PurposeIn a previous study of smoking cessation in veterans with lung cancer, we noted as an incidental finding that current smokers were much younger than former smokers at diagnosis. To confirm and extend this observation, we analyzed the association of smoking status with age at diagnosis and survival of lung cancer patients.MethodsThe Jefferson Cancer Registry collects information on all cancer patients registered at this hospital. Information on smoking status has been recorded since 1995. We determined age at diagnosis and survival of current and former smokers with lung cancer.Results5111 lung cancer cases were identified in the registry from 1995 to 2011 inclusive. Smoking status was recorded in 4687 cases (91.7%). Of these, 1859 (39.7%) were current, 2423 (51.7%) were former, and 405 (8.6%) were never smokers. There was a 6-year difference in median age at lung cancer diagnosis between the current (63years) and former smokers (69years) (P<0.0001). The median survival was 12.1months for current versus 14.5months for former smokers (P<0.0001).ConclusionsThese results confirm and extend our observation that among patients diagnosed with lung cancer, current smokers are younger than former smokers. The possible explanations include higher competing causes of death and increased risk of lung cancer among current smokers as well as increasing proportions of former smokers in older populations. Ongoing exposure to tobacco carcinogens may accelerate the development of lung cancer in continuing smokers. This provides more incentive for smokers to quit at the earliest age possible.

e22049 Background: Lynch Syndrome is an autosomal dominant disorder caused by either germline mutation in a DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2, or epigenetic silencing of MSH2. The syndrome consists of early onset malignancies and multiplicity of cancers. Colonic malignancies predominate with the frequency and distribution of extracolonic cancers dictated by the mutated gene. Methods: A 54 year old man with a family history of Lynch Syndrome and a MSH6 mutation was found to have synchronous colonic adenocarcinomas on screening colonoscopy. Within weeks he presented with a rapidly enlarging anaplastic thyroid cancer (ATC). On PET/CT he was found to have liver metastases (biopsy confirmed as colonic) and pulmonary metastases (biopsy confirmed as ATC). Tumor tissue from his colon and thyroid was sent for FoundationOne analysis of 343 genes. Cell free circulating tumor DNA (CtDNA) was sequenced for 54 genes using Guardant360 technology with blood taken post-thyroidectomy. Results: FoundationOne sequencing is shown below. The only shared mutation was the germline MSH6. Of the 16 mutated genes, 4 were included in the Guardant360 panel. The APC and KRAS mutations were detected in the CtDNA, as was a separate FBXW7 mutation and EGFR and ERBB2 mutations not seen in the Foundation One data. Conclusions: This patient is 1 of 3 cases of ATC in Lynch Syndrome, and the first associated with MSH6 and synchronous colon cancer. Molecular profiling shows a hypermutated phenotype, consistent with a loss of mismatch repair. The unique signatures in the anaplastic and colonic primaries are more likely indicative of tissue-specificity while the discordance with CtDNA may represent tumor heterogeneity, evolution of the tumor during chemotherapy, or the limits of our current technology. FoundationOne Anaplastic Thyroid FoundationOne Colon Guardant360 ctDNA MSH6 G1105fs*3 G1105fs*3, R988fs*11 Not Tested (NT) AKT1 E17K APC G1412* G1412* ARID1A I106fs*4 NT ATM R3008H NT BLM N515fs*16 NT FBXW7 R179C, R465C R385C KRAS A146T A146T MLL3 K2797fs*26 NT NOTCH1 Y550fs*1 NT PI3KCa R38C E81K, H1047R NT PTEN R335* NT RB1 265-1G>T NT SOX9 Q412* NT TSC1 E945* NT TP53 R196* R267W ERBB2 Not Detected (ND) ND R340R EGFR ND ND T130T

Purpose of review The purpose of this study is to review the role of telemedicine in providing oncology care; we describe our long-standing, high-volume telemedicine experience.Recent findings The Interior Health Thoracic Surgical Group (IHTSG) uses telemedicine, through Virtual Thoracic Surgical Clinics (VTSC), to provide service to remote patients. The IHTSG serves a population of 1.01 million people over an area of 807,538 km(2) (1.3 persons/km(2)) in the Interior and North of British Columbia, Canada. Between 2003 and 2015, the IHTSG conducted 15,073 telemedicine patient encounters at 63 geographic sites. Telemedicine saved these patients a total travel distance of 11.5 million km-an average of 766 km per patient. VTSC supports and strengthens the Hub and Spoke model of healthcare delivery-patients residing remotely can easily access centrally delivered service.Summary Telemedicine makes specialized care available to all patients by overcoming a major impediment to access, namely distance.

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.

Tumor growth and progression occur as a result of interactions among the tumors, host-derived stromal tissues and host immune cells. It is currently believed that inflammatory cells in the tumor microenvironment play a significant role in tumor development. A high pretreatment neutrophil count and NLR were found to be a negative prognostic factor for survival in patients with different solid malignancies. This study aims to investigate the association between the pre-diagnosis NLR and survival in a large cohort of patients with lung cancer, treated at a single institution. We analyzed a retrospectively collected, well-characterized clinic-based cohort of 1032 lung cancer patients. The patients were divided into 2 groups according to the median NLR value (low <4.37 or high ≥ 4.37). Using the group with low NLR as reference, the risk of death for the group with high NLR value was calculated by multivariate Cox proportional hazard model, adjusting for major covariates including age, gender, ethnicity, smoking status, TNM stage, tumor grade, surgery, chemotherapy, and radiation therapy, respectively. The mean prediagnosis NLR was significantly associated with lung cancer patient overall survival. Compared to patients with a low NLR level, those with elevated NLR exhibited a significant unfavorable overall survival with a hazard ratio (HR) of 1.50 (95% confidence interval [CI]: 1.30-1.75, P=7.2x10-8) after adjusting for other covariates. The association was internally validated with bootstrap (P<.01 at 99% resampling). The effect of NLR significantly interacted with race (P interaction=.005), and smoking status (P interaction=.02). The association was more pronounced in nonwhite patients (HR=2.16, 95% CI 1.61-2.89, P=2.62x10-7) than in white patients (HR=1.31, 95% CI 1.10-1.57, P=.002) (P interaction=.005), and in never smokers or patients with unknown smoking status (HR=2.60, 95% CI 1.61-4.19, P=9.1 x 10-5) than in past smokers (HR=1.55, 95% CI 1.24-1.93, P=.0001) or current smokers (HR=1.32, 95% CI 1.04-1.68, P=.02). Flexible parametric survival model demonstrated that the increased risk for death associated with elevated prediagnosis NLR persisted over 18 months after diagnosis. Our data suggests that prediagnosis NLR might be used as an independent prognostic marker for overall survival for lung cancer patients. The effect of NLR on overall survival seems to be more pronounced for those patients with races other than white, and for nonsmokers when compared with the past and current smokers. We plan to further analyze the effect of the prediagnosis NLR on overall survival in the context of nutritional status and performance status of patients with lung cancer.

This review will discuss the evolution of the role of chemotherapy in the treatment of locally advanced head and neck cancer (HNC), over the last few decades. Studies were identified by searching PubMed electronic databases. Surgery followed by radiotherapy (RT) or definitive RT are potentially curative approaches for locally advanced HNC. While chemotherapy itself is not curative, it can improve cure rates when given as an adjunct to RT. The benefit of combining chemotherapy with RT is related to the timing of the chemotherapy. Several prospective randomized trials have demonstrated that concurrent delivery of chemotherapy and RT (CRT) is the most promising approach, given that locoregional recurrence is the leading pattern of failure for patients with locally advanced HNC. Induction chemotherapy before CRT has not been shown to be superior to CRT alone and the added toxicity may negatively impact the compliance with CRT. Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT, has been successful as a strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal cancer. Systemic chemotherapy delivered concurrently with RT is used as a standard treatment for locally advanced HNC. (C) 2014 Elsevier Inc. All rights reserved.

Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long‐term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non‐small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n = 773) and testing (n = 388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low‐, medium‐ and high‐risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p < 0.0001). Compared with low‐risk group, patients in the medium‐ and high‐risk groups had a significantly higher risk of death at 1 year, with hazard ratio (HR) of 1.95 (95% CI 1.62–2.36) and 5.22 (4.30–6.34), respectively. These results were validated in the testing cohort. Overall, we developed a prognostic model relying entirely on readily available variables, with similar predictive power to those which depend on more specialized and expensive molecular assays. Further study is necessary to validate and further refine this model, and compare its performance to models based on more specialized and expensive testing.

Pts with NSCLC who cannot receive chemotherapy (CT) due to poor performance status or comorbidities can tolerate thoracic RT. ERL, a tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR) is approved in NSCLC. This Phase II study investigated a combination of ERL with HRT to achieve a favorable progression-free survival (PFS). Secondary objectives were toxicity, survival and examining the relationship between PFS and EGFR-M (mutation) status. Eligible pts had Stage IV/recurrent/Stage I inoperable/Stage II/III NSCLC requiring thoracic RT and were not candidates for concurrent CT, all with FEV1≥1.2 L. Biopsy specimens were tested for the presence of EGFR-M, although pts were eligible regardless of mutation status. Pts with synchronous brain metastases were allowed to receive whole brain RT while on the study. Pts received ERL, 150 mg daily starting 5 days before HRT and continuing during HRT and afterward until tumor progression, death, toxicity, or up to 24 months (mos). Conformal 3D volumetric image-guided HRT (50.4 Gy in 12 fractions) was delivered with 6 MV photons, treating the primary tumor and abnormal lymph nodes. The V15 was limited to 25%. A total of 17 out of planned 25 pts were enrolled from January 2010 to July 2012 and the study closed due to slower than expected accrual. Ten pts were male; median age was 67 years (yrs) (range, 50-85 yrs). Histology was as follows: 9 adenocarcinomas, 2 NSCLC, 6 squamous cell carcinomas; disease stage: I (n = 4); II (4); III (1); IV (7); recurrent (1). All pts completed HRT as planned and no pt was lost to follow-up. ERL was stopped at a median time of 4.5 mo due to disease progression (n = 8), toxicity (6), or death (2). ERL was dose-reduced in 4 pts. One pt continues on ERL. The toxicities were as follows: 3 Grade 5 (1 radiation pneumonitis; 1 aspiration pneumonia; 1 gastrointestinal bleeding, possibly associated with ERL); 18 Grade 3 (1 rash; 2 fatigue; 5 electrolyte abnormalities/dehydration; 3 cough/dyspnea;1 renal failure; 2 esophagitis/mucositis; 2 muscle pain; 2 hematologic); Grade 2: diarrhea and skin rash, 4 pts each. One PET-suspected failure within the HRT field was noted at 10 mos, for a crude local failure rate of 6%. With a median follow-up time for alive pts of 13.6 mos (range, 5-30 mos), the PFS at 1 yr was 30%. Median time to progression (censoring deaths) was 10.4 mos (range, 0.03-30+ mos), with a progression rate at 1 yr of 42%. Median Survival Time was 9.2 mo (range, 2.3-30+ mos). None of 4 pts tested so far had EGFR mutation. ERL with HRT achieves outstanding thoracic tumor control in unselected pts with NSCLC who have comorbidities and/or poor performance, precluding definitive therapy. Long-term ERL use is commonly associated with moderate toxicities in this pt population.

The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained "smoldering activation" occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human α4β2, α3β4 and α7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of α4β2 AChRs was centered at 0.13 µM, a level found in smokers. However, nicotine produced smoldering activation of α3β4 and α7 AChRs at concentrations well above levels found in smokers. The α4β2 expressing cell line contains a mixture of two stoichiometries, namely (α4β2)2β2 and (α4β2)2α4. The (α4β2)2β2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of α4β2 AChRs, but full agonists on α3β4 and α7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (α4β2)2α4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.

Purpose:To explore the incidence and risk factors for treatment-related acute esophagitis associated with involved-field radiation therapy (RT) delivered concurrently with chemotherapy for patients with locoregionally advanced non–small cell lung cancer. Materials and Methods:Forty-nine consecutive patients diagnosed with locoregionally advanced non–small cell lung cancer were treated using involved-field RT. Radiotherapy target volumes included the primary lung tumor and involved mediastinal lymphadenopathy as defined on imaging studies including computed tomography of the chest and [18F] fluorodeoxyglucose-positron emission tomography/computed tomography. The patients were treated to a median total dose of 63 Gy (range, 55.8 to 74 Gy) using daily fractions of 1.8 or 2.0 Gy. No elective radiotherapy of mediastinal lymph nodes was used. Concurrent platinum-based chemotherapy was delivered to all patients. Treatment-related toxicity was evaluated during the course of RT and subsequent follow-up visits. Results:Thirty-one (63%) patients were female and 18 (37%) were male. Median age at the time of diagnosis was 68 years (range, 36 to 83 y). Thirty-one patients (63%) developed treatment-related acute esophagitis: 24 patients (49%) grade 2 and 7 (14%) patients grade 3 esophagitis, with the peak occurring during the seventh week of radiotherapy. No grade ≥4 esophagitis was seen in this cohort. Eighteen patients (37%) did not develop radiation-induced esophagitis associated with their course of chemoradiotherapy. In the univariate analysis, age at the time of diagnosis, radiation dose per fraction, and total volume of the esophagus were significantly associated with the risk of acute esophagitis. Increasing age reduced the risk of acute esophagitis (odds ratio [OR] for 10-y increase=0.40) as did increasing total esophagus volume (OR for 10-U increase=0.27). Dose per fraction of 1.8 Gy was associated with lower risk of acute esophagitis when compared with dose per fraction of 2 Gy (OR=0.19). Marginal associations were observed for all of the volume variables. Higher volume variable values had a nonsignificant association with an increase in risk of acute esophagitis. However, only the total volume of the esophagus (P=0.0032) and larger dose per fraction (2 vs. 1.8 Gy) (P=0.011) remained significantly associated with higher risk of developing grade ≥2 acute esophagitis in the multivariate analysis. Conclusions:Higher risk of grade ≥2 treatment-related esophagitis was associated with lower total esophageal volume and higher radiotherapy dose per fraction and should be taken into consideration during patient treatment planning. Inclusion of total esophageal volume and dose per fraction into future clinical protocols may further help our understanding of treatment-related esophagitis and enable the development of novel preventative approaches.

Synthesis of acetylcholine (ACh) by non-neuronal cells is now well established and plays diverse physiologic roles. In neurons, the Na(+) -dependent, high affinity choline transporter (CHT1) is absolutely required for ACh synthesis. In contrast, some non-neuronal cells synthesize ACh in the absence of CHT1 indicating a fundamental difference in ACh synthesis compared to neurons. The aim of this study was to identify choline transporters, other than CHT1, that play a role in non-neuronal ACh synthesis. ACh synthesis was studied in lung and colon cancer cell lines focusing on the choline transporter-like proteins, a five gene family choline-transporter like protein (CTL)1-5. Supporting a role for CTLs in choline transport in lung cancer cells, choline transport was Na(+) -independent and CTL1-5 were expressed in all cells examined. CTL1, 2, and 5 were expressed at highest levels and knockdown of CTL1, 2, and 5 decreased choline transport in H82 lung cancer cells. Knockdowns of CTL1, 2, 3, and 5 had no effect on ACh synthesis in H82 cells. In contrast, knockdown of CTL4 significantly decreased ACh secretion by both lung and colon cancer cells. Conversely, increasing expression of CTL4 increased ACh secretion. These results indicate that CTL4 mediates ACh synthesis in non-neuronal cell lines and presents a mechanism to target non-neuronal ACh synthesis without affecting neuronal ACh synthesis.

Background The detection of skeletal metastasis, enlarged lymph nodes or parenchymal lesions in patients (pts) with established solid tumors most commonly denotes advanced stage disease. If not confirmed histologically, a subset of pts might be over staged and mismanaged palliatively.Methods We report 7 cases of low-grade B cell lymphomas diagnosed in a bone, lymph node or lung biopsy during staging workup in patients with suspected metastatic solid tumors.Results All pts were men aged 41 to 80 yo diagnosed with: non-small cell lung (NSCL), prostate, lip squamous cell, bladder, renal cell cancer (CA) and nasal adenoid cystic carcinoma. Imaging studies done during initial workup or follow up after resection of the primary tumor revealed bone metastasis, lymphadenopathy or lung nodules suggesting advanced stage of the primary CA. Invasive workup of the lesions in question revealed incidental low-grade B cell lymphomas (2 low grade lymphomas of bone, 2 CLL/SLL, 1 BALT, 1 marginal zone and 1 nodular lymphocyte predominant Hodgkin lymphoma). In all cases, this led to down staging and changed the management of the solid CA. Surgical resection of the tumor was done after it was down staged from non-resectable to resectable in 2 pts with head/neck CA; 1 pt with NSCL was down staged from stage IV to IIIA and received chemo/radiotherapy; 1 pt with prostate CA was down staged from stage IV to I; 3 pts were down staged from stage IV and were in remission from previously resected solid tumors. Only 2 pts required therapy for the newly diagnosed lymphoma. Avidity of the lesions revealed SUV ranging from 1.28 to 14.11 in the bone and from 2.17 to 6.98 in the lymph nodes.Conclusions Accurate staging of pts with solid tumors is critical in defining optimal goals of therapy. The growing use of PET/CT scans results in a higher rate of incidentally detected bone lesions or lymphadenopathy. Whereas a number of solid tumors readily spread to bone and lymph nodes, a spectrum of indolent lymphoid disorders may coexist in pts with established solid tumors. These lymphomas may remain asymptomatic for years. This might be misinterpreted as advanced stage solid tumor unless confirmed histologically.Disclosures: No relevant conflicts of interest to declare.

Purpose: To explore whether tumor biomarkers and pre-treatment factors correlate with treatment outcome in patients with oropharyngeal squamous cell carcinoma (S CC).Methods: Fifty-seven consecutive patients diagnosed with oropharyngeal SCC were treated using intensity modulated radiotherapy (IMRT). Thirty-four (60%) patients were treated with definitive chemoradiotherapy to a median total dose of 70 Gy and 23 (40%) were treated with postoperative RT to a median total dose of 66 Gy. Concurrent platinum-based chemotherapy was used in 51 patients (90%) and cetuximab in 3 (5%) patients.Results: Forty-four (77%) cases were positive and 13 (23%) were negative for p16 expression. Eighty-eight percent of non-smokers, 87% of smokers in their remote past and 56% of active smokers were diagnosed with p16-positive cancer. After 22 months median follow up, 51(89%) patients were alive. Forty-five (77%) patients were without evidence of disease at their last follow up, 82% of the patients with p16-positive tumors vs 58% of those with p16-negative cancer, respectively (p= 0.04). Locoregional disease-free survival was 82% for the entire cohort, 91% for patients treated postoperatively and 76% for patients treated with definitive chemoradiotherapy. Five (9%) patients developed distant metastases, and 3 (5%) developed new malignancies. One third of the patients with pre-RT hemoglobin level of 11 g/dL experienced persistent/recurrent disease; 80% of patients with hemoglobin <= 11 g/dL were smokers and 42% had p16-negative tumors.Conclusions: Smoking, p16 expression and pre-RT anemia are interrelated and influence outcome in oropharyngeal cancer patients and should be evaluated as stratifying variables in further clinical trials.

INTRODUCTION:We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer.METHODS:Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerström Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups.RESULTS:All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction.CONCLUSIONS:These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation.

Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC50 and LD50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD50 values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-XL. These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC. [Mol Cancer Ther 2009;8(8):2221–31]

PURPOSE: Our observation that many LC patients stop smoking prior to diagnosis, often preceding clinical symptoms and without difficulty, led us to speculate that smoking cessation may be a presenting symptom of the disease.

A69 Background: Overall survival of veterans with lung cancer is inferior to the civilian population despite their universal access to health care services. The primary objective of this study is to assess the effects of imaging-to-diagnosis delays on survival for veterans with lung cancer. Our main hypothesis is that delay between first radiological abnormality and diagnosis is correlated with a worse prognosis. Methods: The study consisted of a retrospective chart review of 281 incident cases of lung cancer diagnosed at the Philadelphia VA Medical Center between 1998 and 2002. Cases were identified through the Philadelphia VA Tumor Registry Database and evaluated by chart review for age, gender,race, smoking history, lung cancer stage, histology, and patient comorbidities. The longest patient follow-up was five years. Survival was defined as the time from lung cancer tissue diagnosis to death or the last known date that the patient was reported to be alive. Treatment delay was defined as the median time from radiographic abnormality to pathologic diagnosis and treatment. Results: The median delay between initial abnormal imaging and a pathologic diagnosis was 38 days (mean 85 days, SD 235). For resectable patients, the median delay between initial imaging and surgery was 105 days (SD 122). About a third of all patients experience diagnostic delays of 90 days or greater. Patients with metastatic disease had more expedited workups and shorter treatment delays (mean delay for Stage IV disease was 56 days vs. 115 days for Stage I/II, p=.256) . Patients age 70 and older had the longest imaging-to-diagnosis time intervals with a mean delay of 132 days vs. 59 days for younger patients, ages 45 to 70 (p=.057). African Americans experienced longer delays than their Caucasian counterparts with regional (151 vs. 78 days) and advanced disease (74 vs. 35 days), although these differences were not statistically different. There were no statistical differences in overall survival by race and diagnostic delay when controlling for age and stage of disease. There was a trend for increased mortality in patients with early stage lung cancer who experience diagnostic delays greater than 90 days. Conclusion: There were no disparities in survival by treatment delay among veterans with lung cancer. Older age, early stage of disease, and race are significant predictors of diagnostic delays. Patients with metastatic disease experience expedited workups with no significant impact on survival. The results from this study will inform future interventions emphasizing early detection and treatment for lung cancer patients at risk for delayed care.