基于患者队列的随机对照试验设计:队列内试验(TwiCs)的方法与应用

队列内试验(TwiCs)是随机对照试验的一种衍生设计方法,目前已在肿瘤、心血管疾病等慢性疾病领域内广泛应用。TwiCs设计基础是一个特定疾病的前瞻性队列,当要实施随机对照试验时,从队列中随机抽样部分符合纳入排除标准的患者接受“试验干预”,而队列中符合纳入排除标准但未被抽样的患者继续接受常规治疗并作为对照组。通过比较试验组和对照组干预措施的疗效差异,来评估干预措施的效果。在队列内,可以重复执行同样的过程来实施多个随机对照试验(RCTS),以评估不同干预措施或比较不同剂量或时机的干预效果。相较经典随机对照试验,TwiCs利用队列更易招募患者,具有更高的外部真实性,为提升随机对照试验的效率和适用性提供了临床研究新范式。但同时TwiCs也可能面临队列内患者依从性不高的挑战,需要研究者在TwiCs设计和操作过程中采取有效措施进行控制。该文重点介绍了TwiCs实施过程中的方法学要点,包括多阶段知情同意(患者进入队列、进入试验组、试验结束后3个阶段分别进行知情同意)、随机程序(只从队列中随机抽样接受“试验干预”的患者)、样本量计算、统计分析方法,对比了TwiCs与经典RCTS的差异,并以实例说明TwiCs研究设计与分析的过程,以期为广大临床研究者提供新的研究思路和方法。

HBV infection decreases risk of liver metastasis in patients with colorectal cancer:A cohort study

AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study.Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer.Patients were divided into study (infection) group and control (non-infection) group.Clinical features of patients in two groups were compared.RESULTS:Liver metastasis was found in 319 out of the 1298 colorectal cancer patients.The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%,P < 0.01).HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR):0.50,95% confidence interval (95% CI):0.38-0.66],but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%,P < 0.01).The HR was the lowest in chronic hepatitis B group (HR:0.29,95% CI:0.12-0.72).The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate.However,no significant difference was found in survival rate between the two groups (P=0.95).CONCLUSION:HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.

A population-based cohort study of symptomatic gallstone disease in diabetic patients

AIM:To investigate the prevalence of gallstone dis-ease(GSD) and to evaluate the risk of symptomatic GSD among diabetic patients.METHODS:The study was conducted by analyzing the National Health Research Institutes(NHRI) dataset of ambulatory care patients,inpatient claims,and the updated registry of beneficiaries from 2000 to 2008.A total of 615 532 diabetic patients without a prior history of hospital treatment or ambulatory care visits for symptomatic GSD were identified in the year 2000.Age-and gender-matched control individuals free from both GSD and diabetes from 1997 to 1999 were randomly selected from the NHIR database(n = 614 871).The incidence densities of symptomatic GSD were estimated according to the subjects' diabetic status.The distributions of age,gender,occupation,income,and residential area urbanization were compared between diabetic patients and control subjects using Cox proportion hazards models.Differences between the rates of selected comorbidities were also assessed in the two groups.RESULTS:Overall,60 734 diabetic patients and 48 116 control patients developed symptomatic GSD and underwent operations,resulting in cumulative operation rates of 9.87% and 7.83%,respectively.The age and gender distributions of both groups were similar,with a mean age of 60 years and a predominance of females.The diabetic group had a significantly higher prevalence of all comorbidities of interest.A higher incidence of symptomatic GSD was observed in females than in males in both groups.In the control group,females under the age of 64 had a significantly higher incidence of GSD than the corresponding males,but this difference was reduced with increasing age.The cumulative incidences of operations for symptomatic GSD in the diabetic and control groups were 13.06 and 9.52 cases per 1000 person-years,respectively.Diabetic men exhibited a higher incidence of operations for symptomatic GSD than did their counterparts in the control group(12.35 vs 8.75 cases per 1000 person-years).CONCLUSION:The association of diabetes with increased symptomatic GSD may provide insight to the treatment or management of diabetes in clinical settings.

Clinical impact of selective transarterial chemoembolization on hepatocellular carcinoma:A cohort study

AIM： To prospectively long term clinical impact evaluate the short and of selective transarterial chemoembolization （TACE） on fiver function in patients with hepatocellular carcinoma （HCC）. To assess side effects in relation to treatments. To analyze the overall survival and HCC progression free survival probability. METHODS： One hundred and seventeen cirrhotic patients with HCC were enrolled. Baseline liver function included Child-Pugh score and serum levels of alanine- aminotransferase （ALT）, prothrombin time （PT） and bilirubin. According to Cancer Liver Italian Program （CLIP） and Barcelona Clinic Liver Cancer （BCLC） staging systems, 71 patients were eligible for TACE; 32 had previously received treatment for HCC. No significant differences in liver function were observed between previously treated and not treated patients. TACE was performed by selective catheterization of the arteries nourishing the lesions. While hospitalized, patients underwent clinical, hematologic and ultrasonographic assessments. One month after TACE a CT scan was performed to assess tumor response. A second TACE was performed ＂on demand＂ Liver function tests were checked in all patients every four months. RESULTS： After first TACE, the mean Child-Pugh score increased from a mean baseline 5.62 ±1.12 to 6.11 ±1.57 at discharge time （P 〈 0.0001）, decreasing after four months to 5.81 ± 0.73 （not significant）. ALT, PT and bilirubin significantly （P 〈 0.0001） increased 24 h after TACE and progressively decreased until discharge. After the second TACE, variations in Child-Pugh score, ALT, PT and bilirubin were comparable to that described after the first TACE. No major complications were observed. The mean follow-up was 14.7 ＋ 6.3 mo （median： 16 mo）. Only one patient died. No other patient experienced important long term worsening of clinical status. The overall survival probability at twenty-four months was 98.18% with a correspondent HCC progression free survival probability of 69%. CONCLUSION： Selective TACE may produce significant, but transitory increases in ALT values, with no major impact on liver function and Child-Pugh score. Preservation of liver function is achievable also in patients previously treated with other therapeutic modalities and in patients undergoing multiple TACE cycles. Liver function can remain stable in the long-term, with optimal medium term survival. This result can be achieved through rigorous patient selection on the basis of tumour characteristics and clinical conditions.

Effectiveness of infliximab after adalimumab failure in Crohn's disease

AIM:To evaluate the effectiveness of infliximab as a second-line therapy in Crohn's disease patients after adalimumab failure. METHODS:A historical cohort study in a community-based gastroenterology practice evaluated Crohn's disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. Patients were identified using a large Spanish database (ENEIDA). RESULTS:We included 15 Crohn's disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab. CONCLUSION:Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.

Effect of mild head injury on intelligence in Zahedan, Iran

Objective： To investigate the effects of mild head injury （HI） on the victims＇ intelligence by measuring their intelligence quotient （IQ）.Methods： This cohort study was performed in Khatamol-Anbia Hospital, Zahedan, Iran and the IQs of 30 mild HI patients were measured right after the injury （IQ0） and six months later （IQ6）. The IQs of 90 close relatives of the patients were also measured at the same period of time as the non-exposure group. The IQs were measured with Wechsler adult intelligence scale-revised （WAIS-R）. The IQ0, IQ6 and their differences （IQ change） were compared in HI patients and their relatives using the Student＇s t test.Results： The mean IQ0 of the HI patients was similar to their relatives. The IQ6 of HI patients appeared to be less than those of their relatives. Moreover, the IQ6 of the HI patients appeared to be less than their initial scores. HI was associated with more decrease in IQ6 compared with IQ0and the female subjects showed more decrease in IQ6 compared with their IQ0.Conclusion： HI seems to be associated with decrease in IQ six months after the injury and it is more evident in female HI patients.