ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the ...safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies ADAs). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.
•Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 5 weeks, and FVIII-mimetic procoagulant activity in humans.•ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and white adults.
A shift towards obtaining emergency contraceptives without a prescription have been discussed in Japan. In response to this social background, we aimed at investigating the background of sexual ...intercourse, emergency contraceptive use, and knowledge of sexual and reproductive health education among women of reproductive age in Japan. In this study, we conducted a national wide cross-sectional questionnaire survey using a total of 4 web-based domains (background, sexual history, emergency contraceptives, and sexual and reproduction-related knowledge) composed of 50 questions. We obtained responses from a total of 4,631 participants of varying age groups (18–25, 26–35, and 36–45 years old) and 47 prefectures (84 to 118 from each prefecture). Among participant responses, 69.7% are sexually active, of which 49.0% had experiences of sexual intercourse with an unknown person. The responses from a total of 737 participants who have sexual intercourse, know of emergency contraceptives, and have experienced a situation that necessitated the use of emergency contraceptives, were analyzed. Of these participants, 46.4% (342/737) took emergency contraceptives, while 43.6% (321/737) participants did not take emergency contraceptives. Participants who have the knowledge for obtaining emergency contraceptives through the correct means were 52.6% (2438/4631). This study showed that approximately half of participants may not have correct knowledge of emergency contraceptives. In addition, approximately half of sexually active participants are facing unintended pregnancies due to a lack of sexual and reproductive awareness. Hence, comprehensive sex education is necessary to achieve social and regulatory changes centered on emergency contraceptives.
Introduction
The clinical benefit of vitamin D receptor activators (VDRA) in patients with well‐controlled secondary hyperparathyroidism undergoing dialysis remains unclear.
Methods
This post hoc ...analysis of the LANDMARK study investigates if VDRA use is associated with cardiovascular benefits. Data of 2135 patients undergoing hemodialysis who were at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity‐score matching.
Results
The hazard ratio (HR) for VDRA use was 0.99 (95% confidence interval CI: 0.67–1.46; p = 0.945) for cardiovascular events and 0.89 (95% CI: 0.62–1.28; p = 0.541) for all‐cause mortality at baseline. Among patients who always used VDRA, the HR was 1.12 (95% CI: 0.67–1.89; p = 0.666) for cardiovascular events and 1.11 (95% CI: 0.67–1.85; p = 0.688) for all‐cause mortality compared to those who never used VDRA.
Conclusion
The use of VDRA does not reduce the risks of cardiovascular events or all‐cause mortality in patients on dialysis with well‐controlled secondary hyperparathyroidism.
Background
It is necessary to re-examine the optimal phosphate (P) and calcium (Ca) target values in the contemporary management of chronic kidney disease–mineral and bone disorder to reduce the ...risks of cardiovascular events in patients receiving hemodialysis.
Methods
We performed a post-hoc analysis of the LANDMARK study. The outcomes were defined as cardiovascular events and all-cause death. Data from 2135 patients receiving hemodialysis at risk of vascular calcification were analyzed using a time-dependent Cox proportional hazard model adjusted for background factors.
Results
On the hazard ratio (HR) curve, the ranges where the lower 95% confidence interval (CI) were below the minimum of HR (= 1.00) were as follows: P = 3.5–5.5 mg/dL; albumin-adjusted Ca < 9.1 mg/dL for cardiovascular events; and P = 3.6–5.3 mg/dL; albumin-adjusted Ca < 9.1 mg/dL for all-cause mortality. In stratified analysis, the HRs for cardiovascular events in P < 3.5 mg/dL and P ≥ 5.5 mg/dL were similar to that of P = 3.5–5.5 mg/dL (
P
≥ 0.05), and albumin-adjusted Ca ≥ 9.1 mg/dL had higher HR than values < 9.1 mg/dL 1.30 (95% CI 1.00–1.68;
P
= 0.046). For all-cause mortality, the HR in P < 3.6 mg/dL was higher than that in P = 3.6–5.3 mg/dL 1.76 (95% CI 1.25–2.48;
P
= 0.001), while the HRs between P ≥ 5.3 mg/dL and P = 3.6–5.3 mg/dL as well as those between albumin-adjusted Ca ≥ 9.1 and < 9.1 mg/dL were not significantly different (
P
≥ 0.05).
Conclusions
Managing albumin-adjusted Ca < 9.1 mg/dL may reduce the cardiovascular risk among patients undergoing hemodialysis. Hypophosphatemia < 3.6 mg/dL may be associated with mortality.
Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a ...severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.
The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.
A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.
Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.
The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.
This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly ...individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown.
We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).
The genera
and
were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of
(P = 0.022) and
(P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of
(P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of
(P = 0.001) and
(P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of
(P = 0.013) and the unclassified
(P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group,
and
(both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast,
(P = 0.021) and
(P= 0.033) were statistically significantly more common in those without irAEs.
Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.
The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In ...particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.
: The advancement of multidisciplinary treatment has increased the need to develop tests to monitor tumor burden during treatment. We herein analyzed urinary microRNAs within extracellular vesicles ...from patients with esophageal squamous cell carcinoma (ESCC) and normal individuals using a microarray.
Patients with advanced ESCC who underwent esophagectomy (A), endoscopic submucosal resection (ESD) (B), and healthy donors (C) were included. Based on microRNA expression among the groups (Analysis 1), microRNAs with significant differences between groups A and C were selected (Analysis 2). Of these candidates, microRNAs in which the change between A and C was consistent with the change between B and C were selected for downstream analysis (Analysis 3). Finally, microRNA expression was validated in patients with recurrence from A (exploratory analysis).
For analysis 1, 205 microRNAs were selected. For Analyses 2 and 3, the changes in 18 microRNAs were consistent with changes in tumor burden as determined by clinical imaging and pathological findings. The AUC for the detection of ESCC using 18 microRNAs was 0.72. In exploratory analysis, three of eighteen microRNAs exhibited a concordant trend with recurrence.
The current study identified the urinary microRNAs which were significantly expressed in ESCC patients. Validation study is warranted to evaluate whether these microRNAs could reflect tumor burden during multidisciplinary treatment for ESCC.
Aim
Atomoxetine (ATX) is a non‐central stimulant and a standard treatment for adult attention‐deficit/hyperactivity disorder (ADHD). The long‐term efficacy of Atomoxetine is about 40% at 6 months. ...The variability in efficacy between individuals is thought to be related to patient‐specific factors, but no detailed research has been conducted. In this retrospective cohort study, we aimed to identify the factors associated with Atomoxetine efficacy.
Methods
A total of 147 patients with attention‐deficit/hyperactivity disorder aged ≥18 years who were using Atomoxetine for the first time were included in this study. The outcome was treatment success (treatment maintained for at least 6 months and improvement in symptoms). Symptom assessment was based on the overall improvement in symptoms judged by an expert physician.
Results
Of the patient sample, 103 (70.1%) achieved the outcome. Logistic regression analysis identified “the maximum dose of ATX” and “gambling habit” as factors associated with efficacy ( P < 0.05). In the process of Atomoxetine titration, the larger the maximum dose, the higher the efficacy was shown to be. Gambling habits may be indicative of impulsivity, which is among the core symptoms of attention‐deficit/hyperactivity disorder. Thus, a gambling habit may be considered a surrogate marker for impulsivity.
Conclusions
Knowledge of these factors will help healthcare professionals to predict the likely efficacy of Atomoxetine in a given patient before subscribing it, facilitating individualized pharmacotherapy for adult attention‐deficit/hyperactivity disorder.
We retrospectively examined factors associated with the efficacy of atomoxetine for adult ADHD. The maximum dose of atomoxetine and gambling habit were identified as significant factors related to the efficacy.
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