Hiroshima University Hospital

Objective This study aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez+Bev) as a 2nd line therapy after the administration of durvalumab plus tremelimumab (Dur+Tre) in patients with hepatocellular carcinoma. We focused on the treatment outcomes and adverse event profiles specific to this sequential regimen. Methods A retrospective analysis was conducted on 16 patients who received 2nd line Atez+Bev after Dur+Tre therapy between April 2023 and August 2024 in our hospital and associated institutions. The objective response rate (ORR), disease control rate (DCR), treatment duration, and adverse events were assessed. Results The ORR and DCR for 2nd line Atez+Bev were 25.0% and 75.0%, respectively, thus suggesting favorable disease control. Even among patients who were non-responsive to Dur+Tre, two achieved a tumor response and eight achieved disease control. Regarding safety, pruritus was a common adverse event for both regimens. Colitis and diarrhea were more frequent in the Dur+Tre group, whereas proteinuria, hyperammonemia, and bleeding were more common in the Atez+Bev group. Conclusion This study suggests that Atez+Bev remains a viable option for patients unresponsive to Dur+Tre. Prior Dur+Tre therapy may enhance the immune response within the tumor microenvironment, thereby augmenting the efficacy of Atez+Bev. However, it is important to pay attention to the differences in adverse effect profiles between the two regimens.

Glucocorticoids (GC) comprise a cornerstone in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, prolonged GC exposure leads to substantial toxicity and immune system-related complications. Hence, identifying treatment strategies that enable early GC withdrawal while maintaining disease control is of clinical importance. To investigate the proportion and characteristics of patients achieving GC-free clinical remission (GFCR) 48 weeks after treatment initiation in patients with newly diagnosed microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) and examine their long-term clinical outcomes (up to week 96). We conducted a retrospective cohort study using clinical data from a multicenter, nationwide registry in Japan comprising patients with newly diagnosed MPA or GPA and at least 48 weeks of follow-up. GFCR was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 with complete GC withdrawal. Univariable and multivariable logistic regression analyses were used to identify independent predictors of GFCR at week 48, and a sensitivity analysis using a matched cohort was performed to validate robustness. A total of 728 patients were enrolled in the registry, of whom 544 were followed for ≥ 48 weeks; among them, 29 (5.3%) achieved GFCR at week 48. Use of rituximab (RTX) for induction therapy and avacopan within 48 weeks were independently associated with achieving GFCR (multivariable analysis, model 1: RTX: odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.5–10.0; avacopan: OR: 24.3, 95% CI: 5.8–101.9; both p < 0.01). Conversely, methylprednisolone pulse therapy was associated with a lower likelihood of achieving GFCR (multivariable analysis, model 1: OR: 0.08, 95% CI: 0.02–0.44; p < 0.01). Patient’s demographic and baseline disease characteristics were not predictive of GFCR. In the long-term (weeks 48 through 96), the rates of death, relapse, and serious infection were similar regardless of GFCR status at week 48. The use of RTX for induction therapy and avacopan within 48 weeks is independently associated with achieving GFCR at week 48 in patients with MPA and GPA, supporting their potential as key components of GC-sparing strategies in AAV. Prospective studies are needed to confirm these results and optimize treatment algorithms to ensure disease control and minimize GC-related toxicity.

Candidemia poses diagnostic challenges because of non-specific symptoms and low sensitivity of blood cultures. The Wako (1,3)-β-D-glucan (BDG) assay was recently introduced in Europe; however, its diagnostic performance for Candida parapsilosis compared to that of the Fungitell assay, which has demonstrated lower sensitivity, remains unclear. We evaluated the diagnostic performance of Wako BDG and BDG levels in candidemia, focusing on C. parapsilosis. BDG samples obtained within ± 3 days of blood culture collection were retrospectively analyzed. Diagnostic performance was compared using multiple cutoffs, including manufacturer-recommended thresholds (Japan: 11 pg/mL, Europe: 7.0 pg/mL). BDG levels and clinical characteristics were compared between C. parapsilosis and non-parapsilosis Candida candidemia. We included 154 candidemia episodes (C. parapsilosis: n = 24, non-parapsilosis Candida: n = 130) and 3,856 control episodes. Using 11 pg/mL, sensitivity for C. parapsilosis was 38% (95% confidence interval [CI]: 21–57) versus 62% (95% CI: 54–70) for non-parapsilosis Candida (p = 0.041), with specificity 93%. Lowering the cutoff from 11 to 7.0 pg/mL increased the overall sensitivity from 58% (95% CI: 51–66) to 71% (95% CI: 63–77) while maintaining high specificity (90%) but did not eliminate the sensitivity gap for C. parapsilosis. The median BDG level was lower in C. parapsilosis (5.0 pg/mL, interquartile range [IQR]: 0–68) than in non-parapsilosis Candida (21 pg/mL, IQR: 7.2–97; p = 0.036). C. parapsilosis candidemia was most commonly catheter-related (67%), with 17% in-hospital mortality. Despite high specificity, Wako BDG assay showed significantly lower sensitivity and BDG levels for C. parapsilosis candidemia compared with non-parapsilosis Candida candidemia.

Sedation during colonoscopy is becoming increasingly important. Remimazolam, an ultra-short-acting benzodiazepine, has a shorter pharmacokinetic half-life than that of midazolam. This study examined whether remimazolam provides superior sedation during colonoscopy in Japanese patients. This prospective, multicenter, randomized, single-blind, controlled trial included adults (18-80 years) scheduled for sedated colonoscopy. Participants were randomized to the remimazolam and midazolam groups. The primary outcome was the proportion of ambulatory patients 5 min after colonoscopy. Secondary outcomes were successful pre-procedure sedation (Modified Observer's Assessment of Alertness/Sedation [MOAA/S] ≤ 4), recovery time, total sedative dose, and adverse events. Forty patients were enrolled and analyzed (remimazolam, n = 19; midazolam, n = 21). At 5 min post-colonoscopy, ambulation was achieved in 100% (19/19) of remimazolam patients and 19.1% (4/21) of midazolam patients (p < 0.0001). The median time [interquartile range (IQR)] from procedure end to full alertness (MOAA/S = 5) was 0 [0-0] min for remimazolam and 10 [5-20] min for midazolam (p < 0.0001). The median time [IQR] from procedure end to independent ambulation was 0 [0-5] min for remimazolam and 20 [10-30] min for midazolam (p < 0.001). Pre-procedure sedation was successful (MOAA/S ≤ 4) in 100% of both groups. The median amount [IQR] of total sedative dose was 5 [4-6] mg for remimazolam and 3 [3] mg for midazolam. Hypoxemia occurred in 5.3% and 9.5% of patients in the remimazolam and midazolam groups, respectively. Compared with midazolam, remimazolam resulted in significantly faster recovery after colonoscopy in Japanese patients, with comparable achievement of target sedation and a low incidence of hypoxemia. Trial number: jRCTs071240062.

Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17cells are implicated in chronic AD, yet its efficacy against Th17-dependent pathology remains unclear. We investigated the effects of tacrolimus using a murine model of Th17-mediated allergic skin inflammation. In CD4+ T cells from DO11.10/Rag2-/- mice, which express ovalbumin (OVA)-specific T cell receptor, tacrolimus differentially suppressed stimulation-induced cytokine expression by Th2 cells. At similar concentrations, tacrolimus suppressed Il21, but not Il17a or Il22, expression in Th17cells. Subcutaneous OVA challenge elicited ear thickening in BALB/c mice after adoptive transfer of Th2 or Th17cells, with a stronger response in Th17-transferred mice, but less than OVA-immunized controls. Topical tacrolimus reduced Th17-mediated ear swelling, corroborated by histopathology. In Th2-transferred mice, tacrolimus tended to reduce early skin thickening (day 3) but did not affect late responses (day 7). In Th17-transferred mice, tacrolimus significantly reduced allergen-specific T-cell accumulation in OVA-injected skin and tended to reduce Il21 expression, whereas Th2-cell accumulation and cytokine expression were unaffected. Tacrolimus exerts stronger inhibitory effects on Th17- than Th2-driven responses in this model, suggesting that suppression of Th17 pathways may contribute to its therapeutic benefit in AD.

Centrosome clustering is a cancer-specific adaptation that allows cells with centrosome amplification to evade mitotic catastrophe and has emerged as a potential therapeutic target. We analyzed the prognostic role of several molecules related to centrosome clustering and found that Kinesin Family Member C1 (KIFC1) was strongly associated with a poor prognosis. KIFC1, a kinesin motor protein, plays a central role in centrosome clustering. However, its biological and clinical significance in clear cell renal cell carcinoma (ccRCC) remains poorly understood. We conducted a comprehensive analysis using several public datasets (TCGA KIRC, JAVELIN101, IMmotion151, and others) and a Hiroshima ccRCC cohort (n = 110) to evaluate the expression of KIFC1, clinicopathological associations, the prognosis, and treatment response. Gene Set Enrichment Analysis was performed to explore associated pathways. Immunohistochemical and in silico analyses showed that high KIFC1 expression was significantly associated with high tumor grade, advanced TNM stage, and sarcomatoid differentiation. A multivariate analysis demonstrated that the high-expression of KIFC1 was independently associated with poor overall survival. Gene Set Enrichment Analysis revealed enrichment of epithelial-mesenchymal transition and interferon gamma response pathways in KIFC1-high tumors. The expression of KIFC1 was also correlated with TKI resistance, immune response, high clonal neoantigen load, and BAP1 mutation. KIFC1 serves as a multifunctional molecule linking epithelial-mesenchymal transition, immune modulation, and treatment resistance. It may be a promising prognostic biomarker and therapeutic target in ccRCC, warranting further functional and clinical investigation.

ABSTRACT Background Despite improvements in surgical techniques and perioperative management, the incidence of postoperative surgical site infection after pancreatoduodenectomy remains high. This study aim to assess whether broad‐spectrum antibiotic prophylaxis can reduce complications after pancreatoduodenectomy compared with standard care antibiotics. Methods Data of patients who underwent pancreatoduodenectomy between July 2010 and March 2022 were extracted from a nationwide Japanese inpatient database. First‐ and second‐generation cephalosporins were designated as narrow‐spectrum, and third‐ and fourth‐generation cephalosporins and piperacillin–tazobactam as broad‐spectrum antibiotics. Patients who received either narrow‐ or broad‐spectrum antibiotics on the day of surgery were included in the analysis. Using propensity‐score stabilized inverse probability of treatment weighting, the postoperative complications were compared between patients who received antimicrobial prophylaxis with narrow‐spectrum antibiotics versus broad‐spectrum antibiotics. Results From among 45 099 eligible patients, 36 742 (81.5%) and 8357 (18.5%) patients received narrow‐ and broad‐spectrum antibiotics, respectively. After stabilized inverse probability of treatment weighting, the use of broad‐spectrum antibiotics bore a significant association with the reduction in intra‐abdominal infections [risk difference (RD), −7.4; 95% confidence interval (CI), −8.7 to −6.0], postoperative pancreatic fistula (RD, −3.0; 95% CI, −4.0 to −1.9), post‐pancreatectomy hemorrhage (RD, −1.5; 95% CI, −1.9 to −1.1). The use of broad‐spectrum antibiotics was also associated with a shorter postoperative length of hospital stay and lower total hospitalization costs. The proportion of Clostridioides difficile infection did not differ between the groups. Conclusions The administration of broad‐spectrum antibiotics as antimicrobial prophylaxis was associated with better in‐hospital postoperative outcomes compared with narrow‐spectrum in patients undergoing pancreatoduodenectomy.

Despite the frequent use of both advanced airway management (AAM) and epinephrine during resuscitation, no studies have evaluated the optimal sequencing of these interventions in paediatric out-of-hospital cardiac arrest (OHCA). We therefore aimed to investigate the association between the sequence of AAM and epinephrine administration and outcomes in paediatric patients with OHCA with non-shockable rhythms. This retrospective observational study analysed data from a multicentre OHCA registry in Japan from 2014 to 2022. We included paediatric patients (aged <18 years) with non-shockable OHCA who received AAM (endotracheal intubation or supraglottic airway device placement) and/or epinephrine administration. The primary outcome was 1-month survival, and the secondary outcomes were 1-month favourable neurological outcome (defined as a paediatric cerebral performance category of 1-3) and the return of spontaneous circulation (ROSC). Inverse probability of treatment weighting (IPTW) was applied based on propensity scores to address imbalances in patient characteristics. Of the 952 paediatric patients with non-shockable OHCA (median age (IQR) 2 (0-14) years), 577 (61%) were male. Of these, 455 and 497 belonged to the AAM-first and epinephrine-first groups, respectively. After IPTW, all covariates were well balanced between the AAM-first and epinephrine-first groups (standardised mean difference ≤0.10). Compared with the epinephrine-first group, the AAM-first group showed similar 1-month survival (adjusted OR (aOR), 1.09; 95% CI 0.61 to 1.86), favourable neurological outcome at 1 month (aOR, 0.79; 95% CI 0.12 to 5.07) and ROSC (aOR, 0.98; 95% CI 0.72 to 1.35). The sequence of AAM and epinephrine administration was not associated with 1-month survival, favourable neurological outcome at 1 month or ROSC in paediatric patients with non-shockable OHCA.