResultsAt 1, 3, 5, and 7 years, the cumulative GEV progression rates were 8.7%, 32.8%, 45.6%, and 66.2%, respectively. At 3 years, the cumulative GEV progression rate in the DAA-SVR group was similar to that in the non-SVR group. Beyond 3 years, cases with GEV progression were found in the non-SVR group, but not in the DAA-SVR group. At 7 years, the cumulative GEV progression rate in the DAA-SVR group was significantly lower than that in the non-SVR group (p<0.05, log-rank test). Variceal hemorrhage occurred in eight patients in the non-SVR group, while no bleeding events were observed in the DAA-SVR group during the observational period [8/71 (11.3%) vs. 0/38 (0.0%), p<0.05].ConclusionDAA treatment suppresses the progression of GEV over the long term.

Background/AimSarcopenia is diagnosed based on grip strength and skeletal muscle mass. Although decreased skeletal muscle mass has been reported to be associated with poor outcomes after hepatectomy, a few studies have included data on grip strength in hepatectomy candidates. This multicenter study investigated the clinical factors and postoperative complications associated with sarcopenia by assessing the grip strength and skeletal muscle mass in patients undergoing hepatectomy for hepatocellular carcinoma (HCC).Patients and MethodsData from patients who underwent hepatectomy for HCC between January 2020 and March 2022 were retrospectively collected from multi-institutional databases. Sarcopenia was defined as reduced grip strength and skeletal muscle mass. The patients were categorized into the sarcopenia and non-sarcopenia groups, and baseline characteristics and short term outcomes were compared between the two groups.ResultsOverall, 253 patients were included, among which 36 (14.2%) had sarcopenia. The sarcopenia group was significantly associated with older age, low body mass index, comorbid heart or chronic pulmonary disease, cerebrovascular accident history, and overall and major postoperative complications compared to the non-sarcopenia group. Among major postoperative complications [Clavien-Dindo classification (CDC) ≥Ⅲ], the incidence of bile leakage and intra-abdominal abscess were higher in the sarcopenia group than in the non-sarcopenia group. Multivariate analysis revealed that sarcopenia was an independent risk factor for overall and major postoperative complications (CDC ≥Ⅲ).ConclusionSarcopenia, defined by grip strength and skeletal muscle mass, is a predictor of overall and major complications after hepatectomy for HCC.

Background/AimTremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/β-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/β-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC.Patients and MethodsFifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/β-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated.ResultsFour patients had HCC with WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/β-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/β-catenin signal activation and high-level CD8+ TIL infiltration or WNT/β-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/β-catenin signal activation and low-level CD8+ TIL infiltration group.ConclusionAlthough the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.

Background/AimHypertriglyceridemia is a known cardiovascular risk factor. However, the relationship between serum triglyceride (TG) levels and the clinical outcomes in patients with acute myocardial infarction (AMI) is unclear.Patients and MethodsWe conducted a single-center, retrospective observational study involving 538 consecutive patients with AMI who underwent emergent percutaneous coronary intervention within 12 hours of onset. Patients were categorized into three groups based on their serum TG levels at admission as follows: T1 group (TG <78 mg/dl, n=172), T2 group (78≤TG<141 mg/dl, n=177), and T3 group (141 mg/dl ≤TG, n=176). The primary endpoint was major adverse cardiovascular events (MACEs) defined as a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The median follow-up period was 2.4 (1.5-4.2) years.ResultsPatients in the T1 group were older, had a higher proportion of females, and had fewer cardiovascular risk factors. However, they also had a higher prevalence of multi-vessel coronary artery disease and severely calcified culprit lesions. The T1 group had a significantly higher rate of MACEs (20.4% in T1, 12.4% in T2 and 8.5% in T3, p<0.05 by Log-rank test, respectively). Multivariate analysis revealed that T1 was an independent predictor of MACEs (hazard ratio=2.19, 95% confidence interval=1.16-4.14, p<0.05).ConclusionAlthough patients with AMI with low TG levels at admission had fewer coronary risk factors, they had more severe calcified culprit lesions and worse clinical outcomes.

The aim of this study was to investigate perinatal outcome in singleton pregnancies at term with isolated oligohydramnios, diagnosed by using the single deepest pocket method. In this historic cohort study, the perinatal outcomes of 196 women with isolated oligohydramnios at term, diagnosed by using the single deepest pocket method, were compared to 8,676 women with normal amniotic fluid volume. The primary outcome measure was the Cesarean section rate. Further outcome parameters included the rate of induction of labor, abnormal cardiotocography, umbilical cord pH and base excess, Apgar, meconium-stained liquor and admission to neonatal intensive care unit. In the group with isolated oligohydramnios, there were significantly more Cesarean sections (p=0.0081) and more abnormal cardiotocographies (p=0.0005). Univariate and multivariate analyses showed that this difference was seen particularly in nulliparous women (p=0.0025 for Cesarean section and 0.0368 for abnormal cardiotocography). Peripartal and perinatal outcome parameters were not different between the two groups. In women with isolated oligohydramnios at term, there is no impact on fetal outcome. The influence of isolated oligohydramnios on the rate of cesarean section and abnormal cardiotocography is considered to be less than that of parity.

Since the use of anaesthetics has the drawback of altering radiotracer distribution, preclinical positron emission tomography (PET) imaging findings of anaesthetised animals must be carefully handled. This study aimed at assessing the cerebral [18F]F-FDG uptake pattern in healthy Wistar rats under four different anaesthesia protocols using microPET/magnetic resonance imaging (MRI) examinations. Post-injection of 15±1.2 MBq of [18F]F-FDG, either while awake or during the isoflurane-induced incubation phase was applied. Prior to microPET/MRI imaging, one group of the rats was subjected to forane-only anaesthesia while the other group was anaesthetised with the co-administration of forane and dexmedetomidine/Dexdor® Results: While as for the whole brain it was the addition of dexmedetomidine/Dexdor® to the anaesthesia protocol that generated the differences between the radiotracer concentrations of the investigated groups, regarding the cortex, the [18F]F-FDG accumulation was rather affected by the way of incubation. To ensure the most consistent and highest uptake, forane-induced anaesthesia coupled with an awake uptake condition seemed to be most suitable method of anaesthetisation for cerebral metabolic assessment. Diminished whole brain and cortical tracer accumulation detected upon dexmedetomidine/Dexdor® administration highlights the significance of the mechanism of action of different anaesthetics on radiotracer pharmacokinetics. Overall, the standardization of PET protocols is of utmost importance to avoid the confounding factors derived from anaesthesia.

Transient pain enhancement or flare pain, is observed following the administration of immune checkpoint inhibitors (ICIs). However, the detailed mechanism of this phenomenon remains unclear. In this report, we present our experience of documenting the course of flare pain following ICI administration in six cases. Six patients with advanced solid tumors received ICI monotherapy between July 2017 and November 2019. Their pain increased within hours of ICI administration despite being stable before ICI administration. We evaluated the changes in the numerical rating scale (NRS) score over 72 h after ICI administration. Four non-small cell lung cancer patients, one gastric cancer patient, and one renal cell cancer patient were included. Four patients experienced an increase in NRS, as evidenced by scores on two or more scales compared to the day before administration, whereas two patients showed an increase only on one scale. The NRS score decreased to almost the same level as that on the day before administration. Flare pain is observed in the same area as the primary site. Most of the pain was alleviated without the need for rescue analgesics, although one patient experienced a 4-point increase in the NRS scale. Flare pain may occur following ICI administration. Healthcare providers should be aware of these events and provide patients with suitable information and coping techniques.

The aging population has been growing gradually; therefore, the proportion of elderly patients undergoing colorectal endoscopic submucosal dissection (ESD) has also been increasing. However, there is a lack of large-scale studies on the efficacy and safety of colorectal ESD in elderly patients. This retrospective analysis evaluated colorectal ESDs performed at five tertiary medical institutions between January 2015 and December 2020. Patients were categorized into the following four age groups: Middle-aged (<65 years), young-elderly (≥65 to <75 years), mid-elderly (≥75 to <85 years), and very elderly (≥85 years). Of the 1,446 patients included, 668 (46.2%), 466 (32.2%), 293 (20.3%), and 19 (1.3%) were in the middle-aged, young-elderly, mid-elderly, and very-elderly groups, respectively. Compared to younger patients, more older patients used aspirin, clopidogrel, and anti-thrombotic agents. Additionally, the Charlson comorbidity index increased significantly with increasing age. However, no significant differences were observed in the complete resection rates nor the rates of complications, such as perforation, bleeding, and post-ESD coagulation syndrome, among the different age groups. A restricted cubic spline curve was used to construct predictive models for complete resection and major complications based on age and showed that the need for complete resection did not decrease with increasing age. Furthermore, major complications did not significantly differ with age progression. Colorectal ESD should be actively considered as a relatively safe and effective treatment method for elderly patients.