Background In vitro, halothane appears to affect the role played by nitric oxide in the regulation of vascular tone and cardiac function. In vivo, the results of the interactions between halothane and the nitric oxide pathway remain controversial. The authors investigated the effects of halothane on the cardiac and regional hemodynamic properties of N-methyl-L-arginine (NMA), a specific nitric oxide synthase inhibitor, in dogs. Methods Twenty-five dogs were chronically instrumented. Aortic pressure, the first derivative of left ventricular pressure, cardiac output, heart rate, and carotid, coronary, mesenteric, hepatic, portal and renal blood flows were continuously recorded. N-methyl-L-arginine was infused intravenously at 20 mg/kg over 1 min in awake dogs (n = 11) and in 1.2% halothane-anesthetized dogs (n = 10). As a control group, the remaining four dogs were studied awake and during 1.2% halothane for 2 h in the absence of NMA. Results In awake dogs, NMA produced a sustained pressor response (34%) and systemic vasoconstriction (40%) associated with a decrease in cardiac output (16%). Regional circulation changes included an immediate and transient increase in carotid (43%) and coronary (237%) blood flows and a subsequent decrease in carotid blood flow (25%). Hepatic and mesenteric blood flows also decreased, by 43% and 16%, respectively. Except for the coronary circulation, regional vascular resistance increased significantly. Halothane did not affect the pressor response to NMA but did blunt the cardiac output changes. Consequently, the systemic vasoconstriction after nitric oxide synthase inhibition was of shorter duration and of lesser magnitude during halothane anesthesia. Halothane also blunted the carotid, mesenteric, and renal vasoconstriction induced by NMA. Finally, in 1.2% halothane-anesthetized dogs, NMA induced a coronary vasoconstriction. Conclusions Halothane minimally interferes with the systemic and regional hemodynamic consequences of nitric oxide synthase blockade. The nature and magnitude of the interaction depend on the territory in which they occur.
7016 Background: Since local failure remains frequent after RT in these patients (pts), a randomized trial was designed to assess the efficacy of concurrent daily RT-Cb given after induction chemotherapy (ICT) on local control. Method: Unresectable stage III NSCLC pts (any weight loss, WHO PS 0–2, ± supraclavicular lymph node or superior vena cava syndrom) were eligible. ICT (Vr 30 mg/m2, week (w) 1, 3, 5, and 15 mg/m2, w 2, 4, 6; P 120 mg/m2 w 1 and 5) was modified (Vr 30 mg/m2 w 1 to 9; P 100 mg/m2 w 1, 5 and 9) after 1st interim analysis (190 pts accrued) due to high incidence of metastases. CR, PR, SD pts after ICT were given RT (66 Gy, 33 fractions) with (arm B) or without (arm A) daily Cb (15 mg/m2) according to randomization performed at entry (stratification on gender, PS, histology and center). Evaluation using CT scan was performed 1 month (m) after RT, every 3 m for 3 yrs, every 6 m thereafter. To demonstrate a 10% improvement on the 1-yr local control rate, 585 pts were needed (2 interim and 1 final analysis, type I error 2.21%, type II error 20%, 2-sided logrank test). Results: From June 1996 to February 2003, 291 pts were randomized to arm A and 293 to arm B. Characteristics: mean age 60; 89% men; 94% PS 0–1; 75% non squamous in women, 40% in men. Compliance to ICT was 74–85% for Vr and 92–97% for P. Response (CR + PR) rate to ICT was 46% (initial regimen), 58% (modified regimen); 194 pts received RT alone an d 233 RT+Cb. Compliance to Cb was 97%. Median survival time was 11 and 14 m in arm A and B, respectively. In ICT responders, the 1-yr local control rate was 66 vs 72% (p=.21); it was 62 vs 70% (p=.068) in the overall population. The 3-yr metastasis incidence rate was 64 and 65% in pts given initial and modified ICT. 82% pts developed grade 3–4 toxicity, mainly uncomplicated neutropenia during ICT. 8 pts in each arm had grade 3–4 esophagitis. Toxic death was more frequent in arm B (n=21) than in arm A (n=10). Conclusion: Concurrent RT+Cb does not improve significantly the 1-y local control rate in unresectable stage III NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Pierre Fabre Oncologie
In the current analysis, we characterize the prognostic significance of KRAS mutations with concomitant copy number aberrations (CNA) in early stage non-small cell lung cancer (NSCLC), and evaluate the ability to predict survival benefit from adjuvant chemotherapy.Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; KRAS status was defined as wild type (WT) or mutant (MUT). The following groups were compared in all patients and the adenocarcinoma subgroup, and were correlated to survival endpoints using a Cox proportional hazards model: WT + Neut/Loss (reference), WT + Gain, MUT + Gain and MUT + Neut/Loss. A treatment-by-variable interaction was added to evaluate predictive effect.Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in KRAS MUT + Gain patients relative to KRAS WT + Neut/Loss patients. A negative prognostic effect of KRAS MUT + Neut/Loss was observed for LCSS (HR =1.32; 95% CI, 1.01-1.71, P=0.038) relative to KRAS WT + Neut/Loss on univariable analysis, but to a lesser extent after adjusting for covariates (HR =1.28; 95% CI, 0.97-1.68, P=0.078). KRAS MUT + Gain was associated with a greater beneficial effect of chemotherapy on DFS compared to KRAS WT + Neut/Loss patients (rHR =0.33; 95% CI, 0.11-0.99, P=0.048), with a non-significant trend also seen for LCSS (rHR =0.41; 95% CI, 0.13-1.33, P=0.138) and OS (rHR =0.40; 95% CI, 0.13-1.26, P=0.116) in the adenocarcinoma subgroup.A small prognostic effect of KRAS mutation was identified for LCSS, and a trend towards worse LCSS, DFS and OS was noted for KRAS MUT + Gain. A potential predictive effect of concomitant KRAS mutation and copy number gain was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require validation.
