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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

23 min 22 sek siden
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun. 2018 Aug 13;9(1):3221

Authors: Ji X, Bossé Y, Landi MT, Gui J, Xiao X, Qian D, Joubert P, Lamontagne M, Li Y, Gorlov I, de Biasi M, Han Y, Gorlova O, Hung RJ, Wu X, McKay J, Zong X, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden EHFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty J, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Manz J, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Artigas MS, Tobin MD, Wain LV, Gu F, Byun J, Kamal A, Zhu D, Tyndale RF, Wei WQ, Chanock S, Brennan P, Amos CI

Abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID: 30104567 [PubMed - in process]

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

ons, 08/15/2018 - 09:30
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Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Eur J Cardiothorac Surg. 2018 Jan 01;53(1):221-227

Authors: Bugge AS, Lund MB, Valberg M, Brustugun OT, Solberg S, Kongerud J

Abstract
OBJECTIVES: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death.
METHODS: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions.
RESULTS: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate.
CONCLUSIONS: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

PMID: 28950311 [PubMed - indexed for MEDLINE]

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

tir, 08/07/2018 - 10:00
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Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Acta Oncol. 2018 Aug 03;:1-6

Authors: Kristensen A, Solheim TS, Fløtten Ø, Grønberg BH

Abstract
BACKGROUND: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.
MATERIAL AND METHODS: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).
RESULTS: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).
CONCLUSIONS: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

PMID: 30074418 [PubMed - as supplied by publisher]

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

lør, 08/04/2018 - 09:30
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Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Int J Epidemiol. 2018 Jul 28;:

Authors: Kachuri L, Saarela O, Bojesen SE, Davey Smith G, Liu G, Landi MT, Caporaso NE, Christiani DC, Johansson M, Panico S, Overvad K, Trichopoulou A, Vineis P, Scelo G, Zaridze D, Wu X, Albanes D, Diergaarde B, Lagiou P, Macfarlane GJ, Aldrich MC, Tardón A, Rennert G, Olshan AF, Weissler MC, Chen C, Goodman GE, Doherty JA, Ness AR, Bickeböller H, Wichmann HE, Risch A, Field JK, Teare MD, Kiemeney LA, van der Heijden EHFM, Carroll JC, Haugen A, Zienolddiny S, Skaug V, Wünsch-Filho V, Tajara EH, Ayoub Moysés R, Daumas Nunes F, Lam S, Eluf-Neto J, Lacko M, Peters WHM, Le Marchand L, Duell EJ, Andrew AS, Franceschi S, Schabath MB, Manjer J, Arnold S, Lazarus P, Mukeriya A, Swiatkowska B, Janout V, Holcatova I, Stojsic J, Mates D, Lissowska J, Boccia S, Lesseur C, Zong X, McKay JD, Brennan P, Amos CI, Hung RJ

Abstract
Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.
Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.
Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.
Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

PMID: 30059977 [PubMed - as supplied by publisher]

Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies.

tir, 07/31/2018 - 09:30
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Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies.

J Thorac Oncol. 2017 Dec;12(12):1755-1765

Authors: Meyer M, Vliegenthart R, Henzler T, Buergy D, Giordano FA, Kostrzewa M, Rathmann N, Brustugun OT, Crino L, Dingemans AC, Dusmet M, Fennell D, Grunenwald D, Huber RM, Moniuszko M, Mornex F, Papotti M, Pilz L, Senan S, Syrigos K, Pérol M, Gray JE, Schabel C, van Meerbeeck JP, van Zandwijk N, Zhou CC, Manegold C, Voigt W, Roessner ED

Abstract
Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.

PMID: 28962947 [PubMed - indexed for MEDLINE]

Substantial nation-wide improvement in lung cancer relative survival in Norway from 2000 to 2016.

tor, 07/26/2018 - 09:30
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Substantial nation-wide improvement in lung cancer relative survival in Norway from 2000 to 2016.

Lung Cancer. 2018 Aug;122:138-145

Authors: Brustugun OT, Grønberg BH, Fjellbirkeland L, Helbekkmo N, Aanerud M, Grimsrud TK, Helland Å, Møller B, Nilssen Y, Strand TE, Solberg SK

Abstract
INTRODUCTION: There have been significant changes in both diagnostic procedures and therapy for lung cancer since the beginning of the millennium. National incidence and survival data from 2000 through 2016 are studied.
METHODS: National data on cancer incidence and vital status are virtually complete. Changes in incidence and survival are described by absolute numbers, percentages, and calculation of relative survival (period analysis).
RESULTS: A total of 44,825 individuals were diagnosed with lung cancer in Norway in the study period. The number of incident cases increased with 49% whereas the prevalence increased with 136% from 2000 to 2016. Age-standardised rates rose markedly for women and levelled off for men. In 2016, adenocarcinoma accounted for about 50% of all lung cancers, slightly more for women than for men. The entity "NSCLC not otherwise specified" declined from 24% to 13%, and the fraction of patients with metastatic disease decreased from 54% to 46% during the period, for both sexes combined. The overall median survival time doubled for women and men, reaching 14.3 months and 11.4 months, respectively. For patients with metastatic disease, median survival time showed a small increase but remained less than 6 months. The overall 5-year relative survival increased from 16% to 26% in women and from 16% to 22% in men. The corresponding improvements for the subgroup of non-surgically treated cases with localised disease, were up from 25% to more than 40% in females, and from 10% to almost 40% in males.
CONCLUSION: There have been notable changes in incidence patterns and a remarkable improvement in survival for lung cancer over the last 17 years, most markedly for patients without distant metastases at the time of diagnosis. Hopefully, survival will improve even more when immunotherapy is implemented.

PMID: 30032822 [PubMed - in process]

Mesothelioma diagnosis and prognosis, are we moving beyond histology and performance status towards circulating biomarkers?

tir, 07/24/2018 - 10:30

Mesothelioma diagnosis and prognosis, are we moving beyond histology and performance status towards circulating biomarkers?

J Thorac Dis. 2018 Jun;10(Suppl 17):S1956-S1961

Authors: Røe OD

PMID: 30023090 [PubMed]

Non-occupational exposure to asbestos is the main cause of malignant mesothelioma in women in North Jutland, Denmark.

tir, 07/24/2018 - 10:30

Non-occupational exposure to asbestos is the main cause of malignant mesothelioma in women in North Jutland, Denmark.

Scand J Work Environ Health. 2018 Jul 19;:

Authors: Panou V, Vyberg M, Meristoudis C, Hansen J, Bøgsted M, Omland Ø, Weinreich UM, Røe OD

Abstract
Objectives Diffuse malignant mesothelioma (MM) is mainly caused by asbestos inhalation. The malignancy is rare among women and studies of the prevalence and causative role of non-occupational asbestos exposure among women with MM are scarce. This observational study aimed to elucidate the asbestos exposure patterns among women with MM. Methods All histological and cytological specimens from women diagnosed with MM between 1974-2015 at the Institute of Pathology, Aalborg University Hospital in Denmark, were re-evaluated. Occupational and habitation information were obtained from Danish registries and medical journals based on record linkage via the unique person ID. The number of MM cases in each parish in the region of North Jutland was determined and the incidence density in parishes was used to calculate the spatial relative risk (RR) of MM among women. Results Diagnosis of MM was confirmed in 91 women. Exposure types were classified as occupational (9%), domestic (10%), environmental (22%), combination of domestic and environmental (34%) and unknown (25%). Twenty continuous parishes formed a MM "hotspot" around the asbestos-consuming industries in the city of Aalborg. Of these, the maximum RR was found in a parish housing an asbestos factory [RR 10.5, 95% confidence interval (CI) 5.5-19.4, environmental exposure in particular RR 2.9, 95% CI 0.7-6.1]. Conclusion Non-occupational asbestos exposure is the main cause of MM and may account for up to 66% of MM cases among women in North Jutland, Denmark.

PMID: 30025147 [PubMed - as supplied by publisher]

In vitro transformation of human bronchial epithelial cells by diesel exhaust particles: gene expression profiling and early toxic responses.

fre, 07/20/2018 - 09:30

In vitro transformation of human bronchial epithelial cells by diesel exhaust particles: gene expression profiling and early toxic responses.

Toxicol Sci. 2018 Jul 16;:

Authors: Rynning I, Neca J, Vrbova K, Libalova H, Rossner P, Holme JA, Gützkow KB, Afanou AKJ, Arnoldussen YJ, Hruba E, Skare Ø, Haugen A, Topinka J, Machala M, Mollerup S

Abstract
Occupational exposure to diesel exhaust may cause lung cancer in humans. Mechanisms include DNA-damage and inflammatory responses. Here, the potential of NIST SRM2975 diesel exhaust particles (DEP) to transform human bronchial epithelial cells (HBEC3) in vitro was investigated. Long-term exposure of HBEC3 to DEP led to increased colony growth in soft agar. Several DEP-transformed cell lines were established and based on the expression of epithelial-to-mesenchymal-transition (EMT) marker genes, one of them (T2-HBEC3) was further characterized. T2-HBEC3 showed a mesenchymal/fibroblast-like morphology, reduced expression of CDH1, and induction of CDH2 and VIM. T2-HBEC3 had reduced migration potential compared with HBEC3 and little invasion capacity. Gene expression profiling showed baseline differences between HBEC3 and T2-HBEC3 linked to lung carcinogenesis. Next, to assess differences in sensitivity to DEP between parental HBEC3 and T2-HBEC3, gene expression profiling was carried out after DEP short-term exposure. Results revealed changes in genes involved in metabolism of xenobiotics and lipids, as well as inflammation. HBEC3 displayed a higher steady state of IL1B gene expression and release of IL-1β compared with T2-HBEC3. HBEC3 and T2-HBEC3 showed similar susceptibility towards DEP-induced genotoxic effects. Liquid-chromatography-tandem-mass-spectrometry was used to measure secretion of eicosanoids. Generally, major prostaglandin species were released in higher concentrations from T2-HBEC3 than from HBEC3 and several analytes were altered after DEP-exposure. In conclusion, long-term exposure to DEP transformed human bronchial epithelial cells in vitro. Differences between HBEC3 and T2-HBEC3 regarding baseline levels and DEP-induced changes of particularly CYP1A1, IL-1β, PGE2 and PGF2α may have implications for acute inflammation and carcinogenesis.

PMID: 30010986 [PubMed - as supplied by publisher]

Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease.

tir, 07/17/2018 - 09:30
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Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease.

BMC Cancer. 2018 Jul 13;18(1):739

Authors: Berg J, Halvorsen AR, Bengtson MB, Taskén KA, Mælandsmo GM, Yndestad A, Halvorsen B, Brustugun OT, Aukrust P, Ueland T, Helland Å

Abstract
BACKGROUND: The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown.
METHODS: Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays.
RESULTS: Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status.
CONCLUSION: Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis.

PMID: 30005623 [PubMed - in process]

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

søn, 07/15/2018 - 09:30
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Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

Int Arch Occup Environ Health. 2018 Jul 03;:

Authors: Rosenberger A, Hung RJ, Christiani DC, Caporaso NE, Liu G, Bojesen SE, Le Marchand L, Haiman CA, Albanes D, Aldrich MC, Tardon A, Fernández-Tardón G, Rennert G, Field JK, Kiemeney B, Lazarus P, Haugen A, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Brunnsstöm H, Goodman GE, Doherty JA, Chen C, Teare MD, Wichmann HE, Manz J, Risch A, Muley TR, Johansson M, Brennan P, Landi MT, Amos CI, Pesch B, Johnen G, Brüning T, Bickeböller H, Gomolka M

Abstract
PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon.
METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes.
RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance.
CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

PMID: 29971594 [PubMed - as supplied by publisher]

Mapping Bone Marrow Response in the Vertebral Column by Positron Emission Tomography Following Radiotherapy and Erlotinib Therapy of Lung Cancer.

tor, 07/05/2018 - 09:30
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Mapping Bone Marrow Response in the Vertebral Column by Positron Emission Tomography Following Radiotherapy and Erlotinib Therapy of Lung Cancer.

Mol Imaging Biol. 2018 Jun 18;:

Authors: Abravan A, Eide HA, Løndalen AM, Helland Å, Malinen E

Abstract
PURPOSE: To map functional bone marrow (BM) by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) in the vertebral column of lung cancer patients prior to, during, and after treatment. Moreover, to identify radiation- and erlotinib-induced changes in the BM.
PROCEDURES: Twenty-six patients with advanced non-small cell lung cancer, receiving radiotherapy (RT) alone or concomitantly with erlotinib, were examined by [18F]FDG PET before, during, and after treatment. A total of 61 [18F]FDG PET scans were analyzed. Vertebral column BM [18F]FDG standardized uptake value normalized to the liver (SUVBMLR) was used as uptake measure. Wilcoxon signed-rank test was used to assess changes in BM uptake of [18F]FDG between sessions. Effects of erlotinib on the BM activity during and after treatment were assessed using Mann-Whitney U test.
RESULTS: A homogeneous uptake of [18F]FDG was observed within the vertebral column prior to treatment. Mean SUVBMLR (± S.E.M) in the body of thoracic vertebrae receiving a total RT dose of 10 Gy or higher was 0.64 ± 0.01, 0.56 ± 0.01, and 0.59 ± 0.01 at pre-, mid-, and post-therapy, respectively. A significant reduction in the mean SUVBMLR was observed from pre- to both mid- and post-therapy (p < 0.05). Mean SUVBMLR was significantly higher at post-therapy compared to mid-therapy for patients receiving erlotinib in addition to RT (p < 0.05).
CONCLUSIONS: RT reduces BM [18F]FDG uptake in the vertebral column, especially in the high-dose region. Concomitant erlotinib may stimulate a recovery in BM [18F]FDG uptake from mid- to post-therapy.
TRIAL REGISTRATION: NCT02714530. Registered 10 September 2015.

PMID: 29916117 [PubMed - as supplied by publisher]

Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy.

ons, 06/20/2018 - 09:30
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Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy.

Adv Radiat Oncol. 2018 Apr-Jun;3(2):130-138

Authors: Eide HA, Knudtsen IS, Sandhu V, Løndalen AM, Halvorsen AR, Abravan A, Kure EH, Bogsrud TV, Brustugun OT, Kyte JA, Malinen E, Helland Å

Abstract
Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (18F-FDG) positron emission tomography (PET).
Methods and materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUVmax) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated.
Results: The SUVmax decreased from baseline through midtherapy to posttherapy 18F-FDG PET/computed tomography (P = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUVmax, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 (P = .030) and CXCL6 (P = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 (P = .031), CXCL2 (P = .028), and interleukin-6 (P = .007) were positively correlated to the irradiated volume during the second week of treatment.
Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.

PMID: 29904737 [PubMed]

Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer.

lør, 06/16/2018 - 10:00
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Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer.

Hum Pathol. 2018 Jun 06;:

Authors: Rakaee M, Kilvaer TK, Dalen SM, Richardsen E, Paulsen EE, Hald SM, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund LT

Abstract
The presence of tumor-infiltrating lymphocytes (TILs) positively impacts the outcome of non-small cell lung cancer (NSCLC) patients. Most previous studies have assessed TILs using different immunohistochemical assays. The purpose of this study was to develop and validate a histopathological scoring model for the assessment of TILs in whole tissue hematoxylin and eosin (H&E)-stained section slides of NSCLC patients and to evaluate the model in an immunoscore setting. Therefore, TIL was evaluated manually on H&E slides from 537 surgical specimens of primary resected stage I-III NSCLC patients. Using stromal TIL-score as a stepwise discrete variable, increasing survival was seen with rising TIL level: disease-specific survival (DSS; P=.008), overall survival (P=.036) and disease-free survival (P=.006). Subgroup analysis revealed that high stromal TILs level was associated with superior DSS (P=.047) in patients with squamous cell carcinoma, but not in patients with adenocarcinoma. Multivariable analysis confirmed that high TIL levels independently predict improved prognosis for all endpoints in the overall cohort. In conclusion, high stromal TIL level is an independent favorable prognostic factor in stage I-III NSCLC patients. The comprehensive histological evaluation conducted in this study may be helpful in streamlining TIL quantification for routine clinical use in a future NSCLC-immunoscore setting.

PMID: 29885403 [PubMed - as supplied by publisher]

Muscle mass and association to quality of life in non-small cell lung cancer patients.

søn, 06/10/2018 - 09:30
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Muscle mass and association to quality of life in non-small cell lung cancer patients.

J Cachexia Sarcopenia Muscle. 2017 Oct;8(5):759-767

Authors: Bye A, Sjøblom B, Wentzel-Larsen T, Grønberg BH, Baracos VE, Hjermstad MJ, Aass N, Bremnes RM, Fløtten Ø, Jordhøy M

Abstract
BACKGROUND: Cancer wasting is characterized by muscle loss and may contribute to fatigue and poor quality of life (QoL). Our aim was to investigate associations between skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) and selected QoL outcomes in advanced non-small cell lung cancer (NSCLC) at diagnosis.
METHODS: Baseline data from patients with stage IIIB/IV NSCLC and performance status 0-2 enrolled in three randomized trials of first-line chemotherapy (n = 1305) were analysed. Associations between SMI (cm2 /m2 ) and SMD (Hounsfield units) based on computed tomography-images at the third lumbar level and self-reported physical function (PF), role function (RF), global QoL, fatigue, and dyspnoea were investigated by linear regression using flexible non-linear modelling.
RESULTS: Complete data were available for 734 patients, mean age 65 years. Mean SMI was 47.7 cm2 /m2 in men (n = 420) and 39.6 cm2 /m2 in women (n = 314). Low SMI values were non-linearly associated with low PF and RF (men P = 0.016/0.020, women P = 0.004/0.012) and with low global QoL (P = 0.001) in men. Low SMI was significantly associated with high fatigue (P = 0.002) and more pain (P = 0.015), in both genders, but not with dyspnoea. All regression analyses showed poorer physical outcomes below an SMI breakpoint of about 42-45 cm2 /m2 for men and 37-40 cm2 /m2 for women. In both genders, poor PF and more dyspnoea were significantly associated with low SMD.
CONCLUSIONS: Low muscle mass in NSCLC negatively affects the patients' PF, RF, and global QoL, possibly more so in men than in women. However, muscle mass must be below a threshold value before this effect can be detected.

PMID: 28493418 [PubMed - indexed for MEDLINE]

A gender specific improved survival related to stromal miR-143 and miR-145 expression in non-small cell lung cancer.

lør, 06/09/2018 - 09:30
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A gender specific improved survival related to stromal miR-143 and miR-145 expression in non-small cell lung cancer.

Sci Rep. 2018 Jun 04;8(1):8549

Authors: Skjefstad K, Johannessen C, Grindstad T, Kilvaer T, Paulsen EE, Pedersen M, Donnem T, Andersen S, Bremnes R, Richardsen E, Al-Saad S, Busund LT

Abstract
Micro RNAs (miRNA) are small non-coding RNAs that post-transcriptionally regulate gene expression. Dysregulation of miRNA cluster 143/145 has been reported in several malignancies, but their role in non-small cell lung cancer (NSCLC) remains elusive. This study investigates the prognostic impact of miR-143 and miR-145 in primary tumors and metastatic lymph nodes in NSCLC tissue. Tissue from 553 primary tumors and 143 matched metastatic lymph nodes were collected and tissue microarrays were constructed. In situ hybridization was used to evaluate miR-143 and miR-145 expression in tumor epithelial cells and stromal cells in the primary tumors and lymph nodes. In vivo data was supplemented with functional studies of cell lines in vitro to evaluate the role of miR-143 and miR-145 in NSCLC tumorigenesis. In our cohort, stromal miR-143 (S-miR-143) and miR-145 (S-miR-145) expression in primary tumor tissue were independent prognosticators of improved disease-specific survival (DSS) in female (S-miR-143, HR: 0.53, p = 0.019) and male patients (S-miR-145, HR: 0.58, p = 0.021), respectively. Interesting correlations between the miR cluster 143/145 and previously investigated steroid hormone receptors from the same cohort were identified, substantiating their gender dependent significance.

PMID: 29867125 [PubMed - in process]

Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab.

ons, 06/06/2018 - 09:30
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Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab.

Acta Oncol. 2018 Apr 23;:1-7

Authors: Halvorsen AR, Sandhu V, Sprauten M, Flote VG, Kure EH, Brustugun OT, Helland Å

Abstract
BACKGROUND: The introduction of immune check-point inhibition in non-small cell lung cancer (NSCLC) therapy represents improved prospects for the patients. The response rates to check-point inhibitors are approximately 20% in unselected NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with higher response rates. However, patients with low PD-L1 levels may also have durable responses, and improved strategies for patient stratification are needed.
MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming to identify circulating predictive biomarkers associated with increased overall survival after immune check-point treatment. Using next generation sequencing, we performed microRNA profiling in serum from NSCLC patients (n = 20) treated with nivolumab. Serum samples from 31 patients were used for validation using qPCR assays. Serum samples were collected prior to immune therapy initiation.
RESULTS: Based on multivariate regression analysis, we identified a signature of seven microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p, miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) > 6 months in discovery cohort (p = .0003). We further validated this in another similar set of samples (n = 31) and the model was significantly associated with overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of 71% and 90%, respectively.
CONCLUSIONS: In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.

PMID: 29683761 [PubMed - as supplied by publisher]