Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL.

BACKGROUND: To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial. PATIENTS AND METHODS: Rituximab (375 mg/m(2)) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60. RESULTS: One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0). CONCLUSIONS: Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP.

Neonatal alcohol exposure and the hippocampus in developing male rats: effects on behaviorally induced CA1 c-Fos expression, CA1 pyramidal cell number, and contextual fear conditioning.

Rats exposed to a high binge-like dose of alcohol over postnatal days (PD) 4-9 show reductions in CA1 pyramidal cells and impairments on behavioral tasks that depend on the hippocampus. We first examined hippocampal c-Fos expression as a marker of neuronal activity in normally developing rats following different phases of the context preexposure facilitation effect (CPFE) paradigm (Experiment 1). During the CPFE, preexposure to the training context facilitates contextual conditioning to an immediate shock given on a subsequent occasion. We then examined the relationship between CPFE impairment, hippocampal cell loss, and c-Fos expression in rats exposed to alcohol over PD 4-9 (Experiment 2). Normally developing (Experiment 1), sham-intubated control (SI), and PD 4-9 alcohol-exposed (4.00 g and 5.25 g/kg/d; Experiment 2) juvenile male rats were trained on the CPFE. The CPFE occurs over three phases separated by 24 h. Starting on PD 31, rats were preexposed to Context A or Context B for 5 min. After 24 h, all rats received an immediate 1.5-mA foot shock in Context A. Finally, rats were tested for contextual conditioning in Context A on PD 33. Normally developing and SI rats preexposed to Context A showed enhanced contextual fear compared with those preexposed to Context B (Experiment 1) or alcohol-exposed rats preexposed to Context A (Experiment 2). Rats were sacrificed 2 h following different phases of the CPFE and processed for c-Fos immunohistochemistry (Experiments 1 and 2) and CA1 pyramidal cell quantification (Experiment 2). In Experiment 1, c-Fos positive (c-Fos+) cells in the dentate gyrus (DG) were consistently high among rats preexposed to Context A (Pre), Context B (No Pre), or sacrificed directly from their home cage (Home) and did not differ across CPFE phases. CA3 and CA1 c-Fos+ cells were highest during preexposure and decreased across training phases, with Group No Pre showing greater numbers of c-Fos+ cells during training than Group Pre and Controls. In Experiment 2, SI rats had greater numbers of CA1 c-Fos+ cells compared with alcohol-exposed rats, differing significantly from rats exposed to the high alcohol dose (5.25 g) over PD 4-9. Experiment 2 also revealed a linear decline in CA1 pyramidal cells across treatment groups, again with rats from the high-alcohol dose group showing significantly fewer CA1 pyramidal cells compared with SI. Our results reveal that context novelty may be a significant contributor to differential hippocampal c-Fos expression following different phases of the CPFE. In addition, lower levels of c-Fos+ cells in alcohol-exposed rats following preexposure may be related to general reductions in the number of CA1 pyramidal cells in these rats. The significant CPFE impairments in rats exposed to the lower alcohol dose (4.00 g), who show a 15% reduction in CA1 pyramidal cells compared with SI rats, highlight the sensitivity of the CPFE to hippocampal insult.