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There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes “Core” items for minimal assessment of tobacco use at initial and follow-up time points, and an “Extension” set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients. Clin Cancer Res; 22(8); 1907–13. ©2016 AACR.

Background The purpose of this study was to quantify the effect of treatment duration on locoregional progression after definitive concurrent chemoradiation (CCRT) for squamous cell carcinoma of the head and neck (SCCHN). Methods We conducted a retrospective chart review of patients treated between 2004 and 2010. After a prior analysis, measures were taken to limit therapy beyond 7 weeks. Comparison of outcomes were made between cohorts 1 (2004–2007, n = 78) and 2 (2007–2010, n = 62). Results Median therapy duration was statistically significantly different between cohorts as follows: 51 days, cohort 1 and 46 days, cohort 2 (p < .01). Locoregional progression in cohorts 1 and 2 was 19% and 5% (p = .01), respectively. On multivariate analysis, patients with prolonged treatment (≥57 days) had an 8-fold increase in risk of locoregional progression compared to patients who completed on time (p < .01). Conclusion Treatment duration was a significant predictor of locoregional progression in patients with SCCHN who received definitive CCRT. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Purpose: Stereotactic body radiation therapy(SBRT) is a radiotherapy technique which uses high dose fractions with multiple coplanar and noncoplanar beams. Due to the large fractional doses,treatments are typically protracted and there are more fields than in conventional radiation treatment schemes. The effect of temporal optimization on the biological effectiveness of SBRT is not well established. Methods: In a cohort of actual SBRTpatient treatments, the Lea–Catcheside protraction factor (G-value) was used to determine the optimal ( Δ ) and the least favorable (V) field. An actual field timing delivered in the clinic was included (C) for comparison. The lethal potential lethal (LPL) model was used to quantify the difference in survival fractions. Published data from three cell lines for non-small cell lungcancers: H460, H660, and H157 were used to acquire the parameters needed by the LPL model. The results are expressed as the ratios ( V : Δ ) N and ( C : Δ ) N , where N is the number fractions in the SBRT protocols and Δ , V, and C are the survival fractions calculated from the corresponding temporal patterns. Results: The results indicate that variability in the dose rate between fields does impact the optimization results. This dependence on dose rate, however, is small compared to the impact from the variability in doses between fields. The optimized field arrangements resembled previous studies, that maximization of cell kill is achieved by orienting the fields in a Δ shape sequence, where the fields with greatest dose are positioned in the center. Minimization of cell kill was achieved with a V-shaped orientation. Smallest dose fields were positioned centrally, and higher dose fields were placed in the beginning and end of the fraction. The survival fraction ratios calculated using the LPL demonstrated that regardless of the cell type the Δ shape had lower cell survival fractions compared to both the clinical example (C) and the V arrangement. For H460, with T 1 / 2 = 0.25 h, an average ratio of ( C : Δ ) 5 = 13 . 9 , suggesting the Δ pattern is approximately 14 times more effective than the clinical plan, after 5 fractions. Conclusions: Rearranging field timing for a SBRTtreatment so that maximal dose is deposited in the central fields of treatment may optimize cell kill and potentially affect overall treatment outcome.

Tobacco use significantly increases the risk of developing cancer. Moreover, there is growing evidence that tobacco use decreases survival in cancer patients. Nicotine, a systemically available component of tobacco, is associated with tumor promotion and decreased apoptosis in cell culture; however, the role of nicotine on response to radiotherapy (RT) or chemoradiotherapy (CRT) in vivo has not been evaluated. Our study evaluated the effects of nicotine administration on cancer cell survival in cell culture and mouse models. Nicotine increased survival in two cell lines following RT in vitro. Nicotine administration in mice during fractionated RT or CRT increased xenograft regrowth as compared to RT or CRT alone. Nicotine increased hypoxia-inducible factor 1-alpha (HIF-1α) expression in tumor xenografts without altering expression of carbonic-anhydrase, a clinical marker of tumor hypoxia. The effects of nicotine on HIF-1α expression were transient, returning to baseline levels within 2-3 days after nicotine removal. Further mechanistic studies indicated that inhibition of phosphoinositide-3-kinase (PI3K) prevented nicotine-mediated increases in HIF-1α expression as well as the prosurvival effects of nicotine on RT. These findings imply that during tobacco use, nicotine may function as a systemic agent through acute and reversible regulation of HIF-1α expression and a decreased therapeutic response.

Prospective analysis was performed of self-reported and biochemically confirmed tobacco use in 50 head and neck cancer patients during treatment. With 93.5% compliance to complete weekly self-report and biochemical confirmatory tests, 29.4% of smokers required biochemical assessment for identification. Accuracy increased by 14.9% with weekly vs. baseline self-reported assessments. Data confirm that head and neck cancer patients misrepresent true tobacco use during treatment.

Overview Upper gastrointestinal tract cancers originating in the esophagus, esophagogastric junction (EGJ), and stomach constitute a major health problem around the world. An estimated 37,640 new cases of and 25,070 deaths from upper gastrointestinal cancers occurred in the United States in 2010.1 A dramatic shift in the location of upper gastrointestinal tumors has occurred in the United States.2,3 Changes in hisNCCN

We describe a brief staff training program to improve the delivery of tobacco cessation services to patients with head and neck cancers. This study utilized a quasi-experimental design to compare the delivery of smoking cessation components and outcomes among patients exposed to either usual care (UC) or an enhanced cessation (EC) program implemented following a 1-h staff education program. Of the 179 subjects enrolled, 112 were recontacted by phone 1 month after their clinic visit. More patients in EC compared to UC reported that they were asked about their smoking status (94.2% vs. 76.6%, p = 0.01), advised to quit (92.3% vs. 72.3%, p = 0.01), prescribed cessation medications (30.8% vs. 3.3%, p

1. In patients with cancer and survivors, the evidence is sufficient to conclude a causal relationship between cigarette smoking and adverse health outcomes. Quitting smoking improves the prognosis of patients with cancer. 2. In patients with cancer and survivors, the evidence is sufficient to conclude a causal relationship between cigarette smoking and increased all-cause mortality and cancer-specific mortality. 3. In patients with cancer and survivors, the evidence is sufficient to conclude a causal relationship between cigarette smoking and an increased risk of second primary cancers known to be caused by cigarette smoking, such as lung cancer. 4. In patients with cancer and survivors, the e vidence is suggestive but not sufficient to conclude a causal relationship between cigarette smoking and the risk of disease recurrence, poorer response to treatment, and increased treatment-related toxicity. These conclusions are the first large evidence assessment that causally associates tobacco smoking with adverse health outcomes in patients with cancer. The review pro- vided by O'Malley et al. 1 is a noteworthy contribution, highlighting an important facet of a complex question in cancer care: what are the true adverse effects of smoking on cancer treatment and what can be done to deal with these adverse effects? To begin to understand the depth of this question, we must first recognize the ever increasing complexity of modern cancer care. Oncologists are tasked with coordinating multiple facets of patient care centered around diagnosis and workup, treatment, assessing response, managing toxicity, and arranging follow-up. Each step requires assessment of a patient's comorbid condition and an understanding of each patient's behavioral, social, and financial environment. Oncologists have access to a broad variety of up-to-date resources, often delivered by daily emails, that highlight advances in cancer research and clinical care that often emphasize the potential utility of new biological agents, potentially new genomic prognosticators, and industry sponsored communication that advocate for the use of new agents in cancer care. Many of these new potential advances are untested in large trials and may not accurately reflect clinical effect or impact, but may still garner the attention of

1561Background: Extensive literature confirms that continued smoking by cancer patients and survivors increases overall mortality, but the benefits of smoking cessation specifically after a cancer ...

e18538Background: Smoking cessation even after a cancer diagnosis can improve survival, but access to smoking cessation support is limited. The purpose of this abstract is to describe results from ...

e18555Background: There are little data providing key facilitators to implementing smoking cessation support across cancer care systems. Reported are results from a 15 month project across 7 provin...

e18530Background: Smoking by cancer patients and survivors causes adverse outcomes. Cancer treatment guidelines recommend evidence-based cessation support for all patients who use tobacco. However,...

e18539Background: Though smoking by cancer patients and survivors causes adverse cancer treatment outcomes, most cancer patients do not receive evidence-based treatment for smoking cessation. The p...

1559Background: Smoking by cancer patients causes adverse outcomes including increased cancer specific mortality, but there are no estimates of the effects of continued smoking in cancer patients o...

e13542Background: NCCN Guidelines recommend smoking cessation support for patients who report smoking within the past 30 days. However, few reports have evaluated the utility of standardized questi...

Parthenolide has been shown to have anti-inflammatory and antitumor properties. However, whether and how parthenolide enhances tumor sensitivity to radiation therapy are unknown. In this study, we show that inhibition of the nuclear factor-κB (NF-κB) pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU145, and PC3. Parthenolide inhibits radiation-induced NF-κB DNA-binding activity and the expression of its downstream target sod2, the gene coding for an important antiapoptotic and antioxidant enzyme (manganese superoxide dismutase) in the three prostate cancer cells. Different susceptibilities to parthenolide's effect are observed in two radioresistant cancer cells, DU145 and PC3, with DU145 cells showing higher sensitivity. This differential susceptibility to parthenolide is due, in part, to the fact that in addition to NF-κB inhibition, parthenolide activates the phosphatidylinositol-3-kinase/Akt prosurvival pathway in both cell lines. However, the activated Akt in DU145 cells is kept at a relatively low level compared with that in PC3 cells due to the presence of functional PTEN. Transfection of wild-type PTEN into PTEN-null cells, PC3, confers the enhanced radiosensitization effect of parthenolide in PTEN-expressing cells. When PTEN expression is knocked down in DU145 cells, the cells become more resistant to parthenolide's effect. Taken together, these results suggest that parthenolide inhibits the NF-κB pathway and activates the phosphatidylinositol-3-kinase/Akt pathway in prostate cancer cells. The radiosensitization effect of parthenolide is due, in part, to the inhibition of the NF-κB pathway. The presence of PTEN enhances the radiosensitization effect of parthenolide, in part, by suppressing the absolute amount of activated p-Akt. [Mol Cancer Ther 2007;6(9):2477–86]

To the authors' knowledge, there are currently no standardized measures of tobacco use and secondhand smoke exposure in patients diagnosed with cancer, and this gap hinders the conduct of studies examining the impact of tobacco on cancer treatment outcomes. The objective of the current study was to evaluate and refine questionnaire items proposed by an expert task force to assess tobacco use.Trained interviewers conducted cognitive testing with cancer patients aged ≥21 years with a history of tobacco use and a cancer diagnosis of any stage and organ site who were recruited at the National Institutes of Health Clinical Center in Bethesda, Maryland. Iterative rounds of testing and item modification were conducted to identify and resolve cognitive issues (comprehension, memory retrieval, decision/judgment, and response mapping) and instrument navigation issues until no items warranted further significant modification.Thirty participants (6 current cigarette smokers, 1 current cigar smoker, and 23 former cigarette smokers) were enrolled from September 2014 to February 2015. The majority of items functioned well. However, qualitative testing identified wording ambiguities related to cancer diagnosis and treatment trajectory, such as "treatment" and "surgery"; difficulties with lifetime recall; errors in estimating quantities; and difficulties with instrument navigation. Revisions to item wording, format, order, response options, and instructions resulted in a questionnaire that demonstrated navigational ease as well as good question comprehension and response accuracy.The Cancer Patient Tobacco Use Questionnaire (C-TUQ) can be used as a standardized item set to accelerate the investigation of tobacco use in the cancer setting. Cancer 2016;122:1728-34. © 2016 American Cancer Society.

Smoking is the largest contributor to lung cancer risk, and those who continue to smoke after diagnosis have a worse survival. Screening for lung cancer with low-dose computed tomography (LDCT) reduces mortality in high-risk individuals. Smoking cessation is an essential component of a high-quality screening program.To quantify the effects of smoking history and abstinence on mortality in high-risk individuals who participated in the NLST (National Lung Screening Trial).This is a secondary analysis of a randomized controlled trial (NLST).Measurements included self-reported demographics, medical and smoking history, and lung cancer-specific and all-cause mortality. Cox regression was used to study the association of mortality with smoking status and pack-years. Kaplan-Meier survival curves were examined for differences in survival based on trial arm and smoking status. Current smokers had an increased lung cancer-specific (hazard ratio [HR], 2.14-2.29) and all-cause mortality (HR, 1.79-1.85) compared with former smokers irrespective of screening arm. Former smokers in the control arm abstinent for 7 years had a 20% mortality reduction comparable with the benefit reported with LDCT screening in the NLST. The maximum benefit was seen with the combination of smoking abstinence at 15 years and LDCT screening, which resulted in a 38% reduction in lung cancer-specific mortality (HR, 0.62; 95% confidence interval, 0.51-0.76).Seven years of smoking abstinence reduced lung cancer-specific mortality at a magnitude comparable with LDCT screening. This reduction was greater when abstinence was combined with screening, highlighting the importance of smoking cessation efforts in screening programs.

In cancer patients, cigarette smoking causes poorer response to treatment, treatment toxicity, increased risk of recurrence, higher surgical complication rates, and poorer overall survival. As such a significant determinant of patient prognosis, accurate classification of current smoking status is important. Self-reported smoking status may lead to misclassification if patients conceal their true status. The purpose of this study was to assess the validity of self-reported tobacco use during the previous 48 hours in head and neck cancer patients on the day of surgery.Cross-sectional.Two academic medical centers in the southeastern United States.On the day of surgery, 108 head and neck cancer patients completed a survey asking about tobacco use during the past 48 hours and had semi-quantitative levels of urinary cotinine measured to biochemically validate self-reported recent smoking.Self-reported smoking yielded a sensitivity of 60.9% (95% CI, 45.4%-74.9%) and a specificity of 98.4% (95% CI, 91.3%-100.0%). The sensitivity increased to 76.1% (95% CI, 61.2%-87.4%) when allowing for the possibility that exposure to secondhand smoke or use of nicotine-containing products could have caused a positive cotinine test.In this patient population, self-reported recent smoking yielded a high (39%) proportion of false-negatives, and even 24% remained false-negatives after allowing for other sources of nicotine exposure. This magnitude of underreporting combined with the importance of tobacco use to patient prognosis supports the need for routinely biochemically verifying recent tobacco use in self-reported nonsmokers within the clinical setting.

Smoking affects comorbid disease outcomes, and patients with comorbid conditions may have unique characteristics that are important to consider when treating tobacco use. However, addressing tobacco in patients being treated for comorbid conditions is not a consistent practice. Recognizing the need for a "call-to-action" to address tobacco use in people with comorbid conditions, the Tobacco Treatment Network within the Society for Research on Nicotine and Tobacco (SRNT) convened a Comorbidities Workgroup to explore the relationship between smoking and comorbid disease to identify common themes including: the harms associated with continued tobacco use, the frequency of comorbid disease and tobacco use, the potential effect of comorbid disease on the ability to quit tobacco use, the association between tobacco use and suboptimal disease-specific treatment response, and evidence regarding potential approaches to improve addressing tobacco use in patients with comorbid disease. Five candidate conditions (psychiatric, cancer, cardiovascular, pulmonary, and human immunodeficiency virus infected patients) were explored. Across comorbid conditions, smoking adversely affects treatment efficacy and promotes other adverse health conditions. People with comorbid conditions who smoke are motivated to quit and respond to evidence-based smoking cessation treatments. However, tobacco cessation is not regularly incorporated into the clinical care of many individuals with comorbidities. Optimal strategies for addressing tobacco use within each comorbid disease are also not well defined. Further work is needed to disseminate evidence-based care into clinical practice for smokers with comorbid disease and addiction research should consider comorbid conditions as an important construct to explore.This article explores how physical and psychiatric conditions may interact in the treatment of tobacco dependence, and discusses the need for smoking cessation as a critical component of comorbid condition management. Five common comorbid domains-psychiatric, cancer, pulmonary, cardiovascular, and human immunodeficiency virus (HIV)-are highlighted to illustrate how these different conditions might interact with smoking with respect to prevalence and harm, motivation to quit, and cessation treatment utilization and success.

Combustible tobacco use remains the number-one preventable cause of disease, disability, and death in the United States. Electronic nicotine delivery systems (ENDS), which include electronic cigarettes, are devices capable of delivering nicotine in an aerosolized form. ENDS use by both adults and youth has increased rapidly, and some have advocated these products could serve as harm-reduction devices and smoking cessation aids. ENDS may be beneficial if they reduce smoking rates or prevent or reduce the known adverse health effects of smoking. However, ENDS may also be harmful, particularly to youth, if they increase the likelihood that nonsmokers or former smokers will use combustible tobacco products or if they discourage smokers from quitting. The American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) recognize the potential ENDS have to alter patterns of tobacco use and affect the health of the public; however, definitive data are lacking. The AACR and ASCO recommend additional research on these devices, including assessing the health impacts of ENDS, understanding patterns of ENDS use, and determining what role ENDS have in cessation. Key policy recommendations include supporting federal, state, and local regulation of ENDS; requiring manufacturers to register with the US Food and Drug Administration and report all product ingredients, requiring childproof caps on ENDS liquids, and including warning labels on products and their advertisements; prohibiting youth-oriented marketing and sales; prohibiting child-friendly ENDS flavors; and prohibiting ENDS use in places where cigarette smoking is prohibited. This policy statement was developed by a joint writing group composed of members from the Tobacco and Cancer Subcommittee of the American Association for Cancer Research (AACR) Science Policy and Government Affairs (SPGA) Committee and American Society of Clinical Oncology (ASCO) Tobacco Cessation and Control Subcommittee of the Cancer Prevention Committee (CaPC). The statement was reviewed by both parent committees (ie, the AACR SPGA Committee and the ASCO CaPC) and was approved by the AACR Boards of Directors on August 6, 2014, and the ASCO Executive Committee on September 18, 2014. This policy statement was published jointly by invitation and consent in both Clinical Cancer Research and Journal of Clinical Oncology. Copyright 2015 American Association for Cancer Research and American Society of Clinical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or storage in any information storage and retrieval system, without written permission by the American Association for Cancer Research and the American Society of Clinical Oncology.

Yogic breathing (YB) has been suggested to reduce stress and blood pressure and increase cognitive processes. However, alterations after YB at the molecular level are not well established. Twenty healthy volunteers were randomized into two groups (N=10per group): YB or attention controls (AC). The YB group performed two YB exercises, each for ten minutes, for a total of twenty minutes in a single session. AC group read a text of their choice for 20 minutes. Saliva was collected at baseline and at 5, 10, 15, and 20 minutes. Using Mass Spectrometry (MS), we initially found that 22 proteins were differentially expressed and then validated deleted in malignant brain tumor-1 (DMBT1) and Ig lambda-2 chain C region (IGLC2) using Western Blotting. DMBT1 was elevated in 7 of YB group by 10-fold and 11-fold at 10 and 15 minutes, respectively, whereas it was undetectable in the time-matched AC group (P<0.05). There was a significant interaction between groups and time assessed by two-way ANOVA (P<0.001). IGLC2 also showed a significant increase in YB group as measured by Western Blotting. These data are the first to demonstrate the feasibility of stimulating and detecting salivary protein biomarkers in response to an acute Yoga exercise. This trial is registered with ClincalTrials.govNCT02108769.

Substantial data support the causative nature of tobacco on the development of several cancers [1]. Unfortunately, most cancer studies do not include tobacco use as a variable to consider in the interpretation of outcomes. Increasing evidence demonstrates that tobacco use during cancer treatment is associated with poor outcomes including decreased treatment response, increased treatment-related toxicity, increased noncancer comorbidity, increased risk of second primary cancer, decreased quality of life and increased mortality from cancerand noncancer-related causes [2–7]. The effects of smoking affect both tobacco-related cancers (e.g., head/neck and lung cancer), as well as traditionally non-tobacco-related cancers (e.g., prostate cancer). In fact, data suggest that in cancers with long expected survival, such as prostate cancer, smoking may be a dominant risk factor for overall mortality due to increased risk of cardiovascular disease and death from other tobacco-related disease [8]. A history of ‘ever smoking’ decreases survival in several disease sites [2], but ‘current smoking’ at diagnosis is associated with increased overall and disease-specific mortality compared with those who have never smoked, former smokers (patients who quit ≥12 months prior to diagnosis) and recent quitters (patients who quit during the 12 months prior to diagnosis) [2]. These data suggest that a smoking history is not a fixed variable that affects outcome, but rather suggest that the effects of smoking may be reversible. There are limited studies on the effects of smoking cessation after diagnosis on cancer outcomes; however, available studies indicate that smoking cessation may reverse some of the effects of smoking on cancer outcomes [9–11]. To precisely understand the effects of tobacco on cancer patient outcomes, accurate assessments of current and former tobacco use are necessary. Unfortunately, the overwhelming majority of published literature that reports on the effects of smoking on cancer relies upon nonstandardized tobacco assessments and/or reviews of clinician-based assessments obtained in the medical record [9]. Recommendations for the systematic collection of tobacco use in cancer clinical trials have been proposed and include smoking history, current smoking status and amount, nicotine dependence, readiness to stop smoking, other tobacco use and exposure to secondhand smoke [12]. Cancer patients often report high tobacco quit rates at cancer diagnosis or the beginning of cancer treatment but later show high relapse rates [13]. Due to these unique trends in tobacco use among cancer patients, tobacco status should be collected at cancer diagnosis and treatment intake, as well as throughout treatment and follow up. Failure to assess tobacco use at all patient encounters may miss clinically meaningful changes in tobacco-use status that can dramatically influence cancer treatment response and outcomes. Thus, prospective assessment of tobacco use at multiple time points throughout cancer clinical trials can substantially enhance understanding of the precise impact of tobacco use on cancer treatment outcomes.

Tobacco use is the largest risk factor for lung cancer and many lung cancer patients still smoke at the time of diagnosis. Although clinical practice guidelines recommend that all patients receive evidence-based tobacco treatment, implementation of these services in oncology practices is inconsistent and inadequate. Multidisciplinary lung cancer treatment programs offer an ideal environment to optimally deliver effective smoking cessation services. This article reviews best practice recommendations and current status of tobacco treatment for oncology patients, and provides recommendations to optimize delivery of tobacco treatment in multidisciplinary practice.

Background: Published data suggest that diabetes influences survival of patients with lung cancer. The anti-cancer effect of metformin confounds this association. We sought to study the association of diabetes and metformin with survival in patients undergoing resection of stage I non-small cell lung cancer (NSCLC). Methods: Pathologic stage I NSCLC patients undergoing anatomic resection from 2002 to 2011 were studied. A diagnosis of diabetes and diabetic medication use were identified through records. Univariate and multivariate analyses examined the association of diabetes and metformin usage with overall survival (OS). Results: 409 eligible patients were included in the analysis - excluding patients with neoadjuvant therapy, more than one lung cancer, or resection less than lobectomy. 71 (17.4%) patients were diabetics and 41 (10.0%) used metformin. With a median follow up of 44 months, univariate analysis demonstrates that diabetes had no effect on OS (P=0.75); however, metformin use was associated with improved OS (median survival not reached vs. 60 months; P=0.02). Metformin use remained an important predictor of good survival in multivariate analysis (HR=3.08; P

Unethical, immoral, and underhanded-an accurate description of the cigarette industry’s most recent effort to avoid beingheldresponsible forthe livesit hasruinedin itsunending pursuit ofprofits,no matterhow manysuffer in the process.Thelatest example of its unrestrained corporate greed surfaced in Florida a few weeks ago, when the industry amassed andunleashedanarmyoflobbyiststotrytoconvincetheFloridalegislaturetorewritethelegalrulesforthousandsofFloridians,victimsofBigTobaccowhohavebeenwaitingmorethan20yearstosecuretheirrightsasmembersofthehistoricEngleclassactionlawsuit (Englev.Liggett,etal).

Purpose. The purpose of our research was two-fold: 1) to further characterize the downregulation of CYP3A2 mRNA, protein, and activity during an acute phase response (APR); 2) most importantly, to relate the time-dependent activation of nuclear proteins to putative DNA binding sequences within the CYP3A2 5′-flanking region, with the loss in CYP3A2 expression. Methods. Rats were injected (2.0 mg/animal, i.p.) with LPS and sacrificed at 1,2, 4, 6, 8, 24, 48, and 72 hours. Hepatic nuclear protein was isolated and analyzed for binding activity to AP-1, NFκB, and NF-IL6 consensus sequences. Hepatic CYP3A2 mRNA levels were determined by solution hybridization and CYP3A2 protein, CYP3A2 activity, and total P450 were measured in hepatic microsomes. Results. Computer analysis of the 5′-flanking region of CYP3A2 revealed the presence of 5 NF-IL6 and 4 AP-1 putative DNA binding sites. The strongest increase in AP-1 binding activity occurred between 6 and 24 hr, and the alteration in binding complexes to an NF-IL6 oligonucleotide occurred between 4 and 24 hr. Maximum loss in CYP3A2 mRNA occurred at 8 hr post-LPS injection and remained lowered at the 24 hr timepoint. CYP3A2 protein was significantly decreased at 24, 48, and 72 hours post-LPS treatment with corresponding decreases in CYP3A2 activity and total P450. Conclusions. The changes in NF-IL6 and AP-1 binding after LPS treatment, which appears to correlate with the changes in CYP3A2 mRNA, combined with the presence of putative NF-IL6 and AP-1 sites located in the CYP3A2 5′-flanking region, may indicate a potential role for NF-IL6 and AP-1 in CYP3A2 downregulation during an APR.

Introduction Tobacco use is associated with poor outcomes in cancer patients, but there is little information from oncology providers on their practice patterns or perceptions regarding tobacco use and smoking cessation in these patients. Methods An online survey of practices, perceptions, and barriers to tobacco assessment and cessation in cancer patients was conducted in members of the International Association for the Study of Lung Cancer (IASLC). Responses of physician-level respondents were analyzed and reported. Results Responses from 1507 IASLC members who completed the survey are reported as representing 40.5% of IASLC members. More than 90% of physician respondents believe current smoking affects outcome and that cessation should be a standard part of clinical care. At the initial patient visit, 90% ask patients about tobacco use, 79% ask patients whether they will quit, 81% advise patients to stop tobacco use, but only 40% discuss medication options, 39% actively provide cessation assistance, and fewer yet address tobacco at follow-up. Dominant barriers to physician cessation effort are pessimism regarding their ability to help patients stop using tobacco (58%) and concerns about patient resistance to treatment (67%). Only 33% report themselves to be adequately trained to provide cessation interventions. Conclusion Physicians who care for lung cancer patients recognize the importance of tobacco cessation as a necessary part of clinical care, but many still do not provide assistance to their patients as a routine part of cancer care. Increasing tobacco cessation activities will require increased assessment and cessation at diagnosis and during follow-up, increased clinician education, and improved tobacco cessation methods.

(OPSCC) undergoing definitive concurrent chemoradiation (CCRT) remains unclear. The purpose of this review was to examine these effects on survival outcomes among a single institute population. Materials/Methods: This retrospective review of OPSCC patients treated with CCRT between 2008 and 2015 was conducted. All tumors were examined for HPV 16/18 status (+/). Smoking status and other clinical characteristics were abstracted from the electronic medical record. Former smokers are patients who quit within a month of diagnosis or treatment. Descriptive summaries, overall survival (OS), and multivariate cox proportional hazard ratios (HR) were completed. Results: Out of 134 patients, 94 patients (71%) had HPV-positive (HPV+) tumors. Age, gender, and overall stage were not statistically different between patients with HPV+ or HPV-negative (HPV-) tumors. HPV+ patients had higher tumor grade (P

Signet ring cell esophageal adenocarcinoma histology has been difficult to study in single institution series because of its relative rarity, yet has an anecdotal reputation for poor prognosis. The Surveillance, Epidemiology, and End Results (SEER) database was examined to assess the prognostic implications of this esophageal adenocarcinoma subtype.All patients with esophageal adenocarcinoma in the SEER database from 2004 to 2009 were included. Univariate and multivariate analyses examining the relationship of signet ring cell histology with overall survival were performed in all patients, as well as those undergoing surgical resection.A total of 596 of 11,825 (5%) study patients had signet ring cell histology. Patients with signet ring cell histology were similar in age, race, and sex distribution, but had a higher grade (P .001) and higher stage (P .001) at diagnosis. In both the all-patient group as well as those undergoing surgical resection, univariate analyses showed a worse survival in patients with signet ring cell esophageal cancer (hazard ratio [HR] = 1.24; 95% confidence interval [CI] = 1.13-1.36 and HR = 1.57; 95% CI = 1.29-1.93, respectively). In multivariate analyses adjusting for covariates, patients with signet ring cell cancer had a worse prognosis than those without (HR = 1.18; 95% CI = 1.07-1.30). In surgically resected patients, this remained a trend, but did not reach statistical significance (HR = 1.16; 95% CI = 0.94-1.42).This large study of esophageal adenocarcinoma confirms the clinical impression that signet ring cell variant of adenocarcinoma is associated with an advanced stage at presentation and a worse prognosis independent of stage of presentation.

Stereotactic body radiation therapy (SBRT) is a radiotherapy technique which uses high dose fractions with multiple coplanar and noncoplanar beams. Due to the large fractional doses, treatments are typically protracted and there are more fields than in conventional radiation treatment schemes. The effect of temporal optimization on the biological effectiveness of SBRT is not well established.In a cohort of actual SBRT patient treatments, the Lea-Catcheside protraction factor (G-value) was used to determine the optimal (Δ) and the least favorable (V) field. An actual field timing delivered in the clinic was included (C) for comparison. The lethal potential lethal (LPL) model was used to quantify the difference in survival fractions. Published data from three cell lines for non-small cell lung cancers: H460, H660, and H157 were used to acquire the parameters needed by the LPL model. The results are expressed as the ratios (V:Δ)(N) and (C:Δ)(N), where N is the number fractions in the SBRT protocols and Δ, V, and C are the survival fractions calculated from the corresponding temporal patterns.The results indicate that variability in the dose rate between fields does impact the optimization results. This dependence on dose rate, however, is small compared to the impact from the variability in doses between fields. The optimized field arrangements resembled previous studies, that maximization of cell kill is achieved by orienting the fields in a Δ shape sequence, where the fields with greatest dose are positioned in the center. Minimization of cell kill was achieved with a V-shaped orientation. Smallest dose fields were positioned centrally, and higher dose fields were placed in the beginning and end of the fraction. The survival fraction ratios calculated using the LPL demonstrated that regardless of the cell type the Δ shape had lower cell survival fractions compared to both the clinical example (C) and the V arrangement. For H460, with T(1/2) = 0.25 h, an average ratio of (C:Δ)(5)=13.9, suggesting the Δ pattern is approximately 14 times more effective than the clinical plan, after 5 fractions.Rearranging field timing for a SBRT treatment so that maximal dose is deposited in the central fields of treatment may optimize cell kill and potentially affect overall treatment outcome.

Purpose Substantial evidence suggests that tobacco use has adverse effects on cancer treatment outcomes; however, routine assessment of tobacco use has not been fully incorporated into standard clinical oncology practice. The purpose of this study was to evaluate tobacco use assessment in patients enrolled onto actively accruing cancer clinical trials. Methods Protocols and forms for 155 actively accruing trials in the National Cancer Institute's (NCI's) Clinical Trials Cooperative Group Program were evaluated for tobacco use assessment at enrollment and follow-up by using a structured coding instrument. Results Of the 155 clinical trials reviewed, 45 (29%) assessed any form of tobacco use at enrollment, but only 34 (21.9%) assessed current cigarette use. Only seven trials (4.5%) assessed any form of tobacco use during follow-up. Secondhand smoke exposure was captured in 2.6% of trials at enrollment and 0.6% during follow-up. None of the trials assessed nicotine dependence or interest in quitting at any point during enrollment or treatment. Tobacco status assessment was higher in lung/head and neck trials as well as phase III trials, but there was no difference according to year of starting accrual or cooperative group. Conclusion Most actively accruing cooperative group clinical trials do not assess tobacco use, and there is no observable trend in improvement over the past 8 years. Failure to incorporate standardized tobacco assessments into NCI-funded Cooperative Group Clinical Trials will limit the ability to provide evidence-based cessation support and will limit the ability to accurately understand the precise effect of tobacco use on cancer treatment outcomes.

The effect of smoking on survival in cancer patients is limited by the lack of structured prospective assessments of smoking at diagnosis. To assess the effect of smoking at diagnosis on survival, structured smoking assessments were obtained in a cohort of 5,185 cancer patients within 30 days of a cancer diagnosis between 1982 and 1998. Hazard ratios (HRs) or odds ratios were generated to analyze the effects of smoking at diagnosis on overall mortality (OM) and disease-specific mortality (DSM) in a patient cohort from 13 disease sites containing at least 100 patients in each disease site. With a minimum of 12 years of follow-up, current smoking increased OM risk versus recent quit (HR 1.17), former (HR 1.29) and never smokers (HR 1.38) in the overall cohort. Current smoking increased DSM risk versus former (HR 1.23) and never smokers (HR 1.18). In disease sites with proportionately large (>20%) recent quit cohorts (lung and head/neck), current smoking increased OM and DSM risks as compared with recent quit. Current smoking increased mortality risks in lung, head/neck, prostate and leukemia in men and breast, ovary, uterus and melanoma in women. Current smoking was not associated with any survival benefit in any disease site. Data using prospective structured smoking assessments demonstrate that current smoking increased long-term OM and DSM. Standardized smoking assessment at diagnosis is an important variable for evaluating outcomes in cancer patients.

Approximately 36,000 new cases of head and neck cancer were expected to occur in the United States in 2009 with an estimated 7600 deaths.1 Although the addition of chemotherapy to radiation therapy has improved outcomes, approximately 50% to 60% of these patients are expected to experience treatment failure within 2 years.2 We retrospectively reviewed outcomes of 78 patients with squamous cell carcinoma of the head and neck (SCCHN) at Roswell Park Cancer Institute, to evaluate outcomes following intensity-modulated radiation therapy (IMRT) with definitive concurrent chemoradiotherapy (CCRT).3 We found that total treatment time and baseline hemoglobin level were significant predictors for locoregional failure. Interventions to target anemia have been unsuccessful in cancer patient populations.4–11 Based on the futility of anemia interventions, Prosnitz et al12 suggest that hemoglobin level should serve as a “biologic staging parameter” rather than as a target parameter. This concept of hemoglobin as simply a surrogate marker of patients’ overall biology caused us to consider targeting interventions to more fundamental biological markers such as nutritional status. Inui13 noted that efforts to maintain or improve nutritional status, especially if nutritional state is correlated to anemia, may be helpful in minimizing treatment interruptions. Noting this possible link between anemia, treatment time, and nutritional status, we hypothesized that nutritional markers may also predict outcomes following concurrent chemoradiation therapy for advanced SCCHN. This analysis was performed to determine if differences in nutritional status were independent predictors of locoregional failure in our previously described cohort of 78 patients.

Background: Cancer patients who self-report tobacco use within the past 30 days are at high risk for relapse and benefit from cessation support. However, there is little data on whether assessment of tobacco use within the past 30 days increases referral rates to a cessation program across cancer disease sites. Methods: Structured tobacco assessments were administered to 426 new adult patients in a Radiation Oncology clinic at a single institution. Multiple logistic regression was used to assess if clinical aspects of cancer diagnosis (age, gender, race, disease site [head/neck or thoracic {HNT} vs. other], stage [advanced vs. early], and purpose [curative vs. palliative]) affected cessation service referral rates identified using assessment of tobacco use within the past 30 days. Results: Complete medical and tobacco use data were compiled for 387 adult cancer patients (91%). Of these, 147 (38%) were women, 259 (67%) were Caucasian, 115 (30%) were black, 177 (46%) were diagnosed with HNT cancer, and 289 (74%) were being considered for curative cancer treatment. Ever smoking was reported in 273 patients (71%), and 83 (21%) reported current smoking everyday or some days. In 180 former smokers who reported time since last cigarette, 21 (12%) reported smoking within with past 30 days and 9 (7%) of these reported smoking within the past day or week. In 21 patients who were identified for cessation support through evaluation of smoking within the past 30 days, 6 (29%) were women, 7 (33%) were black, 15 (71%) were being considered for curative treatment, and 15 (71%) were diagnosed with a HNT cancer. Multiple logistic regression identified that younger age (10 yr OR 2.41, 95% CI 1.47 - 3.98) and HNT cancer (OR 8.13, 95% CI 2.2-30.3) but not gender, race, stage, and purpose were significantly associated with referral based on assessment of tobacco use within the past 30 days. Identification of smoking within the past 30 days increased cessation referrals by 25% from 83 to 114 patients. Conclusions: Assessment of tobacco use within the past 30 days increased referrals to a smoking cessation program from a Radiation Oncology clinic using a standardized tobacco assessment. In clinical trials and practice, including this question has particular benefit for younger patients and patients with head/neck or thoracic tumors. Citation Format: Samuel Lewis Cooper, Katherine Hoover, Elizabeth Garrett-Mayer, Kenneth Michael Cummings, Matthew J. Carpenter, Kelly Crowley, David T. Marshall, Graham W. Warren. Assessment of tobacco use within 30 days increases referral for cessation support. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3736. doi:10.1158/1538-7445.AM2015-3736

Tobacco use is the single largest preventable risk factor for developing cancer. Furthermore, tobacco is associated with poor therapeutic outcomes in part because its continued use has been shown to decrease the efficacy of conventional chemotherapy and/or radiotherapy (RT). Preclinical data suggests that nicotine administration decreases RT efficacy by activating the alpha-7-nicotinic acetylcholine receptor (a7-nAChR). Our study evaluated the effects of nicotine and selective a7-nAChR agonists (LY 2087101, PHA 543613, PNU 282987, and TC 1698) administration on radiotherapeutic efficacy. H460 and A549 human lung cancer cell lines were dose escalated with nicotine and the a7-nAChR agonists alone or in combination with single fraction X-ray radiation (2, 6 Gy) and cell survival was assessed by clonogenic assay. Nicotine administration and activation of a7-nAChR by LY 2087101 or PHA 543613 was found to have a radioprotective effect in both cell lines by increasing cell survival following RT. Conversely, activation of a7-nAChR by PNU 282987 or TC 1698 did not modulate radiotherapeutic response. Western blot analysis demonstrated that although all four tested a7-nAChR agonists increased phosphorylation of AKT (S473), only PHA 543613 and LY 2087101 were found to also activate mTOR (S2448). Additional clonogenic studies were performed to further examine the role of mTORC1 in governing response to RT. Inhibition of mTORC1 by rapamycin alone sensitized both A549 and H460 cells to the effect of RT. Interestingly, rapamycin treatment was sufficient to block the radioprotective effects of nicotine, PHA 543613, and LY 2087101 in A549 cells, however, in H460 cells rapamycin did not restore radiotherapeutic efficacy. Moreover, examination of Deptor, a key component of mTOR complexes shown to be associated with RT response, demonstrated that a7-nAChR activation by nicotine, PHA 543613, or LY 2087101 increased Deptor degradation in A549 cells, while a7-nAChR activation decreased Deptor degradation in H460 cells. These observations suggest that differences in the regulation of Deptor level may contribute to the variation in both rapamycin sensitivity and restoration of therapeutic efficacy to RT between H460 and A549 cell lines. Additional studies will be necessary to further elucidate the role of the mTOR complexes in mediating a7-nAChR induced modulation of response to RT. Citation Format: Samantha L. Sobus, Sundaravadivel Balasubramanian, Michelle A. Romano, Graham W. Warren. The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3305. doi:10.1158/1538-7445.AM2015-3305

Purpose Tobacco use is not only associated with the development of cancer, but after a patient develops cancer, its continued use is associated with poorer cancer treatment outcomes. Despite this fact, most oncologists do not regularly provide tobacco cessation support. The purpose of this study was to implement an expedited process of patient identification and tobacco cessation for cancer patients. Methods The Michigan Oncology Quality Consortium (MOQC) collaborated with the Michigan Department of Community Health, Blue Cross and Blue Shield of Michigan, and the Michigan Cancer Consortium to enhance tobacco cessation support for cancer patients. A statewide tobacco cessation demonstration project using a lean engineering approach was developed to provide structured tobacco assessments, referral to state quitline resources, and provide tailored cessation support to cancer patients consisting of behavioral counseling and free pharmacotherapy where appropriate. These steps were rapidly deployed in over 30 locations including those in private oncology practices and cancer centers in the first year. Data were analyzed to evaluate participation, retention, and quit rates for cancer patients enrolled in the program. Results Previous reports have described high rates of patient contact and participation in the cessation program. In the 690 patients with at least 12 months since program enrollment, 200 (29%) participated in only 1 call, 313 (45%) participated in 1-2 follow-up calls, and 177 (26%) participated in 3 or more follow-up calls. Follow-up 30 day quit rate data was obtained in 198, 138, and 199 patients at 3, 6, and 12 months respectively. Self-reported quit rates remained largely consistent with 29.8% at 3 months, 27.5% at 6 months, and 30.2% at 12 months. Conclusions The MOQC demonstration project represents a model partnership between payors, clinicians, and statewide quitlines that maintained consistent and moderate quit rates in cancer patients. Large-scale deployment of this model program may provide a clinically efficient and effective mechanism to enhance widespread tobacco cessation efforts for cancer patients. Citation Format: Laura Petersen, Hilary Baca, Karen Brown, Jamie Lindsay, Sarah Mott, Jane Severson, Anna Schulze, Graham Warren. Rapid deployment of statewide tobacco cessation program for cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3728. doi:10.1158/1538-7445.AM2015-3728

Background: The 2014 Surgeon General's Report concludes that cigarette smoke (CS) causes increased cancer specific mortality. Clinical data support that the effects of CS are reversible, but there are no extant biologic models that have shown therapeutic response profiles for cancer cells exposed to CS. Methods: An acute, subacute, and chronic dose escalated CS exposure model was developed to test the hypothesis that CS decreases therapeutic response to chemotherapy (CT, cisplatin) and radiotherapy (RT, 0, 2, 4, and 6 Gy) in a reversible manner in cancer cells. Results: H460, A549, and FaDu cancer cells were treated with single and multiple exposure CS for up to 12 weeks. Subacute and prolonged exposure to CS significantly decreased response to CT and RT. CS increased survival fraction following CT or RT between 30-157% across all cell lines. Exposure of cancer cells to CS for 6 or 9 weeks followed by removal of CS for 3 and 6 weeks resulted in a partial to complete restoration of baseline therapeutic response in a cell specific manner; however, all cell lines required several weeks to achieve a partial or full restoration of therapeutic response. Dose response curves for CS exposure demonstrate that H460 and A549 cells had a decreased therapeutic response profile at higher CS concentrations while FaDu cells were more sensitive to lower concentrations to CS. Dose response curves further demonstrated that high dose CS exposure was cytotoxic in all cell lines. Results were verified in all cell lines using 2 additional repeated experiments with freshly thawed cancer cells purchased from ATCC over 10 months. Conclusions: CS exposure reproducibly decreases therapeutic response to CT and RT in a dose dependent and reversible manner, reflective of clinical observations. Dose specific effects may vary between cancer cells. Data suggest that the biologic effects of CS removal, such as with acute smoking cessation in cancer patients, may not manifest in an immediate restoration of cancer cell response to CT or RT. Citation Format: Graham W. Warren, Michelle Romano, Samantha Sobus, Sundaravadivel Balasubramanian. Cigarette smoke and therapeutic response to chemotherapy and radiotherapy in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2015-5593

e12566 Background: Tobacco is the single largest preventable cancer risk factor, and continued tobacco use by cancer patients causes adverse treatment outcomes. The purpose of this study was to eva...

e22265 Background: According to the 2014 Surgeon General’s Report, smoking causes adverse outcomes in cancer patients including increased cancer specific mortality. There are no existing biologic m...

Lung cancer is the leading cause of cancer-related deaths in the United States. Despite improvements in radiation, surgery and chemotherapy the 5 year survival statistics of non-small cell lung cancer (NSCLC) have improved little over the past two decades. It has been proposed that NF-kappaB is a participant in the cytoprotection against several redox-mediated therapeutic agents including ionizing radiation. Cyclooxygenase-2 (COX-2) inhibition has become an attractive target for enhancing the efficacy of radiation and chemotherapy. Numerous mechanistic pathways have been proposed as the means through which COX-2 inhibition enhances the efficacy of radiation. We hypothesize that the COX-2 inhibitor, nimesulide, will improve the efficacy of radiation therapy (RT), at least in part, via the suppression of NF-kappaB mediated cytoprotective pathways. In this study we used the COX-2 inhibitor nimesulide to improve the efficacy of RT when measured by tumor regrowth assays in vivo and clonegenic survival in vitro. For the in vivo assay, A549 tumor cells representing NSCLC were subcutaneously injected into the right flanks of female athymic nude mice (n=10/group). Mice were given nimesulide via drinking water at a concentration of 5 microg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured bi-weekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-kappaB mediated mechanism of nimesulide was measured by Western blot analysis of NF-kappaB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 microg/g b.w. nimesulide and 30 Gy radiation (3 Gy/fraction, 10 daily fractions) had significant reduction in tumor size in comparison to the 30 Gy radiation control group (p

Lung cancer is the leading cause of cancer-related deaths in the United States. Despite improvements in radiation, surgery and chemotherapy the 5 year survival statistics of non-small cell lung cancer (NSCLC) have improved little over the past two decades. It has been proposed that NF-kappaB is a participant in the cytoprotection against several redox-mediated therapeutic agents including ionizing radiation. Cyclooxygenase-2 (COX-2) inhibition has become an attractive target for enhancing the efficacy of radiation and chemotherapy. Numerous mechanistic pathways have been proposed as the means through which COX-2 inhibition enhances the efficacy of radiation. We hypothesize that the COX-2 inhibitor, nimesulide, will improve the efficacy of radiation therapy (RT), at least in part, via the suppression of NF-kappaB mediated cytoprotective pathways. In this study we used the COX-2 inhibitor nimesulide to improve the efficacy of RT when measured by tumor regrowth assays in vivo and clonegenic survival in vitro. For the in vivo assay, A549 tumor cells representing NSCLC were subcutaneously injected into the right flanks of female athymic nude mice (n=10/group). Mice were given nimesulide via drinking water at a concentration of 5 microg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured bi-weekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-kappaB mediated mechanism of nimesulide was measured by Western blot analysis of NF-kappaB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 microg/g b.w. nimesulide and 30 Gy radiation (3 Gy/fraction, 10 daily fractions) had significant reduction in tumor size in comparison to the 30 Gy radiation control group (p0.05). In vitro, nimesulide alone produced a significant decrease in clonogenic survival at doses from 0-300 microM. Nimesulide demonstrated an additive effect in combination with radiation. Nimesulide alone reduced MnSOD and survivin protein levels in a dose-dependent manner. 6 Gy radiation caused an initial elevation of MnSOD protein levels which was inhibited by prior treatment of nimesulide suggesting an inhibition of radiation induced NF-kappaB target genes. These results support the hypothesis that COX-2 inhibitors such as nimesulide can increase the efficacy of radiation therapy. In vitro, our results suggest that the radiosensitization of A549 tumor cells by nimesulide is mediated by the suppression of NF-kappaB-mediated, radiation-induced cytoprotective genes.