Bridging continual reassessment method for phase I clinical trials in different ethnic populations

Accumulating evidence shows that the conventional one‐size‐fits‐all dose‐finding paradigm is problematic when applied to different ethnic populations. Because of inter‐ethnic heterogeneity, the dosage established in a landmark trial for a certain population may not be generalizable to a different ethnic population, and a follow‐up bridge trial is often needed to find the maximum tolerated dose for the new population. We propose the bridging continual reassessment method (B‐CRM) to facilitate dose finding for such follow‐up bridge trials. The B‐CRM borrows information from the landmark trial through a novel estimate of the dose‐toxicity curve and accommodates the inter‐ethnic heterogeneity using the Bayesian model averaging approach. Extensive simulation studies show that the B‐CRM has desirable operating characteristics with a high probability to select the target dose. This article focuses on ethnic heterogeneity, but the proposed method can be directly used to handle other types of patient heterogeneity, for example, patient subgroups defined by prognostic factors or biomarkers. The software to implement the B‐CRM design is available for free download at http://odin.mdacc.tmc.edu/~yyuan/ . Copyright © 2015 John Wiley & Sons, Ltd.     

Unravelling Fibromyalgia—Steps Toward Individualized Management

The heterogeneity of the clinical presentation and the pathophysiologic mechanisms associated with fibromyalgia (FM), and the modest results on average for any therapy, call for a more individualized management strategy. Individualized treatment can be on the basis of subgrouping of patients according to associated conditions (mental health problems, chronic overlapping pain conditions, other somatic diseases) or on disease severity. Categorizing FM as mild, moderate, or severe can be on the basis of clinical assessment (eg, degree of daily functioning) or on questionnaires. Shared decision-making regarding treatment options can be directed according to patient preferences, comorbidities, and availability in various health care settings. The European League Against Rheumatism guidelines recommend a tailored approach directed by FM key symptoms (pain, sleep disorders, fatigue, depression, disability), whereas the German guidelines recommend management tailored to disease severity, with mild disease not requiring any specific treatment, and more severe disease requiring multicomponent therapy (combination of drug treatment with aerobic exercise and psychological treatments). When indicated, treatments should follow a stepwise approach beginning with easily available therapies such as aerobic exercise and amitriptyline. Successful application of a tailored treatment approach that is informed by individual patient characteristics should improve outcome of FM.

Subgroup Perspectives on Chronic Pain and Its Management After Spinal Cord Injury

The present study was part of a larger mixed-methods study concerning facilitators and barriers to living with chronic pain after spinal cord injury. The agreement with themes obtained in qualitative interviews were quantified in a large online survey and overarching themes were defined by factor analysis. The present study aimed to define subgroups based on cluster analysis of the overarching themes’ factor scores and to compare the subgroups on pain-related variables. Three subgroups—high pain impact, moderate pain impact, and low pain impact—emerged. The high pain impact subgroup experienced severe pain with neuropathic pain characteristics; used pain medication, multiple coping strategies, and self-remedies; and considered information about pain and its management critical, but were not able to communicate well about their pain. The moderate pain impact subgroup carried on despite pain, considered pain information important, and used multiple approaches to manage their pain, but used less medication owing to concerns about side effects and addiction. The low pain impact subgroup considered information about pain, pain treatments, and communication regarding pain less important than the other subgroups did. This study suggests that treatment approaches need to be individually tailored not only to type of pain, but also to personal factors and preferences.

肺结核合并糖尿病患者的T细胞亚群与血糖水平的相关分析

目的探讨肺结核合并2型糖尿病患者的血糖水平与T细胞亚群的相关性。方法回顾分析51例2002年1月～2004年12月入院的初治肺结核合并2型糖尿病患者,选择空腹血糖FBG和糖化血红蛋白HbAlc作为血糖水平的观察指标,T淋巴细胞亚群作为细胞免疫功能的指标,分别比较其相关性。结果T淋巴细胞亚群各值与单次的空腹血糖测量水平无明显相关性,P值均〉0．05;而CD3与HbAlc负相关,相关系数r值为-0．286,CD8与HbAlc正相关,r值为0．306,P值均〈0．05。结论肺结核合并2型糖尿病患者的细胞免疫功能与长期血糖控制水平有一定的关联,高HbAlc水平常伴随细胞免疫功能低下。提示长期高血糖状态会加重细胞免疫功能紊乱。     

Blood group A1 and A2 revisited: an immunochemical analysis

Background and Objective  The basis of blood group A₁ and A₂ phenotypes has been debated for many decades, and still the chemical basis is unresolved. The literature generally identifies the glycolipid chemical differences between blood group A₁ and A₂ phenotypes as being poor or no expression of A type 3 and A type 4 structures on A₂ red cells, although this assertion is not unanimous.
Materials and Methods  Using purified glycolipids and specific monoclonal antibodies, we revisited the glycolipid basis of the A₁ and A₂ phenotypes. Purified glycolipids were extracted from four individual A₁ and four individual A₂ blood units. One blood unit from an A weak subgroup was also included. Monoclonal anti-A reagents including those originally used to define the basis of A₁ and A₂ phenotypes were used in a thin layer chromatography – enzyme immunoassay to identify the presence of specific glycolipids.
Results  A type 3 glycolipid structures were found to be present in large amounts in all phenotypes. In contrast, the A type 4 glycolipid structure was virtually undetectable in the A₂ phenotype, but was present in the A₁ and A subgroup samples.
Conclusion  The major glycolipid difference between the A₁ and A₂ phenotypes is the dominance of A type 4 glycolipids in the A₁ phenotype.     

Human variability in glucuronidation in relation to uncertainty factors for risk assessment

The appropriateness of the default uncertainty factor for human variability in kinetics has been investigated for glucuronidation using an extensive database of substrates metabolised primarily by this pathway. Inter-individual variability was quantified for 15 compounds from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time–curve (AUC)) and acute exposure (C_max). Low inter-individual variability (about 30–35%) was found for all parameters (clearance corrected or not corrected for body weight, metabolic clearance, oral AUC and C_max) after either iv or oral administration to healthy adults. The overall variability of 31% for glucuronidation in healthy adults supported the validity of the default kinetic uncertainty factor of 3.16 for this group, because it would cover more than 99% of individuals. Comparisons between potentially sensitive subgroups and healthy adults using differences in means and variability indicated that neonates showed the greatest impairment of glucuronidation, and that the 3.16 kinetic default factor applied to the mean data for adults would be inadequate for this subpopulation. The in vivo data have been used to derive pathway-related default factors for compounds eliminated largely via glucuronidation.     

Identification of prognostic subgroups among patients with metastatic `IGCCCG poor-prognosis' germ-cell cancer: An explorative analysis using cart modeling

Objectives:The IGCCCG classification has identified threeprognostic groups of patients with metastatic germ-cell tumors. `Poorprognosis' is based on primary tumor localization, the presence of visceralmetastases, and/or high tumor-marker levels. The overall survival rate ofthese patients is about 45%–55%. The present analysisattempts to identify subsets of patients with a more or less favorable outcomeamong the `poor-prognosis' group. Patients and methods:We retrospectively explored prognosticsubgroups in 332 patients with `IGCCCG' poor-risk GCT using theclassification-and-regression-tree model (CART). The following variables wereincluded: primary tumor localization, presence of visceral or lung metastases,presence of an abdominal tumor, number of metastatic sites, serum levels of-HCG, AFP and LDH. All patients had been treated withcisplatin–etoposide-based chemotherapy within controlled clinical trialsbetween 1984 and 1997. Results:Patient characteristics: gonadal/retroperitoneal (G/R)primary tumor 260 patients (78%), mediastinal primary tumor 72 patients(22%), visceral metastases 205 patients (62%) including 33patients with CNS metastases, lung metastases 247 patients (74%),abdominal tumor 241 patients (72%), elevated AFP, -HCG or LDHlevels 235 (71%), 253 (76%) and 275 (83%) of patients,respectively. Patients with primary mediastinal disease plus lung metastasesexhibited the worst two-year PFS (28%), whereas patients with a primaryG/R tumor and without visceral metastases showed the highest chance oftwo-year PFS (75%). The latter group of patients without visceralmetastases and with a primary G/R tumor also had the most favourable two-yearOS (84%). In contrast, patients with a primary mediastinal tumor andvisceral metastases displayed the worst two-year OS (49%). Conclusions:Different prognostic subsets of patients can beidentified among the group of `poor-prognosis' GCT patients. The CART analysismodel results in a hierarchy of prognostic factors which may allow to moreprecisely estimate the individual patient's prognosis. Identifying subgroupsof `very poor-prognosis' among `poor-prognosis' patients may allow to test fornew treatment strategies in selected subgroups.     

Treatment recommendations for the various subgroups of neurocytomas

Summary Neurocytomas gained importance since 1995, which is reflected by the increasing number of reports on this entity. This study was performed to determine the best available treatment for typical and atypical neurocytomas (MIB-1 labeling index >‰3%, atypical histology) in various age groups (‰≤‰18 years, >‰18 years). The data of all neurocytoma patients reported since 1982, when this entity were reviewed for age, gender, extent of resection, MIB-1 labeling index, histology, radiotherapy, and outcome of therapy. Patients were treated with complete resection alone (CTR), CTR plus radiotherapy (CTR + RT), incomplete resection alone (ITR), or ITR plus radiotherapy (ITR + RT). If the reported data were incomplete, the authors were contacted for additional data. Follow up had to be at least 12 months. Data were complete in 438 patients (73 children, 365 adults). Three hundred and fifty-one patients had typical, 87 atypical lesions. Typical lesions were associated with better local control and survival than atypical lesions (P < 0.001). CTR was superior to ITR (P < 0.001). After CTR, outcome was not significantly improved by RT. After ITR, RT improved survival in typical lesions (P = 0.03) and atypical lesions (P = 0.05), not in children (P = 0.16). Local control was improved in all groups (P < 0.001, children P = 0.01). Doses >‰54 Gy appeared beneficial after ITR of atypical lesions. In children, ≤50 Gy and >50 Gy were comparable. CTR does not require post-operative RT. Following ITR, RT improves outcome. Of 50–54 Gy appear sufficient for typical lesions, 50 Gy for children. Atypical lesions require 56–60 Gy.     

不同中医证型肝硬化患者T细胞亚群NK细胞及补体系统检测的意义

目的：探讨不同中医证型肝硬化与血T细胞亚群、NK细胞、补体系统的关系。方法：对92例肝硬化患者进行中医分型，分为气滞湿阻型、肝脾血瘀型、脾肾阳虚型，并进行了外周血T细胞亚群、NK细胞以及补体C3、C4、B因子的测定；并设立正常对照组。结果：不同中医证型肝硬化的血CD3^＋、CD4^＋、CD4^＋／CD8^＋、NK细胞均有不同程度的降低，CD3^＋无明显变化；补体C3、C4、B因子均有不同程度的降低。结论：肝硬化的血T细胞亚群、NK细胞、补体系统存在着不同程度的变化，并与中医证型相关。     

Delirium in dementia

Delirium is a common mental disorder in the elderly with old age being a major risk factor for delirium. Another major risk factor is dementia. The aim of the present study was to identify differences in occurrence of episodes of delirium between the most common dementia diagnoses and the possible importance of age, gender, severity and duration of dementia for the development of delirium. Included in the study were 175 consecutive patients with probable Alzheimer's disease, vascular dementia (VAD) or frontotemporal dementia (FTD) who were admitted to a neuropsychiatric diagnostic unit. There were no significant differences in sex distribution or duration of dementia between the delirious and non delirious patients. The rate of delirium was higher in late onset Alzheimer's disease (LAD) than in early onset Alzheimer's disease (EAD) and FTD. It was also higher in VAD than in EAD. The differences in occurrence of delirium between the diagnostic groups in this sample could not be explained by differences in age. It seems that delirium is more common in brain disorders such as LAD and VAD in which the damage to the brain is more widespread. In the two brain disorders that are predominantly cortical, EAD and FTD, the occurrence of delirium was comparatively low. © 1998 John Wiley & Sons, Ltd.