A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.

BACKGROUND: Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. METHODS: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax. RESULTS: Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. CONCLUSION: Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.

Chronic graft-versus-host disease in the era of reduced-intensity conditioning.

In the past decade the field of hematopoietic stem cell transplantation has entered a new era with the introduction of reduced intensity conditioning (RIC) regimens. The impact of RIC on the incidence of chronic graft-versus-host disease (GVHD) has not been evaluated systematically. Factors confounding such analyses include short follow-up in studies, absence of prospective comparison trials, use of a variety of RIC regimens, lack of uniform GVHD prophylaxis and lack of rigorous criteria for the diagnosis and staging of chronic GVHD. This review discusses factors that appear to influence the incidence and clinical presentation of chronic GVHD in the RIC transplantation era. Overall, RIC seems to decrease the incidence and severity of acute GVHD through day 100 post-transplant when compared to conventional conditioning; however, there is little evidence to suggest that chronic GVHD is reduced after RIC. For the more definitive assessments of chronic GVHD after RIC it will be important to study this question in prospective comparison trials with long duration of follow-up. The recent National Institutes of Health chronic GVHD consensus project recommendations provide now the critically needed standardized guidelines for the diagnosis, classification and staging of chronic GVHD.

Characterization of atherosclerotic plaques at the carotid bifurcation: correlation of high-resolution MR imaging with histologic analysis--preliminary study.

The clinical symptoms and morbidity that result from carotid artery disease, the primary cause of stroke, are mainly due to plaque ulceration, thrombosis, intraplaque hemorrhage, and thinned fibrous caps. The contents of atherosclerotic plaques of the carotid artery can be determined with in vivo high-resolution magnetic resonance imaging with flow suppression. Eight patients scheduled to undergo endarterectomy and four healthy volunteers were imaged with a 1.5-T imager and custom-made carotid phased-array coils. T1-weighted spin-echo images and cardiac-gated proton-density--weighted fast spin-echo images were acquired. In vivo imaging findings as determined by three radiologists were correlated with ex vivo imaging and histologic findings. Among the eight plaque specimens, regions of hemorrhage, calcium, lipid deposits, and fibrous plaques were identified on T1- and proton-density-weighted images. Calcium and lipid deposits were detectable on both T1- and proton-density--weighted images. Hemorrhage and fibrous plaques were better demonstrated on proton-density--weighted images.

Atherosclerosis of the carotid artery: evaluation by magnetic resonance angiography.

Carotid artery atherosclerotic plaques (APs) can lead to brain ischemia, an event shown to correlate with both the degree of stenosis and the composition of the AP. Currently, accurate estimates of stenosis can be obtained by either x-ray angiography or three-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA). Our purpose was to determine whether three-dimensional TOF MRA images could also provide information on plaque location, morphology, and composition. Seven pre-endarterectomy patients underwent three-dimensional TOF MRA. After endarterectomy, plaque histology was evaluated. Three-dimensional TOF MRA images contained sufficient soft tissue contrast to differentiate the plaques from the surrounding tissues in all cases. Estimation of plaque morphology had 80% correlation with histology. Finally, intraplaque hemorrhage and calcification were deplicted as regions of moderately high and very low intensity, respectively. These preliminary results suggest that three-dimensional TOF MRA may be useful in studying the development and progression of carotid atherosclerosis.