Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.     

Association of cardiovascular risk factors with pattern of lower limb atherosclerosis in 2659 patients undergoing angioplasty.

OBJECTIVES: Aim of this study is to correlate distribution pattern of lower limb atherosclerosis with cardiovascular risk factor profile of patients with peripheral arterial occlusive disease (PAD). PATIENTS AND METHODS: Analysis is based on a consecutive series of 2659 patients (1583 men, 1076 women, 70+/-11 years) with chronic PAD of atherosclerotic origin undergoing primary endovascular treatment of lower extremity arteries. Pattern of atherosclerosis was grouped into iliac (n=1166), femoropopliteal (n=2151) and infrageniculate (n=888) disease defined according to target lesions treated. A multivariable multinomial logistic regression analysis was performed to assess relation with age, gender and classical cardiovascular risk factors (diabetes mellitus, arterial hypertension, hypercholesterolemia, cigarette smoking) using femoropopliteal disease as reference. RESULTS: Iliac disease was associated with younger age (RRR 0.95 per year of age, 95%-CI 0.94-0.96, p<0.001), male gender (RRR 1.32, 95%-CI 1.09-1.59, p=0.004) and cigarette smoking (RRR 2.02, 95%-CI 1.68-2.42, p<0.001). Infrageniculate disease was associated with higher age (RRR 1.02, 95%-CI 1.01-1.02, p<0.001), male gender (RRR 1.23, 95%-CI 1.06-1.41, p=0.005) and diabetes mellitus (RRR 1.68, 95%-CI 1.47-1.92, p<0.001). Hypercholesterolemia was less prevalent in patients with lesions below the knee (RRR 0.82, 95%-CI 0.71-0.94, p=0.006), whereas no distinct pattern was apparent related to arterial hypertension. CONCLUSION: Clinical phenotype of peripheral atherosclerosis varies with prevalence of cardiovascular risk factors suggesting differences in mechanisms involved in iliac as compared with infrageniculate lesions. Identification of molecular mechanism might have influence on future therapeutic strategies in PAD patients.     

Different effects of unilateral versus bilateral subthalamic nucleus stimulation on walking and reaching in Parkinson's disease.

The purpose of this study was to determine the effects of unilateral versus bilateral subthalamic nucleus (STN) stimulation on quantitative measures of walking and reaching in Parkinson's disease (PD). We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 6 people with PD who had bilateral STN stimulators implanted for at least 6 months and withheld their anti-parkinson medication for at least 8 hours. Subjects were studied with both stimulators off, one on, and both on. Kinematic data were collected as subjects walked, reached to a target, and were rated using the UPDRS motor subscale. STN stimulation improved walking speed and stride length, with the greatest benefit from bilateral stimulation. Reaching speed was improved by unilateral STN stimulation alone, with no additive effect of bilateral stimulation. UPDRS motor subscale ratings paralleled the kinematic findings. STN stimulation did not restore PD subjects' movements to the level of age-matched controls. Overall, these results provide further evidence that the basal ganglia pathways involved in control of walking and reaching may be distinct. We speculate that basal ganglia may influence walking through bilateral pedunculopontine projections and reaching through ipsilateral thalamocortical projections. Our findings also suggest that maximal improvement of walking requires bilateral rather than unilateral STN stimulation.     

Bovine mesenteric vein graft (ProCol) in critical limb ischaemia with tissue loss and infection.

OBJECTIVES: Poor results have been reported following infrainguinal reconstructions using heterogenous grafts. The objective of this study was to assess the use of bovine mesenteric vein (ProCol) graft in patients with critical limb ischaemia (CLI), tissue loss/infection and no autologous vein available for reconstruction. METHODS: Prospective analysis of 32 patients with CLI and tissue loss/infection, in whom reconstruction with ProCol was undertaken between October 1999 and May 2002. RESULTS: The primary patency rate was 16% at 1 month. After thrombectomy, the secondary patency rate was 50% at 1 month and 26% at 14 months. No graft infections were seen. Aneurysmal dilatation of the graft occurred in 2 (6%). Limb salvage at 14 months was 47%. CONCLUSION: In patients with critical limb ischaemia, tissue loss/infection and no available vein, the ProCol graft may be an alternative. However, primary patency is a problem. In situations without tissue loss/infection, where the risk of graft infection is less, prosthetic material may be a better alternative.     

Less invasive surgical treatment of renal cell carcinomas extending into the right heart and pulmonary arteries: surgery for renal cell carcinoma

BACKGROUND: Radical resection using deep hypothermic circulatory arrest improves the survival of patients with transvenous intracardiac tumor extension of renal cell carcinomas. A less invasive surgical approach avoiding deep hypothermia, circulatory arrest, and cross-clamping of the aorta is presented. METHODS: Between 1987 and 1999, 12 patients (mean age 57+/-8 years) underwent resection of a renal cell carcinoma extending into the right atrium, right ventricle, or pulmonary arteries. After median sterno-laparotomy, normothermic cardiopulmonary bypass is used cannulating the ascending aorta, superior caval vein, and inferior caval vein below the renal veins. The tumor and the corresponding kidney are radically excised, including the renal vein. Tumor fragments from the inferior caval vein, the right heart, and pulmonary arteries are removed either on the fibrillating or beating heart. RESULTS: Operative mortality was 0%. Mean cardiopulmonary bypass time was 53+/-27 minutes (median 36; range 32-110 minutes). Mean blood loss per patient was 1200 mL. Mean duration of postoperative mechanical ventilation was 36+/-12 hours (median 36; range 30-77 hours), mean intensive care stay 5.5+/-5 days (median 3; range 1-48 days), and mean duration of hospitalization 22+/-12 days (median 21; range 10-58 days). All patients were discharged home. Patients with multiple tumor manifestations outside the cardiovascular systems died within 9 months after the operation. CONCLUSIONS: The use of normothermic cardiopulmonary bypass is a less invasive method for radical resection of renal cell carcinoma with intracardiac tumor extension. Radical resection does not improve survival in patients with multiple distant metastases.     

Intravascular ultrasound-guided creation of re-entry sites to improve intermittent claudication in patients with aortic dissection.

PURPOSE: To report percutaneous fenestration of aortic dissection flaps to relieve distal ischemia using a novel intravascular ultrasound (IVUS)-guided fenestration device. CASE REPORTS: Two men (47 and 62 years of age) with aortic dissection and intermittent claudication had percutaneous ultrasound-guided fenestration performed under local anesthesia. Using an ipsilateral transfemoral approach, the intimal flap was punctured under real-time IVUS guidance using a needle-catheter combination through which a guidewire was placed across the dissection flap into the false lumen. The fenestration was achieved using balloon catheters of increasing diameter introduced over the guidewire. Stenting of the re-entry was performed in 1 patient to equalize pressure across the dissection membrane in both lumens. The procedures were performed successfully and without complications. In both patients, ankle-brachial indexes improved from 0.76 to 1.07 and from 0.8 to 1.1, respectively. Both patients were without claudication at the 3- and 6-month follow-up examination. CONCLUSION: Percutaneous intravascular ultrasound-guided fenestration and stenting at the level of the iliac artery in aortic dissection patients with claudication is a technically feasible and safe procedure and relieves symptoms.