Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Lung cancer has been the leading cause of cancer death in women forthe past three decades. Although smoking is the most important riskfactor for lung cancer, not all lung cancer deaths in American womenare attributed to smoking and the role of dietary exposures remainunclear.In particular, the effect of coffee consumption and teaconsumption on lung cancer risk remains inconclusive. Therefore weassessed these associations prospectively in 83,777 women between theages of 50-79 who did not have a previous history of cancer. Dailycoffee and tea consumption (cups/d) were assessed via a baselinequestionnaire while the 1,038 lung cancer cases included in analysiswere self-reported and verified by outcome assessors. Cox proportionalhazard models, adjusted for important lung cancer risk factors, wereused to model the associations. 71% of women reported drinking coffeedaily while only 26% of participants drank tea. Preliminary resultssuggested a significant increase in lung cancer risk for caffeinated(HR=1.47, 95% CI 1.21-1.79), decaffeinated (HR=1.56, 95% CI 1.17-2.07)and total coffee (HR= 1.58, 95% CI 1.29-1.93) when comparing those inthe highest consumption categories to non-drinkers, but no significantresults were observed in these consumption groups in an analysisconducted with only non-smokers. Daily tea consumption wassignificantly associated with a reduction of risk (HR= 0.82, 95% CI0.71-0.96). Our data suggests that there is no association betweencoffee consumption and lung cancer risk or tea consumption and lungcancer risk.

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BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

The aim of this thesis was to develop and evaluate a complex intervention for major depression in patients with lung cancer. Major depression is a leading cause of disease burden worldwide and is particularly important in patients with lung cancer, not only because it is common in this poor prognosis cancer group but also because it substantially reduces the quality of the often short period of time that patients have left to live. The thesis describes a systematic review of the relevant research literature, the development of a complex intervention and a multi-centre randomised controlled trial. I found no trials, in my systematic review, that had evaluated the effectiveness of treatments for depression in patients with lung cancer. I did, however, find six trials of interventions intended to improve symptoms or quality of life in this patient group, the findings of which suggested that enhanced care approaches were more effective in reducing depressive symptoms than standard medical care. I developed the complex intervention ‘Depression Care for People with Lung Cancer’ (DCPLC) with 12 patients who had major depression and lung cancer. DCPLC was delivered by a team of cancer nurses and psychiatrists in collaboration with the patient’s GP. It included education about depression, antidepressant medication, psychological treatments (behavioural activation and problem solving therapy) and systematic progress monitoring. The trial comparing DCPLC with usual care included 142 patients. Patients who received DCPLC reported significantly lower average depression severity during their time in the trial, and better self-rated depression improvement, anxiety, quality of life, role functioning and perceived quality of depression care. The methodological limitations, relevant literature and implications of these findings for future research and for clinical practice are discussed.

Dajun DaiRadon is a colorless, odorless, naturally occurring gas. It is currently the second leading cause of lung cancer and the number one cause of lung cancer to non-smokers in the United States. DeKalb County offers free screening for radon for residents. However, screening rates vary across the county. This pilot study focused on 14 selected tracts within DeKalb County with relatively low levels of radon screening. Over 200 households were recruited and homes were tested for indoor radon concentrations on the lowest livable floor over an 8-week period from March – May 2016. Tract-level characteristics were examined to understand the varitations of race, income, education, and poverty status between the 14 selected tracts and all of DeKalb County. The 14 selected tracts were comparable to all of DeKalb County in most factors besides race. Radon was detected in 73% of the homes sample and 4% had levels above the EPA guideline of 4 pCi/L. Multi-variate linear regression was used to compare all housing construction characteristics with radon concentrations and suggested that having a basement was the strongest predictive factor for detectable and/or hazardous levels of radon. Radon screening can identify problems and spur home owners to remediate but low screening rates may impact the potential health impact of free screening programs. More research should be done to identify why screening rates vary in order to identify ways to enhance screening and reduce radon exposure in DeKalb County.

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