Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat-induced anxiety and the acquisition of conditioned defeat in Syrian hamsters.

Conditioned defeat is a model in Syrian hamsters (Mesocricetus auratus) in which normal territorial aggression is replaced by increased submissive and defensive behavior following acute social defeat. The conditioned defeat response involves both a fear-related memory for a specific opponent as well as anxiety-like behavior indicated by avoidance of novel conspecifics. We have previously shown that systemic injection of a 5-HT2a receptor antagonist reduces the acquisition of conditioned defeat. Because neural activity in the basolateral amygdala (BLA) is critical for the acquisition of conditioned defeat and BLA 5-HT2a receptors can modulate anxiety but have a limited effect on emotional memories, we investigated whether 5-HT2a receptor modulation alters defeat-induced anxiety but not defeat-related memories. We injected the 5-HT2a receptor antagonist MDL 11,939 (0 mM, 1.7 mM or 17 mM) or the 5-HT2a receptor agonist TCB-2 (0 mM, 8 mM or 80 mM) into the BLA prior to social defeat. We found that injection of MDL 11,939 into the BLA impaired acquisition of the conditioned defeat response and blocked defeat-induced anxiety in the open field, but did not significantly impair avoidance of former opponents in the Y-maze. Furthermore, we found that injection of TCB-2 into the BLA increased the acquisition of conditioned defeat and increased anxiety-like behavior in the open field, but did not alter avoidance of former opponents. Our data suggest that 5-HT2a receptor signaling in the BLA is both necessary and sufficient for the development of conditioned defeat, likely via modulation of defeat-induced anxiety.

High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study.

PURPOSE: To determine whether high-dose radiation leads to improved outcomes in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: This analysis included 106 patients with newly diagnosed or recurrent Stages I-III NSCLC, treated with 63-103 Gy in 2.1-Gy fractions, using three-dimensional conformal radiation therapy (3D-CRT) per a dose escalation trial. Targets included the primary tumor and any lymph nodes > or =1 cm, without intentionally including negative nodal regions. Nineteen percent of patients (20/106) received neoadjuvant chemotherapy. Patient, tumor, and treatment factors were evaluated for association with outcomes. Estimated median follow-up was 8.5 years. RESULTS: Median survival was 19 months, and 5-year overall survival (OS) was 13%. Multivariate analysis revealed weight loss (p = 0.011) and radiation dose (p = 0.0006) were significant predictors for OS. The 5-year OS was 4%, 22%, and 28% for patients receiving 63-69, 74-84, and 92-103 Gy, respectively. Although presence of nodal disease was negatively associated with locoregional control under univariate analysis, radiation dose was the only significant predictor when multiple variables were included (p = 0.015). The 5-year control rate was 12%, 35%, and 49% for 63-69, 74-84, and 92-103 Gy, respectively. CONCLUSIONS: Higher dose radiation is associated with improved outcomes in patients with NSCLC treated in the range of 63-103 Gy.

Prospective quality-of-life assessment in patients receiving concurrent gemcitabine and radiotherapy as a bladder preservation strategy.

OBJECTIVES: To assess, in a Phase I study, whether bladder preservation with concurrent gemcitabine and radiotherapy (RT) influenced patient-reported quality of life (QOL) as determined by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL). METHODS: Between January 1998 and March 2002, 24 patients with urothelial carcinoma of the bladder were enrolled, and 23 patients underwent transuretheral resection of bladder tumor, followed by twice-weekly gemcitabine with concurrent RT. The initial dose was 10 mg/m2 given twice weekly and increased as tolerated. To assess treatment-related QOL, patients completed the FACT-BL questionnaire. RESULTS: Of the 24 patients enrolled, 23 (96%) were assessed for toxicity and response. The FACT-generic (G) QOL assessment was obtained from 22 (92%) of 23 patients. No statistically significant difference was found in the FACT-G or FACT-BL or the combination before, during, or after treatment. The FACT-BL values were lower in patients who received higher doses of gemcitabine (greater than 20 mg/m2 versus 20 mg/m2 or less). At least one dose-limiting toxicity (DLT) was experienced by 5 (23%) of 22 patients. The FACT-G values were lower for those patients who experienced DLT (difference of -13.1, P = 0.07). The physical well-being scores for patients who experienced DLT were lower after treatment (difference of -5.2, P = 0.03) compared with those without DLT. CONCLUSIONS: Concurrent RT and gemcitabine failed to statistically influence patient-reported QOL, although patients who received higher doses reported lower FACT-BL scores. The results of this study suggest that concurrent gemcitabine with conformal RT is a tolerable treatment regimen for bladder preservation, as demonstrated by the excellent treatment compliance and similar FACT measurements.

Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer.

BACKGROUND AND PURPOSE: The University of Michigan lung dose escalation study has increased the dose of external beam radiation for non-small cell lung cancer based on the volume of normal lung irradiated. The results of patients treated to either 92.4 or 102.9 Gy are reported. MATERIALS AND METHODS: Seventeen patients have completed treatment to 92.4 or 102.9 Gy and have been followed for at least 6 months. The treatment planning goal was to minimize the effective volume (V(eff)) of total lung irradiated as computed using the Kutcher-Burman DVH reduction scheme. Dose was escalated independently within each of five V(eff) bins. Toxicity, freedom from local progression (FFLP), overall survival (OS) and cause specific survival (CSS) are reported. RESULTS: Thirteen patients were Stage I, one was Stage II and three were Stage III. V(eff) ranged from 0.06 to 0.21. The median pretreatment FEV(1) was 1.24 L or 44% of predicted. Median follow-up for survivors was 37.9 months. No patient had significant pulmonary toxicity. One patient each had grades 2 and 3 esophagitis. Median percent change in FEV1 was -11%. Two- and three-year actuarial FFLP and OS rates for the entire group were 68 and 58% and 51 and 26%, respectively. For Stage I patients, the 2 and 3 year FFLP, OS and CSS rates were 82 and 68%, 54 and 33%, 76 and 48% respectively. CONCLUSIONS: These results suggest that doses of radiation of 92.4 and 102.9 Gy can be delivered safely to limited lung volumes with minimal toxicity.