Explore the vast range of titles available.

Natural killer T (NKT) cells show intense tumor-killing activity through direct and indirect pathways. However, humans have less than 0.01% of NKT cells in the peripheral blood, making it difficult to apply NKT cells for cancer treatment. We have successfully produced invariant NKT cells derived from induced pluripotent stem cells (iPSC-iNKT cells) and demonstrated the tolerability of this product in a previous phase 1 clinical trial. Although the iPSC-iNKT cells showed substantial anti-tumor activity against various tumor cell types when combined with α-Galactosylceramide-pulsed autologous dendritic cells (DC/Gal) in non-clinical experiments, the tolerability of this combination therapy for humans has not demonstrated yet. Thus, we planned this first-in-human phase 1 open-label clinical trial to demonstrate data on tolerability and safety, as well as explore the immunological changes that occur following this combination treatment. We hypothesize that the sequential induction of nasal submucosal DC/Gal injection and intra-arterial administration of the iPSC-iNKT cells is tolerable and has a favorable safety profile for cancer patients. This trial provides vital and fundamental information for next-phase clinical trials and future applications of iPSC-iNKT cells for various cancer patients (jRCTa030220741; URL: https://jrct.mhlw.go.jp/en-latest-detail/jRCTa030220741 ).

ObjectivesThe LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance glucocorticoid requirements and long-term outcomes are unknown.MethodsA total of 140 patients with new-onset ANCA-associated vasculitis without severe glomerulonephritis or alveolar haemorrhage were randomised to receive reduced-dose prednisolone (0.5 mg/kg/day) plus rituximab (375 mg/m2/week×4) or high-dose prednisolone (1 mg/kg/day) plus rituximab. After achieving remission, patients received the rituximab maintenance therapy (1 g/6 months).ResultsA total of 134 patients were analysed. Among patients who achieved remission with the protocolised treatments, the majority of patients in the reduced-dose group (89.7%) and 15.5% in the high-dose group discontinued prednisolone (median time to withdrawal, 150 and 375 days, respectively). During 24-month trial period, two patients in the reduced-dose group (2.8%) died, while five patients in the high-dose group (7.6%) died (p=0.225). Relapse occurred in nine patients in the reduced-dose group (13.0%) (two major and seven minor) and five in the high-dose group (7.6%) (two major and three minor) (p=0.311). Serious adverse events (SAEs) were less frequent in the reduced-dose group (36 events in 19 patients, 27.5%) than in the high-dose group (54 events in 30 patients, 46.2%) (p=0.025).ConclusionAt 24 months, frequencies of relapse did not differ between the groups, and SAEs were less frequent in the reduced-dose group due to the lower event rate in the 6-month induction phase. The bias to myeloperoxidase-ANCA positivity (85.8%) in the trial population should be noted.Trial registration number NCT02198248.

This study evaluated the reliability and validity of the Forgotten Joint Score-12 (FJS-12)-a measure of patients' ability to forget their joints in daily life-in patients who underwent total ankle replacement (TAR) or ankle arthrodesis (AA). Patients who underwent TAR or AA were recruited from seven hospitals. The patients completed the Japanese version of FJS-12 twice, at an interval of two weeks, at a minimum of one year postoperatively. Additionally, they answered the Self-Administered Foot Evaluation Questionnaire and EuroQoL 5-Dimension 5-Level as comparators. The construct validity, internal consistency, test-retest reliability, measurement error, and floor and ceiling effects were evaluated. A total of 115 patients (median age, 72 years), comprising 50 and 65 patients in the TAR and AA groups respectively, were evaluated. The mean FJS-12 scores were 65 and 58 for the TAR and AA groups, respectively, with no significant difference between groups (P = 0.20). Correlations between the FJS-12 and Self-Administered Foot Evaluation Questionnaire subscale scores were good to moderate. The correlation coefficient ranged from 0.39 to 0.71 and 0.55 to 0.79 in the TAR and AA groups, respectively. The correlation between the FJS-12 and EuroQoL 5-Dimension 5-Level scores was poor in both groups. The internal consistency was adequate, with Cronbach's α greater than 0.9 in both groups. The intraclass correlation coefficients of test-retest reliability was 0.77 and 0.98 in the TAR and AA groups, respectively. The 95% minimal detectable change values were 18.0 and 7.2 points in the TAR and AA groups, respectively. No floor or ceiling effect was observed in either group. The Japanese version of FJS-12 is a valid and reliable questionnaire for measuring joint awareness in patients with TAR or AA. The FJS-12 can be a useful tool for the postoperative assessment of patients with end-stage ankle arthritis.

Invariant Natural killer T (iNKT) cells exhibit cytotoxic activity and immunomodulatory functions and have gained interest in cancer immunotherapy. We conducted a phase 1, first-in human clinical trial to evaluate the safety and efficacy of clinical-grade allogeneic iNKT cells generated from induced pluripotent stem cells (iPSC-iNKT cells) in patients with recurrent head and neck cancer (jRCT2033200116). The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were to assess safety and efficacy, as well as to evaluate immunological dynamics. iPSC-iNKT cells were administered intra-arterially to 10 patients. One subject developed grade 3 skin rash at the second dose, identified as DLT. No other severe adverse events were observed in any patients. Tumor progression was suppressed in two patients, in whom clonal expansion of memory- and effector-phenotype CD8 + T cells was observed, along with activation of the IFN-γ signaling pathway. Here, we show that iPSC-iNKT cells are safe and possess therapeutic potential as an immunotherapy for solid tumors. A first-in-human clinical trial of iPS cell-derived invariant natural killer T cells in patients with recurrent head and neck cancer demonstrated safety and early signs of efficacy, showing tumor growth suppression and activation of immune pathways.

Background Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease which encompasses patients with heterogenous presentation and a wide range of clinical courses. In this study, we aimed to identify potential subgroups of AOSD and reveal risk factors for relapse. Methods We included a total of 216 AOSD patients who received treatment in nine hospitals between 2000 and 2019. All patients fulfilled the Yamaguchi classification criteria. We retrospectively collected information about baseline characteristics, laboratory tests, treatment, relapse, and death. We performed latent class analysis and time-to-event analysis for relapse using the Cox proportional hazard model. Results The median age at disease onset was 51.6 years. The median follow-up period was 36.8 months. At disease onset, 22.3% of the patients had macrophage activation syndrome. The median white blood cell count was 12,600/μL, and the median serum ferritin level was 7230 ng/mL. Systemic corticosteroids were administered in all but three patients (98.6%) and the median initial dosage of prednisolone was 40mg/day. Ninety-six patients (44.4%) were treated with concomitant immunosuppressants, and 22 (10.2%) were treated with biologics. Latent class analysis revealed that AOSD patients were divided into two subgroups: the typical group (Class 1: 71.8%) and the elderly-onset group (Class 2: 28.2%). During the follow-up period, 13 of 216 patients (6.0%) died (12 infections and one senility), and 76 of 216 patients (35.1%) experienced relapses. Overall and relapse-free survival rates at 5 years were 94.9% and 57.3%, respectively, and those rates were not significantly different between Class 1 and 2 ( p =0.30 and p =0.19). Time-to-event analysis suggested higher neutrophil count, lower hemoglobin, and age ≥65 years at disease onset as risk factors for death and age ≥65 years at disease onset as a risk factor for relapse. Conclusions AOSD patients were divided into two subgroups: the typical group and the elderly-onset group. Although the survival of patients with AOSD was generally good, the patients often experienced relapses. Age ≥65 years at disease onset was the risk factor for relapse.

Aims/Introduction Severe diabetic macular edema (DME) is often resistant to anti‐vascular endothelial growth factor therapy. Steroids are particularly effective at reducing edema by suppressing inflammation; they are also used as an alternative to expensive anti‐vascular endothelial growth factor therapy in some patients. Therefore, the use of steroids in DME reflects an unmet need for anti‐vascular endothelial growth factor therapy. Notably, triamcinolone acetonide (TA) injections are widely used in Japan. Here, we evaluated the frequency of TA as an indicator of the efficacy of sodium–glucose cotransporter 2 inhibitors (SGLT2is) in DME treatment using a health insurance claims database. Materials and Methods In this cohort study, we retrospectively analyzed the health insurance claims data of 11 million Japanese individuals from 2005 to 2019. The frequency and duration of TA injection after the initiation of SGLT2is or other antidiabetic drugs were analyzed. Results Among the 2,412 matched patients with DME, the incidence rate of TA injection was 63.8 times per 1,000 person‐years in SGLT2i users and 94.9 times per 1,000 person‐years in non‐users. SGLT2is reduced the risk for the first (P = 0.0024, hazard ratio 0.66, 95% confidence interval 0.50–0.87), second (P = 0.0019, hazard ratio 0.53, 95% confidence interval 0.35–0.80) and third TA (P = 0.0053, hazard ratio 0.44, 95% confidence interval 0.25–0.80) injections. A subanalysis of each baseline characteristic of the patients showed that SGLT2is were effective regardless of the background factors. Conclusions The use of SGLT2is reduced the frequency of TA injection in patients with DME. Therefore, SGLT2i therapy might be a novel, noninvasive and low‐cost adjunctive therapy for DME. This study was carried out to evaluate the frequency of triamcinolone acetonide injections as an indicator of the efficacy of sodium–glucose cotransporter 2 inhibitors in the treatment of diabetic macular edema using data from a nationwide health insurance claims database in Japan. Triamcinolone acetonide is thought to reflect some of the unmet needs of anti‐vascular endothelial growth factor therapy in diabetic macular edema, as severe diabetic macular edema is often resistant to anti‐vascular endothelial growth factor therapy, and is also used as an alternative to expensive anti‐vascular endothelial growth factor therapy in some patients. We found that the use of sodium–glucose cotransporter 2 inhibitors significantly reduced the frequency of triamcinolone acetonide injections required in this vulnerable patient group.

Background The purpose of this study was to develop an internet-based Guided Self-Help CBT (iGSH-CBT) for Bulimia Nervosa (BN) / Binge Eating Disorder (BED) for Japanese patients and to test its feasibility. Methods A single-arm feasibility study. After baseline assessment, patients underwent a 16-week iGSH-CBT program, our Japanese adaption of the European-based Salut BN program. During the treatment period, weekly email support from trained counselors was provided. Evaluations were performed at baseline, after 8 weeks, at the end of the 16-week intervention, and at 2 months after treatment had ended. The primary outcome measure was the change in the weekly frequency of objective binging. Secondary outcomes were the change in the weekly frequency of objective purge episodes, responses on self-report questionnaires of the frequencies of binging and purging, psychopathological characteristics of eating disorders found on BITE, EDE-Q, EDI-2, HADS and EQ-5D, measurements of motivation, and completion of intervention (vs. dropout). Results Participants were 9 female outpatients with BN ( n  = 5) or BED ( n  = 4), of whom 8 (88.9%) attended the assessment at the end of the 16-week intervention. Mean age was 28 years (SD = 7.9). Percent change of the weekly frequency of objective binging was -4.40%, and at the end of the 16-week intervention 25% of the participants had achieved symptom abstinence. Conclusions No adverse events were observed during the treatment period and follow-up, and the implementation and operation of the program could be performed without any major problems, confirming the feasibility of iGSH-CBT for BN and BED for Japanese patients. Although no significant change was observed in the weekly frequency of objective binging, the abstinence rate from bulimic behaviors of those who completed the assessments was 25.0% at the end of treatment, and the drop-out rate was 11.1%. iGSH-CBT may be an acceptable and possibly even a preferred method of CBT delivery for Japanese patients with BN or BED, and our Japanese adaptation of Salut BN seems feasible. Trial registration UMIN, UMIN000031962. Registered 1 April 2018 - Retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000036334

Background and AimsThis randomized controlled trial (RCT) was designed to evaluate the short-term outcomes of underwater endoscopic mucosal resection (UEMR) and endoscopic submucosal dissection (ESD) of 21–30 mm colonic polyps.MethodWe conducted a single-center RCT. Patients diagnosed with suspected colorectal intramucosal carcinoma (21–30 mm and adaptable for both UEMR and ESD) were randomly assigned to the UEMR and ESD groups at a 1:1 ratio. The primary endpoint was the R0 resection rate. We independently performed one-sample tests against the set threshold for each treatment. The significance level was set at p = 0.224.ResultEleven polyps each in the UEMR and ESD groups, respectively, were analyzed. The R0 resection rate (%) was 36 (95% confidence interval 11–69) and 100 (72–100) for UEMR and ESD, respectively, with a significant difference between the two groups (p = 0.002). The p-value against the set threshold for UEMR was 0.743, whereas that for ESD was < 0.001 (one-sample binomial test). The en bloc resection rates (%) were 82 (48–97) and 100 (72–100) for UEMR and ESD, respectively; however, no significant difference was observed (p = 0.167). The mean treatment time (min) was significantly shorter in the UEMR group (8 ± 6) than in the ESD group (48 ± 29) (p = 0.001).ConclusionESD could achieve a high R0 resection rate, while the en bloc resection rate was comparable between the two treatment techniques with less burden on patients undergoing UEMR for 21–30-mm colorectal polyps.Clinical Trial RegistrationThe study was registered at the Japan Registry of Clinical Trial as jRCT1030210015 and jRCT1030210177.

IntroductionThere are a substantial number of patients developing heart failure after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), even though AS has been successfully treated. The purpose of this randomised controlled trial was to determine whether the addition of an angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, is superior to conventional medications in lowering N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients undergoing TAVI for AS.Methods and analysisThe study design is a prospective, single-centre, open-label, randomised, parallel-group, two-arm study, in which participants will be randomised in a 1:1 ratio to receive either conventional medications plus ARNI or conventional medications only. In the ARNI group, if a patient was on an ACE inhibitor or angiotensin II receptor blocker before TAVI, it will be switched to ARNI 100 mg/day (50 mg two times per day) on the first postoperative day. If not, candesartan 4 mg/day will be started 1–2 days before TAVI, and switched to ARNI 100 mg/day on the first postoperative day. As the patient has tolerability to ARNI, dosage will be increased stepwise to 400 mg/day 2–4 weeks apart. ARNI will be continued until at least 6-month follow-up. In the control group, the patient will receive conventional medications. The primary endpoint is the serum NT-proBNP value at 6-month follow-up after TAVI. Each group includes 42 patients (84 total patients).Ethics and disseminationEthical approval for this study has been obtained from the Chiba University Hospital Certified Clinical Research Review Board (CRB3180015). The study is ongoing. Findings from this study will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberThis trial has been registered on the Japan Registry of Clinical Trials: jRCT1031220344.

Mitochondrial dysfunction causes maternally inherited deafness and diabetes (MIDD). Herein, we report improved glycemic control in a 47‐year‐old Japanese woman with MIDD using imeglimin without major adverse effects. Biochemical tests and metabolome analysis were performed before and after imeglimin administration. Blood glucose level fluctuations were determined. Sulfonylureas, dipeptidyl peptidase‐4 inhibitors (DPP4is), and sodium glucose transporter‐2 inhibitors (SGLT2i) were administered to evaluate the efficacy of their combination with imeglimin. Imeglimin decreased the HbA1c and ammonia levels and increased the time‐in‐range, C‐peptide reactivity, and glucagon level. Elevated citrulline and histamine levels were decreased by imeglimin. The hypoglycemic effect was not enhanced by imeglimin when combined with sulfonylurea or DPP4i, but the blood glucose level was improved when combined with SGLT2i. Imeglimin improved glucose concentration‐dependent insulin secretion and maximized the insulin secretory capacity by improving mitochondrial function and glutamine metabolism and urea circuit abnormalities by promoting glucagon secretion. Imeglimin could improve glycemic control in MIDD. We studied the effect of imeglimin in a patient with maternally inherited diabetes and deafness (MIDD). Imeglimin potentially improves glucose concentration‐dependent insulin secretion and metabolism in MIDD. Imeglimin shows potential as a new treatment for MIDD.