Could BEACOPP be the new standard for the treatment of advanced Hodgkin's lymphoma?

In 1992, the German Hodgkin Study Group (GHSG) developed the BEACOPP regimen for further improving the outcome of patients with advanced Hodgkin's lymphoma (HL). Since then, BEACOPP has been introduced in 3 different prospective randomized clinical trials of the GHSG to find an equilibrium between maximal efficacy and least toxicity with the BEACOPP principle for the treatment of advanced stage HL. In the HD9 trial of the GHSG, with 1,186 patients, after a median observation time of 7 years, the rates for FFTF are 85 percent and for overall survival 90 percent for dose-escalated BEACOPP, and for COPP/ABVD (C/ABVD comparable to ABVD) the rate for FFTF is 67 percent and for overall survival it is 79 percent. These superior BEACOPP results are obtained inspite of a higher rate of secondary AML/MDS in the escalated BEACOPP arm. The number of toxic deaths during treatment, however, was lower for escalated BEACOPP (1.6 percent) than for C/ABVD (1.8 percent). The majority of patients were treated in an outpatient setting, in a multicenter study with more than 400 centers, including 120 private doctors, located in Germany and 9 other European countries. To reduce acute and long-term toxicity, the GHSG started in the consecutive studies HD12 and HD15 for advanced stage HL to de-escalate BEACOPP by reducing the number of escalated BEACOPP cycles and by applying the baseline dose BEACOPP, a time dense regimen, called BEACOPP-14. The excellent results obtained with the BEACOPP principle challenge the seemingly global consensus that ABVD is the gold standard treatment strategy for advanced stage HL.     

The effect of enterectomy on gastric secretion in dogs with biliary fistulas

Bile was excluded from the gastrointestinal tract of 5 dogs with Heidenhain pouches by total external biliary fistulas. After a major portion of the jejunum and the ileum was resected Heidenhain pouch secretions increased in all instances. The results indicate that the increase in gastric secretion which regularly follows small-bowel resection is independent of the presence or absence of bile in the gastrointestinal tract.Supported by Grant AM-7750 from the US Public Health Service.The opinions expressed in this publication are those of the authors and not necessarily those of the US Air Force Medical Service.     

Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer

BACKGROUND: Unpredictable and severe diarrhea (NCI grade > or =3) remains a life-threatening adverse event in patients treated with irinotecan (CPT-11). The aim of this study was to evaluate the efficacy and safety of orally administered budesonide for prevention of CPT-11-induced delayed diarrhea in patients with advanced colorectal cancer. PATIENTS AND METHODS: A total of 56 patients with advanced colorectal cancer receiving CPT-11 therapy (125 mg/m2 once weekly) were enrolled in this multicenter trial. Patients were randomly treated with 3 mg budesonide orally 3 times daily versus placebo. Detailed assessment of diarrhea by monitoring stool frequency, stool consistency and loperamide rescue medication was made by keeping a diary. RESULTS: Diarrhea, defined as number of stools >4 occurring on a single day during the study period, could be prevented in 58.3% of the budesonide-treated patients compared to 38.5% of the patients under placebo. Patients in the budesonide group had less episodes (0.7 vs. 2.2 episodes) and a considerably shorter total duration of diarrhea (1.8 vs. 4.2 days) episodes than patients in the placebo group. Loperamide use was more frequent in the placebo than in the budesonide arm (55.6 vs. 41.7%). Also, exposure to rescue medication of loperamide was higher for placebo (36.2 capsules) than for budesonide (24.9 capsules). A superior prevention of diarrhea was observed for budesonide compared to placebo in the first cycle (14 vs. 10; p = 0.257), with more failures observed in the placebo group (16 vs. 10). CONCLUSION: This double-blind randomized trial failed to show that budesonide has a significant benefit in preventing CPT-11-induced diarrhea. While a trend exists, further trials are warranted.     

Electrical conduction along endothelial cell tubes from mouse feed arteries: confounding actions of glycyrrhetinic acid derivatives

BACKGROUND AND PURPOSE

Electrical conduction along endothelium of resistance vessels has not been determined independently of the influence of smooth muscle, surrounding tissue or blood. Two interrelated hypotheses were tested: (i) Intercellular conduction of electrical signals is manifest in endothelial cell (EC) tubes; and (ii) Inhibitors of gap junction channels (GJCs) have confounding actions on EC electrical and Ca²⁺ signalling.

EXPERIMENTAL APPROACH

Intact EC tubes were isolated from abdominal muscle feed (superior epigastric) arteries of C57BL/6 mice. Hyperpolarization was initiated with indirect (ACh) and direct (NS309) stimulation of intermediate- and small-conductance Ca²⁺-activated K⁺ channels (IK_Ca/SK_Ca). Remote membrane potential (V_m) responses to intracellular current injection defined the length constant (λ) for electrical conduction. Dye coupling was evaluated following intracellular microinjection of propidium iodide. Intracellular Ca²⁺ dynamics were determined using Fura-2 photometry. Carbenoxolone (CBX) or β-glycyrrhetinic acid (βGA) was used to investigate the role of GJCs.

KEY RESULTS

Steady-state V_m of ECs was −25 mV. ACh and NS309 hyperpolarized ECs by −40 and −60 mV respectively. Electrical conduction decayed monoexponentially with distance (λ∼1.4 mm). Propidium iodide injected into one EC spread into surrounding ECs. CBX or βGA inhibited dye transfer, electrical conduction and EC hyperpolarization reversibly. Both agents elevated resting Ca²⁺ while βGA inhibited responses to ACh.

CONCLUSIONS AND IMPLICATIONS

Individual cells were effectively coupled to each other within EC tubes. Inhibiting GJCs with glycyrrhetinic acid derivatives blocked hyperpolarization mediated by IK_Ca/SK_Ca channels, regardless of Ca²⁺ signalling, obviating use of these agents in distinguishing key determinants of electrical conduction along the endothelium.