Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

Risk factors for the recurrence of relapsing polychondritis

再発性多発軟骨炎の再発リスク因子の同定. 京都大学プレスリリース. 2022-06-06.[Background] Although the survival rates of patients with relapsing polychondritis (RP) have increased remarkably, the high recurrence rate remains a significant concern for physicians and patients. This retrospective study aimed to investigate the risk factors for RP recurrence. [Methods] Patients with RP who presented to Kyoto University Hospital from January 2000 to March 2020 and fulfilled Damiani’s classification criteria were included. Patients were classified into recurrence and non-recurrence groups. Risk factors for RP recurrence were analysed using a Cox proportional hazards model, and Kaplan–Meier survival curves were drawn. [Results] Thirty-four patients were included. Twenty-five patients (74%) experienced 64 recurrences (mean: 2.56 recurrences per patient). The median duration before the first recurrence was 202 [55−382] days. The median prednisolone dose at the initial recurrence was 10 [5−12.75] mg/day. Tracheal involvement was significantly more frequent in the recurrence group at the initial presentation (44.0% vs. 0.0%, p=0.0172) than in the non-recurrence group, and pre-treatment C-reactive protein levels were significantly higher in the recurrence group than in the non-recurrence group (4.7 vs 1.15 mg/dL, p=0.0024). The Cox proportional hazards model analysis revealed that tracheal involvement (hazard ratio [HR] 4.266 [1.535−13.838], p=0.0048), pre-treatment C-reactive protein level (HR 1.166 [1.040−1.308], p=0.0085), and initial prednisolone monotherapy (HR 4.443 [1.515−16.267], p=0.0056) may be associated with recurrence. The median time before the initial recurrence was significantly longer in patients who received combination therapy with prednisolone and immunosuppressants or biologics (400 vs. 70 days, p=0.0015). [Conclusions] Tracheal involvement, pre-treatment C-reactive protein level, and initial prednisolone monotherapy were risk factors for recurrence in patients with RP. Initial combination therapy with prednisolone and immunosuppressants may delay recurrence

Quantitative analysis of the effect of docetaxel-induced edema on quality of life in patients with breast cancer and related factors: a prospective cohort study

Abstract Background Systemic edema is an adverse effect of docetaxel chemotherapy and causes distress to patients, including those receiving this agent for breast cancer. However, its characteristics and factors related to its effect on quality of life (QoL) have not been adequately investigated. In this study, we assessed systemic edema quantitatively, explored related factors, and evaluated QoL in patients receiving docetaxel for breast cancer. Methods The study had a prospective cohort design and included 37 patients with no known history of swelling who were treated with docetaxel between September 2019 and April 2022. Patients were examined at the start, middle, and end of their course of treatment and 1 and 2 months later. Body water content, body mass, fat mass, and muscle mass were quantified using bioelectrical impedance analysis. Systemic edema was evaluated with reference to the Common Terminology Criteria for Adverse Events. The timing of development of systemic edema at any anatomical site that was grade 2 or worse was recorded. QoL was assessed using the Quality of Life-Anti Cancer Drug scale. Nutrition was evaluated using the Brief-type self-administered diet history questionnaire. Multivariable logistic regression analysis was performed to identify related factors. QoL was also compared between patients with edema and those without edema. Results Systemic edema developed in 67% of the study participants and was most prevalent at the end of treatment. Body fat mass (adjusted odds ratio [aOR] 0.802, 95% confidence interval [CI] 0.651–0.988, p = 0.038), disease stage (aOR 3.279, 95% CI 0.493–21.793, p = 0.219), and history of alcohol consumption (aOR 0.141, 95% CI 0.013–1.521, p = 0.106) were identified as risk factors for docetaxel-induced edema. Participants who developed systemic edema experienced more physical, vital, and emotional distress 1 month after treatment than those who did not. There was no association between systemic edema and nutrition. Conclusions Systemic edema may develop after treatment with docetaxel and increase distress in patients with a high body fat mass. Patients at risk of systemic edema should be informed in advance about the potential frequency, location, and timing of its onset and encouraged to self-manage this condition

Protocol of a phase II study to evaluate the efficacy and safety of deep-inspiration breath-hold daily online adaptive radiotherapy for centrally located lung tumours (PUDDING study)

Abstract Background Centrally located lung tumours present a challenge because of their tendency to exhibit symptoms such as airway obstruction, atelectasis, and bleeding. Surgical resection of these tumours often requires sacrificing the lungs, making definitive radiotherapy the preferred alternative to avoid pneumonectomy. However, the proximity of these tumours to mediastinal organs at risk increases the potential for severe adverse events. To mitigate this risk, we propose a dual-method approach: deep inspiration breath-hold (DIBH) radiotherapy combined with adaptive radiotherapy. The aim of this single-centre, single-arm phase II study is to investigate the efficacy and safety of DIBH daily online adaptive radiotherapy. Methods Patients diagnosed with centrally located lung tumours according to the International Association for the Study of Lung Cancer recommendations, are enrolled and subjected to DIBH daily online adaptive radiotherapy. The primary endpoint is the one-year cumulative incidence of grade 3 or more severe adverse events, as classified by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Discussion Delivering definitive radiotherapy for centrally located lung tumours presents a dilemma between ensuring optimal dose coverage for the planning target volume and the associated increased risk of adverse events. DIBH provides measurable dosimetric benefits by increasing the normal lung volume and distancing the tumour from critical mediastinal organs at risk, leading to reduced toxicity. DIBH adaptive radiotherapy has been proposed as an adjunct treatment option for abdominal and pelvic cancers. If the application of DIBH adaptive radiotherapy to centrally located lung tumours proves successful, this approach could shape future phase III trials and offer novel perspectives in lung tumour radiotherapy. Trial registration. Registered at the Japan Registry of Clinical Trials (jRCT; https://jrct.niph.go.jp/ ); registration number: jRCT1052230085 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1052230085 )

Peripheral nerve regeneration following scaffold-free conduit transplant of autologous dermal fibroblasts: a non-randomised safety and feasibility trial

Abstract Background The use of Bio 3D nerve conduits is a promising approach for peripheral nerve reconstruction. This study aimed to assess their safety in three patients with peripheral nerve defects in their hands. Methods We describe a single institution, non-blinded, non-randomised control trial conducted at Kyoto University Hospital. Eligibility criteria included severed peripheral nerve injuries or a defect in the region distal to the wrist joint not caused by a congenital anomaly; a defect with a length of ≤20 mm in a nerve with a diameter ≤2 mm; failed results of sensory functional tests; ability to register in the protocol within 6 months from the day of injury; refusal of artificial nerve or autologous nerve transplantation; age 20–60 years; and willingness to participate and provide informed written consent. Six weeks before transplantation, skin was harvested, dermal fibroblasts were isolated and expanded, and Bio 3D nerve conduits were created using a Bio 3D printer. Bio 3D nerve conduits were transplanted into the patients’ nerve defects. The safety of Bio 3D nerve conduits in patients with a peripheral nerve injury in the distal part of the wrist joint were assessed over a 48-week period after transplantation. Results No adverse events related to the use of Bio 3D nerve conduits were observed in any patient, and all three patients completed the trial. Conclusions Bio 3D nerve conduits were successfully used for clinical nerve reconstruction without adverse events and are a possible treatment option for peripheral nerve injuries