Improved overall survival for Stage III NSCLC patients treated with curative-intended therapy from 2010 to 2018-a cohort study in Denmark.

BACKGROUND: Despite advances in treatment strategies and improved clinical outcomes, an unmet need remains for NSCLC patients. With an increased real-world knowledge of NSCLC, clinicians could offer patients optimal tailored treatment and disease management. In this retrospective cohort study, we describe patient characteristics, treatment patterns and modality, and survival in NSCLC patients diagnosed and treated at Aarhus University Hospital, Denmark. METHODS: Data on Stage III NSCLC patients aged ≥18 years diagnosed 2010-2018 were obtained from a regional cancer database and linked to national registries for information on socioeconomic and vital status. Patients were stratified by planned treatment intention at diagnosis (curative/palliative). Treatment patterns and overall survival (OS) were estimated using time-to-event methods. RESULTS: Broad patient and diseases characteristics and multiple treatment options demonstrated the heterogeneity of this patient cohort. Of 851 Stage III NSCLC patients, 599 (70%) and 252 (30%) were offered curative- and palliative-intended treatment, respectively, upon evaluation by a multidisciplinary team (MDT). The most frequent treatment modalities were CRT (n = 328; 55%) and RT (n = 97; 38%) in the curative and palliative setting, respectively. Age, disease stage, performance status and comorbidity were associated with curative-intended treatment initiation. Curative-intended treatment was associated with an improved OS of 14.6 months (median OS 24.4 months, 95% CI 21.1-27.6). Being offered curative-intended treatment and/or being diagnosed in the more contemporary study period (2016-2018) were significantly correlated with better OS (p < 0.001). CONCLUSION: Stage III NSCLC is a heterogeneous disease as regards patient and clinical characteristics, multiple treatment options, and outcomes. Age, disease staging, performance status, and comorbidity, as well as MDT evaluation and matching treatment intent, are important determinants of curative-intended treatment. Notably, an NSCLC diagnosis in the more contemporary study period was statistically significantly associated with better OS.

DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy.

Macroautophagy/autophagy is a central component of the cytoprotective cellular stress response. To enlighten stress-induced autophagy signaling, we screened a human kinome siRNA library for regulators of autophagic flux in MCF7 human breast carcinoma cells and identified the catalytic subunit of DNA-dependent protein kinase PRKDC/DNA-PKcs as a positive regulator of basal and DNA damage-induced autophagy. Analysis of autophagy-regulating signaling cascades placed PRKDC upstream of the AMP-dependent protein kinase (AMPK) complex and ULK1 kinase. In normal culture conditions, PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity. Instead, the disturbance of PRKDC-mediated phosphorylation of PRKAG1 inhibited the lysosomal localization of the AMPK complex and its starvation-induced association with STK11 (serine/threonine kinase 11). Taken together, our data suggest that PRKDC-mediated phosphorylation of PRKAG1 primes AMPK complex to the lysosomal activation by STK11 in cancer cells thereby linking DNA damage response to autophagy and cellular metabolism. Abbreviations: AXIN1: axin 1; 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; AA mutant: double alanine mutant (S192A, T284A) of PRKAG1; ACACA: acetyl-CoA carboxylase alpha; AICAR: 5-Aminoimidazole-4-carboxamide ribonucleotide; AMPK: AMP-activated protein kinase; ATG: autophagy-related; ATM: ataxia telangiectasia mutated; ATR: ATM serine/threonine kinase; AV: autophagic vacuole; AVd: degradative autophagic vacuole; AVi: initial autophagic vacuole; BECN1: beclin 1; BSA: bovine serum albumin; CBS: cystathionine beta-synthase; CDK7: cyclin dependent kinase 7; CDKN1A: cyclin dependent kinase inhibitor 1A; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GST: glutathione S transferase; H2AX/H2AFX: H2A.X variant histone; HBSS: Hanks balanced salt solution; IP: immunopurification; IR: ionizing radiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K9: mitogen-activated protein kinase kinase kinase 9; mRFP: monomeric red fluorescent protein; mCh: mCherry; MCM7: minichromosome maintenance complex component 7; MTORC1: mechanistic target of rapamycin kinase complex 1; NHEJ: non-homologous end joining; NRBP2: nuclear receptor binding protein 2; NTC: non-targeting control; NUAK1: NUAK family kinase 1; PBS: phosphate-buffered saline; PIK3AP1: phosphoinositide-3-kinase adaptor protein 1; PIK3CA: phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha; PIKK: phosphatidylinositol 3-kinase-related kinase; PRKAA: protein kinase AMP-activated catalytic subunit alpha; PRKAB: protein kinase AMP-activated non-catalytic subunit beta; PRKAG: protein kinase AMP-activated non-catalytic subunit gamma; PRKDC: protein kinase, DNA-activated, catalytic subunit; RLuc: Renilla luciferase; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TP53: tumor protein p53; TSKS: testis specific serine kinase substrate; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild type.

Educational level and first-time PSA testing in general practice.

Introduction: Different patterns in the use of prostate-specific antigen (PSA) testing might explain socioeconomic differences in prostate cancer incidence and mortality. We examined the association between socioeconomic position, measured as education and first-time PSA testing in general practice.Material and Methods: A population-based cohort study of men aged 45-79 years without prior prostate cancer diagnosis living in the Capital Region of Denmark between 2000 and 2014. Information on socioeconomic indicators (education, income, cohabitation status and work market affiliation), prostate cancer diagnoses, and vital status were obtained from national registries. Date of first PSA test was obtained from the Copenhagen Primary Care Laboratory database. Temporal trends of PSA testing were calculated as annual age-standardised incidence rates and the association was examined by a multivariable Cox proportional hazards model.Results: The cohort consists of 431,997 men of which 105,476 (24%) had a first-time PSA test in the study period. Men with longer education, higher income, living with a partner, and employed had higher rates of PSA testing. For men with short education, the rate of PSA test was 28.3 tests per 1000 person-years compared to 31.2 tests among men with long education. The fully adjusted hazard ratio for a first PSA test among men with short education was 0.87 (95% CI, 0.85-0.89) compared to men with long education.Conclusion: The association between education and first-time PSA testing indicates socioeconomic disparities in health care utilisation, which could explain part of the observed socioeconomic difference in prostate cancer incidence and mortality.

Does HPV status influence survival after vulvar cancer?

High-risk human papillomavirus (HPV) infection is essential in the carcinogenesis of a substantial part of anogenital and oropharyngeal cancers and has additionally been shown to be a possible predictive marker for survival, especially in oropharyngeal cancer. Studies examining the influence of HPV status on survival after vulvar cancer have been conflicting and limited by small study populations. Therefore, the aim of this review and meta-analysis was to examine whether HPV status influences survival after vulvar cancer, which, to our knowledge, has not been done before. We conducted a systematic search of PubMed, Cochrane Library and Embase to identify studies examining survival after histologically verified and HPV tested vulvar cancer. A total of 18 studies were eligible for inclusion. Study-specific and pooled HRs of the 5-year OS and DFS were calculated using a fixed effects model. The I2 statistic was used to describe heterogeneity. The studies included a total of 1,638 women with HPV tested vulvar cancers of which 541 and 1,097 were HPV-positive and HPV-negative, respectively. Fifteen studies included only squamous cell carcinomas. We found a pooled HR of 0.61 (95% CI: 0.48-0.77) and 0.75 (95% CI: 0.57-1.00) for 5-year OS and DFS, respectively. Across study heterogeneity was moderate to high (OS: I2 = 51%; DFS: I2 = 73%). In conclusion, women with HPV-positive vulvar cancers have a superior survival compared to women with HPV-negative, which could be of great clinical interest and provides insight into the differences in the natural history of HPV-positive and negative vulvar cancers.

Progressive strength training to prevent LYmphoedema in the first year after breast CAncer - the LYCA feasibility study.

BACKGROUND: Lymphoedema is a common late effect after breast cancer (BC) that has no effective cure once chronic. Accumulating evidence supports progressive strength training (PRT) as a safe exercise modality in relation to the onset and exacerbation of lymphoedema. In the 'preventive intervention against LYmphoedema after breast CAncer' (LYCA) feasibility study we examined the feasibility of a program of PRT in the first year after BC to inform a planned randomised controlled trial (RCT). MATERIAL AND METHODS: LYCA was a one-group prospective pilot trial inviting women operated with axillary lymph node dissection for unilateral primary BC. Participants exercised three times a week for 50 weeks (20 weeks supervised followed by 30 weeks home-based exercise). The program ensured slow individualised progression during the exercise program. The primary outcome was feasibility measured by eligibility and recruitment rates, as well as questionnaire-assessed satisfaction and adherence to exercise. Furthermore, we assessed arm interlimb volume difference by water displacement, muscle strength by dynamic and isometric muscle testing and range of movement in the shoulder by goniometry. RESULTS: In August 2015, eight of 11 eligible patients accepted participation. Two of them dropped out early due to other health issues. The remaining six participants had high exercise adherence through the supervised period, but only three maintained this through the home exercise period. Program satisfaction was high and no serious adverse events from testing or exercising were reported. One participant presented with lymphoedema at 50-week follow-up. Muscle strength markedly increased with supervised exercise, but was not fully maintained through the home exercise period. Range of shoulder movement was not negatively affected by the program. CONCLUSION: Recruitment, testing, and exercise in LYCA was safe and feasible. At the 50-week follow-up, there was one case of lymphoedema. The LYCA program will be further tested in a full-scale RCT.

Evaluation of a digital method to assess evening meal intake in a free-living adult population.

BACKGROUND: In recent years new applications of technologies, including digital images, to capture dietary behaviour in real time have been explored. OBJECTIVES: To validate a digital method for estimating evening meal intake in a free-living adult population, and to examine the feasibility of the method for recording evening meal intake over a prolonged period of time. DESIGN: The digital method was compared against weighed records of 19 participants' usual evening meals for five consecutive days. Two trained image analysts independently estimated the weight of individual foods within the meals into major food categories, and the nutrient content was calculated. A second study included interviews with 28 participants recording their evening meals on weekdays for three consecutive weeks to get their perspective on the feasibility of the method. RESULTS: High correlation coefficients between the digital method and weighed records were found for all measured food categories and nutrients. Comparable means and acceptable limits of agreement (mean difference +/- 2 SD) were found with regard to macronutrient distribution (e.g. fat content -5 to 6 E%), energy density (-75 to 91 kJ/100 g), and energy-adjusted foods (e.g. fruit and vegetable content -241 to 236 g/10 MJ). The majority of the participants expressed satisfaction with the method and were willing to record their evening meals for 1 month or more using the digital method. CONCLUSION: The digital method is valid and feasible for evening meal estimation in real-time where a prolonged recording period of participants' meals is needed.