Effects of informant replacement in Alzheimer's disease clinical trials.

INTRODUCTION: Alzheimer's disease (AD) trials require enrollment with an informant. METHODS: We assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18-month change from baseline, and an F-test to compare the variance of this change. RESULTS: Among 1336 participants, 63 (≈5%) experienced replacement. Between-visit mean change in ADCS-ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: -3.91, -0.98). The difference in between-visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18-month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99). DISCUSSION: Informant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS-ADL.

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study.

OBJECTIVE: In order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs. METHODS: This retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0-33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed. RESULTS: In the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly. CONCLUSIONS: This retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.

Flexible magnifying endoscopy with narrow band imaging for the diagnosis of uterine cervical tumors: A cooperative study among gastrointestinal endoscopists and gynecologists to explore a novel microvascular classification system.

Narrow band imaging with magnifying endoscopy (NBI-ME), which is useful for the assessment of micro-vessels, has excellent diagnostic potential for early gastrointestinal epithelial neoplasia. Conventional diagnostic tools for uterine cervical epithelial tumors are still unsatisfactory. An accurate diagnostic tool for uterine cervical epithelial tumors is required to preserve the reproductive ability of young women with uterine cervical tumors. Flexible NBI-ME was performed in patients with cervical squamous cell lesions that required further examinations based on their Pap smear results (cytology ≥ low-grade squamous intraepithelial lesion) at Kagawa University Hospital between April 2014 and April 2015. NBI-ME results concordant with the punch biopsy sites were compared with the histological results. A retrospective review of the NBI-ME images identified abnormal NBI-ME results regarding micro-vascular patterns. All images were categorized as having abnormal features. NBI-ME revealed the following vascular pattern differences of different stage tumors: Dot-like vessels without irregular arrangements and high density in cervical intraepithelial neoplasia (CIN) CIN1-CIN2; dot-like vessels with irregular arrangements and high density in CIN3-carcinoma in situ; crawling vessels in minimum invasive cancer; and willow branch vessels and new tumor vessels in invasive cancer. NBI-ME may be an effective diagnostic tool for uterine cervical epithelial tumors, which may lead to the establishment of a novel classification system.

Integrating Post-Abortion family planning services into existing abortion services in hospital settings in China (INPAC) Project Management Characteristics / 中华医学科研管理杂志

Integrating Post-Abortion family planning services into existing abortion services in hospital settings in China (INPAC) Project under European Union Framework 7 is an international cooperative study underwent by 7 Sino-European research institutions and non-profit organizations.By learning experiences and integrating the methods of tree-like hierarchical management, whole process management and fine management, the Chinese Medical Association explored a characteristic management method of international cooperative study suitable for non-profit organization, which effectively facilitated project management and financial management and stimulated the disciplinary development and talents building.

Using baseline cognitive severity for enriching Alzheimer's disease clinical trials: How does Mini-Mental State Examination predict rate of change?

BACKGROUND: Post hoc analyses from clinical trials in Alzheimer's disease suggest more cognitively impaired participants respond differently from less impaired on cognitive outcomes. We examined pooled clinical trials data to assess the utility of enriching trials using baseline cognition. METHODS: We included 2,882 participants with mild to moderate AD in 7 studies from a meta-database. We used mixed effects models to estimate rate of decline in ADAS-cog scores among MMSE groups. FINDINGS: Baseline MMSE category was associated with baseline scores and rate of decline on the ADAS-cog, adjusting for age and education (both p<0.001). Greater baseline cognitive impairment was associated with more rapid progression. INTERPRETATIONS: Although we found significant differences in rate of decline, the majority of differences between individuals were from baseline ADAS-cog values. Enrichment based on MMSE would reduce the recruitment pool while adding only slightly to detecting differences in rate of progression and is not advised.

Antidepressants for depression in patients with dementia: a review of the literature.

OBJECTIVE: To evaluate the literature investigating the efficacy and safety of antidepressants for treating depression in individuals with dementia. DATA SOURCES: A literature search was conducted using MEDLINE, PUBMED, EMBASE, and Cochrane databases from inception to May 2013 for studies in English that evaluated the treatment of depression in patients with dementia. All relevant randomized controlled trials (RCTs) and meta-analyses were identified using the search terms "dementia" or "Alzheimer's disease," and "depression" or "major depressive disorder." Reference lists from retrieved articles and practice guidelines were also searched for relevant literature. STUDY SELECTION AND DATA EXTRACTION: Only randomized, placebo-controlled trials and meta-analyses that compared an antidepressant with placebo for the treatment of depression in patients with dementia were included. DATA SYNTHESIS: In this systematic review, 10 RCTs and 3 meta-analyses were identified that examined the efficacy and safety of antidepressants compared with placebo in treating depression in patients with dementia. The majority of the RCTs consisted of a small sample size, and the antidepressants studied were not routinely used in practice. CONCLUSIONS: The evidence for antidepressants in the treatment of depression in patients with dementia is inconclusive. The accumulation of evidence suggests nonpharmacologic approaches and watchful waiting be attempted for the first 8 to 12 weeks in a patient who presents with both mild-to-moderate depression and dementia. In cases of severe depression, or depression not managed through nonpharmacologic means, a trial of an antidepressant may be initiated. However, further well-designed trials are needed to support these recommendations.

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease.

BACKGROUND: The apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. METHODS: We tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. RESULTS: Enrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. CONCLUSIONS: Although samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.

Comparing clinical profiles in Alzheimer's disease and Parkinson's disease dementia.

BACKGROUND: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. METHODS: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1]. RESULTS: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. CONCLUSION: Differing patterns of impairment occur in AD and PDD.

Early outcomes of open abdominal repair versus endovascular repair for abdominal aortic aneurysm: report from national hospital organization network study in Japan.

OBJECTIVE: Early outcomes of open abdominal repair (OS) versus endovascular repair (EVAR) for abdominal aortic aneurysm were retrospectively analyzed, after commercialized devices for EVAR had become available in Japan. PATIENTS AND METHODS: A total of 781 consecutive patients (OS, n = 522; EVAR, n = 259) were treated at ten medical centers between January 2008 and September 2010. The OS group comprised patients with preoperative shock (SOS, n = 34) and without shock (NOS, n = 488). RESULTS: Patients in the EVAR group were 3 years older than those in the NOS group. There was greater prevalence of hostile abdomen, on dialysis, chronic obstructive pulmonary disease on inhaled drug, and cerebrovascular disease in the EVAR group than in the NOS group. Surgical mortality was 16 cases (2.0% in all patients, EVAR: 0.8%, NOS: 1.4%, SOS: 21%). Hospital stay >30 days was documented in 52 (11%) with NOS, 11 (33%) with SOS, and 8 (3%) with EVAR. Thirty late deaths included 6 aneurysm related death and 14 cardiovascular causes at a mean follow up of 1.0 year. The survival rates freedom from all cause death at one year, were 95 ± 1% in NOS and 94 ± 2% in EVAR respectively. CONCLUSION: Though significant differences in patient characteristics among three groups were noted, early results were satisfactory.

Analysis of current situation of domestic multi-center study from medicine papers / 中华医学科研管理杂志

Objective To analyze the current situation of domestic multi-center study of medicine research in order to improve the scientific research level.Method Using the bibliometrics method to analyze the number of coauthors,research institutions, research states distribution,foundation paper numbers and large sample papers of 200 multicenter original research papers published in 10 domestic and foreign journals in 2010.Results There were 112 domestic original research papers,the number of average coauthor was 6.1± 1.1; 15.2％ of them were more than 3research institutions; 2.7％ of them were cooperative study of more than 2 countries.49 papers (43.8％)were supported by fund; 10.7％ of which were more than 3 foundations; large sample papers account for 24.1 ％.In 88 foreign original research papers,the number of average coauthors is 9.8± 2.7; 86.4％ of them are under more than 3 research institutions; 44.3％ of them are cooperative study of more than 2 countries.Fund papers account for 69.3 ％ ; large sample papers account for 50％.There were significant difference in the number of coauthors,research institutions,number of countries,large sample papers and the number of ≥3 foundation papers between both domestic and international paper(P ＜ 0.05).The number of domestic and foreign funded papers had no significant difference (P ＞0.05).ConclusionThere are some differences between domestic and foreign medical cooperative research. We should strengthen the international and domestic cooperative research in order to improve the scientific research level and reduce the waste of resources.

Effect of donor and recipient variables on the long-term live-donor renal allograft survival in children.

OBJECTIVE: We aimed to analyse donor and recipient predictors of graft survival in children who received live-donor renal grafts. PATIENTS AND METHODS: The study comprised 273 children who received live-donor renal transplants at our center between March 1976 and October 2010. The follow-up ranged from 6 months to 25 years. Donor variables included donor age, gender, donor/recipient body weight ratio (DR BWR), ABO blood groups, human leukocyte antigen, and DR mismatching. Donor-specific problems, e.g., ischemia time during surgery and number of renal arteries, were included. Recipient variables included recipient age, sex, original kidney disease, ischemia time, acute tubular necrosis (ATN) after transplantation, immunosuppression, number of acute rejection episodes, re-transplantation, and development of hypertension. RESULTS: Independent variables with a sustained effect on the 5- and 10-year graft survival on multivariate analysis were: ATN after transplant, number of acute rejections, hypertension, and DR BWR. At the last follow-up, 185 patients (67.8%) had a functioning graft, while 82 (30.0%) had graft failure. Only six patients (0.02%) were lost to follow-up. CONCLUSION: Donor and recipient variables that affect short- and long-term graft survival in children with a live-donor renal allograft are DR BWR, number of acute rejections, ATN and hypertension after transplant. Considering these variables provides a better outcome.

Preliminary Summary of a Cooperative-study on Treatment of Hypertension With Domestic Urapidil: Re- port of 41 Cases in Clinical Trial / 中国药房

OBJECTIVE: To verify the therapeutic effect and adverse reactions of ?-receptor blocker, domestic urapidil, on severe hypertension. METHODS: Observation was carried out in a multi-center, random sampling and controlled pattern. Drug was iv injected first and then infused. At the same time, the patients' systolic pressure, diastolic pressure, heart rate, EKG, blood & urine routine, serum GPT and urea nitrogen were measured and examined.RESULTS: Of 41 cases in this series. 16 satis- factory(39.0%), 23 improved (56.1%), 2 unsatisfactory(4.9%) .The total effective rate was 95.1%. After drug administra- tion, systolic pressure was lowered by 43 .97mmHg(P