The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

SRS for benign head and neck paragangliomas is a safe and efficacious treatment associated with minimal morbidity. SRS is suitable for patients with skull base tumors <3 cm when FRT is logistically unsuitable. Surgery is reserved for patients in good health whose risk of associated morbidity is low. Observation is a reasonable option for asymptomatic patients with a limited life expectancy.

Secretory pituitary adenomas have a worse prognosis than nonsecretory tumors after 45 to 50 Gy of conventionally fractionated RT. As a result of this finding, our plan is to increase the intensity of RT in secretory tumors, but our data did not evaluate this approach. The treatment guidelines that we currently use in pituitary adenoma are as follows. Radiosurgery (20 to 30 Gy) is our first-choice treatment of a secretory tumor that cannot be completely resected. When treating gross residual pituitary adenoma with fractionated RT, we use the following dose schedules: Nonsecretory: 45 Gy at 1.8 Gy/fraction, once-daily fractionation. Secretory: 54 Gy at 1.8 Gy/fraction once daily or 55.2 Gy at 1.2 Gy/fraction with twice-daily treatment.

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Results: 8,408 patients were included for analysis: 2122 patients (25.2%) treated with 45-50.3Gy, 4704 patients (56.0%) treated with 50.4-54Gy, and 1579 patients (18.8%) treated with >54Gy. Patients who received moderate dose escalation (50.4-54Gy) had significantly higher survival on multivariate analysis (HR 0.8 [95% CI 0.72-0.88]; p<.001) when compared with patients who received 45-50.3Gy. Patients who received >54Gy did not have a significantly different OS (HR 0.96 [95% CI 0.85-1.09]; pZ.553). Factors significantly associated with worse OS on multivariate analysis included male gender, age >67 years, Charlson-Deyo score of 1 or 2+, node-positive disease, having non-private medical insurance, not receiving chemotherapy and having medical contraindications to surgery as the reason no surgical intervention was performed. The median survival was 43.2 months for all included patients, with 1-year and 5-year OS of 41.3% [95% CI 25.3-28.7%] and 83.9% [95% CI 83.1-84.7%]. After case-matching and adjusting for other significant prognostic factors on IPWRA analysis, patients receiving 50.4-54Gy had a significantly longer median, 1-year and 5-year OS (49.4 months, 85.8%, 44.7%) compared with patients receiving 45-50.3Gy or >54Gy (37.2 months, 79.2%, 38.4% and 34.2 months, 84.5%, 35.3%, respectively; Log rank pvalue <.0001). Conclusions: In an unselected group of patients treated at NCDBparticipating institutions, survival rates with a non-surgical approach to non-metastatic rectal adenocarcinoma are much lower than those reported in well-selected single-institutional studies. Moderate dose escalation from 50.4-54Gy seems to be associated with better overall survival compared with doses <50.4Gy or >54Gy after adjusting for other significant covariants. These data may be useful in counseling patients who either refuse surgery or who are not surgical candidates on their expected outcomes with a non-surgical approach.