Decker, Paul A.

Abstract Purpose: Glioblastoma multiforme is the most frequent primary brain tumor in adults and represents one of the most lethal malignancies with a median survival of 12-16 months. We have previously shown that an oncolytic measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) has significant antitumor activity against glioblastoma multiforme cell lines and xenografts. Radiation therapy (RT) represents one of the mainstays of glioma treatment. Here we tested the hypothesis that the combination of RT with MV-CEA would have synergistic activity against gliomas. Experimental Design: 3-(4,5-Dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and clonogenic assays were used to test cytoxicity of the combination treatment in vivo. To examine the mechanism of synergy, one-step viral growth curves, terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assays, and Western blot analyses were performed. In vivo assessment of synergistic antitumor activity was conducted in a U87 glioma model. Results: MTS and clonogenic assays showed a strong synergistic interaction between MV-CEA and RT in glioblastoma multiforme cells including both primary and established glioma lines. Furthermore, significant antitumor efficacy was observed in vivo in a subcuteneous U87 xenograph model. There was significant prolongation of survival (P = 0.001) in the combination treatment group as compared with single modality– or control-treated animals. One-step viral growth curves showed increased viral burst size by up to 2 log in MV/RT combination–treated cells, as compared with single agent MV-CEA–treated glioma cells. Changes in CEA levels and expression of viral N and H protein were also consistent with increased viral production. Furthermore, TUNEL assays and Western blot analysis showed increase in apoptosis in MV/RT combination–treated cells. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected glioma cells from MV-CEA/RT–induced cleavage of poly(ADP-ribose) polymerase (PARP), indicating that the apoptotic death in combination-treated cells is mostly mediated via the extrinsic caspase pathway. The Fas/Fas ligand interaction blocking antibody NOK-1 blocked MV/RT–induced PARP cleavage whereas the Fas agonistic antibody CH11 increased PARP cleavage in MV/RT combination–treated cells. Reverse transcription-PCR, fluorescence-activated cell sorting analysis and immunohistochemistry showed up-regulation of Fas in combination-treated tumor in vitro and in vivo cells. Conclusions: There is synergy between MV-CEA and RT in vitro and in vivo. The synergistic effect of the combination seems to be due to increase in viral burst size and increase in apoptotic cell death. This latter effect is mostly mediated via the extrinsic caspase-8 pathway, activated via increased signaling through the Fas death receptor pathway. These results could have translational implications in glioma therapy.

Tobacco cessation interventions developed for Alaska Native adolescents do not exist. This study employed focus group methodology to explore preferences for tobacco cessation interventions and barriers to participation among 49 Alaska Natives (61% female) with a mean age of 14.6 ( SD = 1.6) who resided in western Alaska. Using content analysis, themes from the 12 focus groups were found to be consistent across village, gender, and age groups. Program location or site (e.g., away from the village, hunting, fishing), a group-based format, and inclusion of medication and personal stories were reported to be important attributes of cessation programs. Motivators to quit tobacco were the perceived adverse health effects of tobacco, improved self-image and appearance, and the potential to be a future role model as a non—tobacco user for family and friends. Parents were perceived as potentially supportive to the adolescent in quitting tobacco. The findings will be used to develop tobacco cessation programs for Alaska Native youth.

PURPOSE: There is a current lack of consensus about the effectiveness of nicotine dependence treatment for cancer patients. This retrospective study examined the 6-month tobacco abstinence rate among lung cancer patients treated clinically for nicotine dependence. PATIENTS AND METHODS: A date-of-treatment matched case control design was used to compare lung cancer patients (201 lung cancer patients, 41% female) and nonlung cancer patients (201 controls, 45% female) treated in the Mayo Clinic Nicotine Dependence Center between 1988 and 2000. The intervention involves a brief consultation with a nicotine dependence counselor. A treatment plan individualized to the patient’s needs is then developed. The primary end point was the self-reported, 7-day point prevalence abstinence from tobacco at 6-month follow-up. RESULTS: At baseline, compared with the controls, the lung cancer patients were significantly older (P < .001), reported higher motivation to stop smoking (P = .003), and were at a higher stage of change (P = .002). The 6-month tobacco abstinence rate was 22% for the lung cancer patients compared with 14% of the control patients (P = .024). After adjusting for age, sex, baseline cigarettes smoked per day, and stage of change, no significant difference was detected between lung cancer patients and controls on the tobacco abstinence rate. CONCLUSION: The results suggest that nicotine dependence treatment is effective for patients with a diagnosis of lung cancer. The majority of lung cancer patients were motivated to stop smoking.