Akihiro Hirakawa

Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer

Background:To evaluate the impact of change in the hormone receptor (HR) status (HR status conversion) on the long-term outcomes of breast cancer patients treated with neoadjuvant chemotherapy (NAC).Methods:We investigated 368 patients for the HR status of their lesions before and after NAC. On the basis of the HR status and the use/non-use of endocrine therapy (ET), the patients were categorised into four groups: Group A, 184 ET-administered patients with HR-positive both before and after NAC; Group B, 47 ET-administered patients with HR status conversion; Group C, 12 ET-naive patients with HR status conversion; Group D, 125 patients with HR-negative both before and after NAC.Results:Disease-free survival in Group B was similar to that in Group A (hazard ratio, 1.16; P=0.652), but that in Group C was significantly lesser than that in Group A (hazard ratio, 6.88; P<0.001). A similar pattern of results was obtained for overall survival.Conclusion:Our results indicate that the HR status of tumours is a predictive factor for disease-free and overall survival and that ET appears to be suitable for patients with HR status conversion. Therefore, both the CNB and surgical specimens should be monitored for HR status.

Irinotecan plus carboplatin for patients with carcinoma of unknown primary site.

Carcinoma of unknown primary site (CUP) is rarely encountered in clinical practice and optimal chemotherapy has not yet been established. This phase II study was conducted to evaluate the efficacy and toxicity of combined irinotecan+carboplatin therapy in chemotherapy-naive patients with CUP. Irinotecan was administered at 60u2009mgu2009m−2 as a 90-min intravenous infusion on days 1, 8 and 15. Carboplatin was administered at an area-under-the curve of 5u2009mgu2009ml−1u2009min as a 60-min intravenous infusion on day 1. This cycle was repeated every 28 days for up to six cycles. Forty-five patients were enrolled in the study. An intent-to-treat analysis revealed an objective response rate to the treatment of 41.9% (95% confidence interval, 27.0–57.9%). The median time to progression was 4.8 months and the median survival was 12.2 months. The 1- and 2-year survival rates were 44 and 27%, respectively. The most frequent grade 3 or more severe adverse events were leukopaenia (21%), neutropaenia (33%), anaemia (25%) and thrombocytopaenia (20%). Thus, the combination of irinotecan plus carboplatin was found to be active in patients with CUP. Therefore, the regimen may be one of the potentially available chemotherapeutic options for community standard of care in patients with a good performance status.

Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials

Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who were initially treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in 9 phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDI of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In both groups, however, the decreasing RDI over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.

Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials

ABSTRACT In Phase I/II trials for a combination therapy of two agents, we ideally want to explore as many dose combinations as possible with limited sample size in Phase I and to reduce the number of untried dose combinations before moving to Phase II. Efficient collection of toxicity data in Phase I would eventually improve the accuracy of optimal dose combination identification in Phase II. In this paper, we develop a novel dose-finding method based on efficacy and toxicity outcomes for two-agent combination Phase I/II trials. We propose a “zone-finding stage” that determines the most admissible toxicity zone on the dose combination matrix and subsequently select the dose combination allocated to the next patient from that zone in Phase I. Upon completion of this zone-finding stage, we allocate the next patient to the dose combination determined by adaptive randomization of the admissible toxicity and efficacy dose combinations in Phase II. Simulation studies demonstrated the utility of the proposed zone-finding stage and proved that the operating characteristic of the proposed method was no worse than the existing method. The sensitivity of the proposed method, as well as the operating characteristic of this method when the efficacy outcome is delayed, was also examined.

Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes

Objective To compare magnetic resonance spectroscopy (MRS) metabolite ratios in preterm infants at term-equivalent age with those in term infants and to evaluate the association between MRS metabolites and neurodevelopmental outcomes at 18 months corrected age in preterm infants. Design We studied infants born at a gestational age <37 weeks and weighing <1500 g during 2009–2013 using MRS at term-equivalent age. Infants with major brain abnormalities were excluded. The ratios of N-acetylaspartate (NAA) to creatine (Cre), NAA to choline-containing compounds (Cho) and Cho to Cre in the frontal white matter and thalamus were measured using multivoxel point-resolved proton spectroscopy sequence. Neurodevelopmental outcomes were assessed at 18 months corrected age. Results Thirty-three preterm infants and 16 term infants were enrolled in this study. Preterm infants with normal development at 18 months showed significantly lower NAA/Cho ratios in the frontal white matter than term infants. There were no differences in the Cre/Cho ratios between preterm and term infants. At 18 months corrected age, 9 preterm infants with a mild developmental delay showed significantly lower NAA/Cho ratios in the thalamus than 24 preterm infants with normal development. Conclusions Preterm infants at term-equivalent age showed reduced MRS metabolites (NAA/Cho) compared with term infants. Decreased NAA/Cho ratios in the thalamus were associated with neurodevelopmental delay at 18 months corrected age in preterm infants.

Early Prediction Model for Successful Bridge to Recovery in Patients With Fulminant Myocarditis Supported With Percutaneous Venoarterial Extracorporeal Membrane Oxygenation ― Insights From the CHANGE PUMP Study ―

BACKGROUNDnCardiac recovery and prevention of end-organ damage are the cornerstones of establishing successful bridge to recovery (BTR) in patients with fulminant myocarditis (FM) supported with percutaneous venoarterial extracorporeal membrane oxygenation (VA-ECMO). However, the timing and method of successful BTR prediction still remain unclear. We aimed to develop a prediction model for successful BTR in patients with FM supported with percutaneous VA-ECMO.Methodsu2004andu2004Results:This was a retrospective multicenter chart review enrolling 99 patients (52±16 years; female, 42%) with FM treated with percutaneous VA-ECMO. The S-group comprised patients who experienced percutaneous VA-ECMO decannulation and subsequent discharge (n=46), and the F-group comprised patients who either died in hospital or required conversion to other forms of mechanical circulatory support (n=53). At VA-ECMO initiation (0-h), the S-group had significantly higher left ventricular ejection fraction (LVEF) and lower aspartate aminotransferase (AST) concentration than the F-group. At 48 h, the LVEF, increase in the LVEF, and reduction of AST from 0-h were identified as independent predictors in the S-group. Finally, we developed an S-group prediction model comprising these 3 variables (area under the curve, 0.844; 95% confidence interval, 0.745-0.944).nnnCONCLUSIONSnWe developed a model for use 48 h after VA-ECMO initiation to predict successful BTR in patients with FM.

Design of a single-arm clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells for male stress urinary incontinence in Japan: the ADRESU study protocol

BackgroundMale stress urinary incontinence is a prevalent condition after radical prostatectomy. While the standard recommendation for the management of urine leakage is pelvic floor muscle training, its efficacy is still unsatisfactory. Therefore, we have focused on regenerative therapy, which consists of administering a periurethral injection of autologous regenerative cells from adipose tissue, separated using the Celution® system. Based on an interim data analysis of our exploratory study, we confirmed the efficacy and acceptable safety profile of this treatment. Accordingly, we began discussions with Japanese regulatory authorities regarding the development of this therapy in Japan. The Ministry of Health, Labour and Welfare suggested that we implement a clinical trial of a new medical device based on the Pharmaceutical Affaires Act in Japan. Next, we discussed the design of this investigator-initiated clinical trial (the ADRESU study) aimed at evaluating the efficacy and safety of this therapy, in a consultation meeting with the Pharmaceuticals and Medical Device Agency.MethodsThe ADRESU study is an open-label, multi-center, single-arm study involving a total of 45 male stress urinary incontinence patients with mild-to-moderate urine leakage persisting more than 1xa0year after prostatectomy, in spite of behavioral and pharmacological therapies. The primary endpoint is the rate of patients at 52xa0weeks with improvement of urine leakage volume defined as a reduction from baseline greater than 50% by 24-h pad test. Our specific hypothesis is that the primary endpoint result will be higher than a pre-specified threshold of 10%.DiscussionThe ADRESU study is the first clinical trial of regenerative treatment for stress urinary incontinence by adipose-derived regenerative cells using the Celution® system based on the Japanese Pharmaceutical Affaires Act. We will evaluate the efficacy and safety in this trial to provide an adequate basis for marketing approval with the final objective of making this novel therapy widely available for Japanese patients.Trial registrationThis trial was registered at the University Hospital Medical information Network Clinical Trial Registry (UMIN-CTR Unique ID: UMIN000017901; Registered July 1, 2015) and at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT02529865; Registered August 18, 2015).

Real-time feedback, debriefing, and retraining system of cardiopulmonary resuscitation for out-of-hospital cardiac arrests: a study protocol for a cluster parallel-group randomized controlled trial

BackgroundThe quality of cardiopulmonary resuscitation (CPR) performed by emergency medical services (EMS) personnel affects patient outcomes after cardiac arrest. A CPR feedback device with an accelerometer mounted on a defibrillator can monitor the motion of the patient’s sternum to display and record CPR quality in real time. To evaluate the utility of real-time feedback, debriefing, and retraining using a CPR feedback device outside of the hospital, an open-label, cluster randomized controlled trial will be conducted in five municipalities of Osaka Prefecture, Japan.MethodsEach EMS station within a fire department will be randomly assigned to: 1) the treatment group with real-time feedback, debriefing, and retraining using the CPR feedback device (intervention group); or 2) the conventional treatment group without real-time feedback, debriefing, and retraining (control group). This trial will include 2850 to 3020 patients over about 4xa0years. The primary outcome of the trial is 1-month favorable neurological survival, defined as cerebral performance category scale score 1 or 2. Secondary outcomes are 1-month survival, survival to hospital discharge, return of spontaneous circulation, and quality of CPR including fraction, depth, tempo, and ventilation rate.DiscussionThe trial will assess whether treatment monitored by the CPR feedback device, which allows for real-time feedback, debriefing, and retraining using CPR quality data, outperforms conventional treatment without real-time feedback, debriefing, and retraining in terms of 1-month favorable neurological survival in cardiac arrest patients receiving CPR outside the hospital.Trial registrationUniversity Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000021431. Registered on 11 March 2016.

Utility of Bayesian Single-Arm Design in New Drug Application for Rare Cancers in Japan: A Case Study of Phase 2 Trial for Sarcoma

Investigational drugs for rare cancers are often approved based solely on a single-arm phase II trial that primarily evaluates response rate in Japan. Such trials typically use a fixed sample size determined on the basis of the frequentist manner. However, since predicting the speed of patient enrollment is challenging because of the disease rarity, the time needed to complete the enrollment of the fixed number of patients is prolonged in some cases. A Bayesian design without fixing the sample size is useful for single-arm phase II trials of rare cancers. However, the arbitrariness of prior distribution specifications and the frequentist operating characteristics are regulatory issues. We recently started a Bayesian single-arm phase II trial of nivolumab in patients with sarcoma for new drug application in Japan and examined the statistical rationale and design consideration. In the Bayesian design, we specify the minimum and maximum numbers of enrolled patients during the enrollment period and the prior distributions of response rates. Considering these parameters, we obtain the minimum number of responders needed for the positive conclusion of the efficacy of nivolumab for each sample size. Simulation studies demonstrated that the operating characteristics of this design would be acceptable from the frequentist view. The Bayesian design provided an adaptive decision rule for efficacy conclusion for the drug without fixing the sample size. We hope our trial’s success will provide a new drug development option for rare cancers in Japan.

Prognostic parameter for high risk prostate cancer patients at initial presentation

High‐risk prostate cancer can be defined by a patients Gleason score (GS), prostate‐specific antigen (PSA) level, and clinical T (cT) stage, but a novel marker is needed due to heterogeneity of the disease. In this study, we evaluated whether intraductal carcinoma of the prostate (IDC‐P) confirmed by needle biopsy is an adverse prognostic parameter for progression‐free survival (PFS) and cancer‐specific survival (CSS) in patients with high‐risk prostate cancer.