Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.

PURPOSE: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy. PATIENTS AND METHODS: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity. RESULTS: The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05). CONCLUSION: SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.

Absence of linkage between VO2max and its response to training with markers spanning chromosome 22.

An extensive search for linkage between DNA markers and the response of VO2max to training has recently been launched in the HERITAGE Family Study. This is the first report on a genome-wide search strategy to locate chromosomal regions and positional candidate genes for cardiorespiratory endurance phenotypes. Linkage between seven markers spanning chromosome 22 spaced approximately 10 cM apart (D22S264, D22S274, D22S301, D22S304, D22S421, IL2RB, and PDGFB) and VO2max at baseline, as well as its response to endurance exercise training, was examined using the sib-pair linkage method. Markers were genotyped in at least 210 sib-pairs derived from 128 adult brothers (25 +/- 6 yr; mean +/- SD) and 138 sisters (24 +/- 6 yr) from 86 Caucasian families. VO2max, maximal heart rate, and maximal oxygen pulse were measured during stationary cycle tests before and after a standardized 20-wk endurance training program. On average, the initial VO2max was 2654 +/- 767 mL.min-1 while training increased VO2max significantly by 430 +/- 239 mL.min-1 or 16% (P < 0.0001). The VO2max response was adjusted for age and initial VO2max. No evidence of linkage was found between any of these markers on chromosome 22 and VO2max or its trainability.

Defensive burying following injections of cholecystokinin, bombesin, and LiCl in rats.

Past research indicates that feeding is reduced for animals injected with cholecystokinin and bombesin. One explanation for this effect suggests that these peptides act as natural satiety signals; an opposing view asserts that bombesin and cholecystokinin reduce feeding through malaise. The present experiment tested the basic assumptions associated with these positions using the defensive burying procedure. Groups of rats were given sweetened condensed milk followed by IP injections of bombesin (6, 16, and 32 micrograms/kg), cholecystokinin (0.7, 1.4, and 2.9 micrograms/kg), LiCl (6.4 mg/ml), or saline. The results showed that animals injected with cholecystokinin, bombesin, and LiCl developed learned aversions to the milk and actively buried the milk spout with their bedding. The findings provide further support for the view that bombesin and cholecystokinin induce malaise rather than satiety.