The practical aspects of utilizing electrically stimulated leg cycling (ESLC) to counteract alterations in body composition were investigated in five tetraplegic subjects with long-standing complete spinal cord injuries (C5-C7). After a 2-wk adaptation period, the subjects performed seven ESLC sessions per week for 8 wk. No adverse reactions were noted in response to the ESLC program. The ESLC sessions were accompanied by higher lactate concentrations compared with arm exercise. Heart rate and blood pressure response revealed clear, but not serious, signs of autonomic dysreflexia in the beginning of the ESLC sessions. Body temperature increased moderately during the ESLC sessions. Peak oxygen uptake (Vo2) during an ESLC session increased by 70% (P < 0.05) after 8 wk of training. Body composition, evaluated by dual-energy X-ray absorptiometry (DEXA), demonstrated an increase in lean body mass (LBM) from 66.2 +/- 2.6 to 68.2 +/- 2.1% (P < 0.05), with a concomitant decrease in whole body fat (BF) content from 29.7 +/- 2.6 to 27.8 +/- 2.1% (P < 0.05) after training. The cross-sectional area of quadriceps, hamstrings, gluteus maximus, and gluteus medius muscles, measured by computer tomographic scans, increased from 267 +/- 27 to 324 +/- 27 cm2 (P < 0.05) after the training. In conclusion, daily ESLC sessions during a 2-mo period resulted in increased LBM, decreased BF content, and increased muscular endurance in tetraplegic subjects without any noticeable adverse effects.

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With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.

6047 Background: This study investigates the impact of smoking on radiotherapy (RT) outcome and survival in a population based cohort of HPV+ oropharynx cancer (OPC). Methods: We identified all OPC with positive p16 staining from 2007 –2015 who received curative IMRT according to approved guidelines in two oncology groups. Associations between smoking and locoregional control (LRC) and distant control (DC) were estimated by competing risk regression. Disease free survival (DFS) and overall survival (OS) were estimated by proportional-hazards regression model. Multivariable analyses (MVA) adjusted for age, gender, performance status (PS), T- and N-category, and treatment regimen. Results: A total of 1875 patients were included. Median age was 59.2 [31.3-86.8]; 79% (1481) were males; 96% (1651) had PS <2; 71% (1337) received concurrent chemo-radiotherapy (CRT) +/- hypoxic modification (Nimorazole); and 538 (29%) received RT alone +/- Nimorazole. 23% (425) were current smokers (at time of diagnosis) and 46% (853) were ex-smokers. Median smoking pack-years (PY) was 20.1 in the total cohort, and higher in current smokers vs ex-smokers (38 vs 20 PY, p<0.001). 63% of current smokers had >30 PYs. Median follow-up was 4.8 years. Actuarial 5-year univariate analysis showed that current smokers had a reduced probability of LRC (85% vs 92%, p=0.002), DC (88% vs 92%, p=0.046), DFS (69% vs 84%, p<0.001), and OS (73% vs 88%, p=<0.001) compared to never-smokers (n=567). Outcomes for ex-smokers and never-smokers were similar. In MVA current smoking retained strong independent significance for LRC (HR 1.73 [1.18-2.53]), DFS (1.79 [1.35-2.36]) and OS (2.06 [1.49-2.84]). However, DC was not significantly influenced by current smoking status (1.27 [0.83-1.95]). Similar observations were found for >30PY. Conclusions: Heavy lifetime and current smoking negatively impacts LRC and survival in HPV+ OPC. While smoking mediated hypoxia could interfere with RT efficacy, a putative impact on tumor biology remains uncertain in the absence of a detriment to distant metastasis risk. The findings support encouraging smoking cessation to improve therapeutic efficacy of RT and to avoid excess smoking related mortality.

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