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

16 min 24 sek siden

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]

A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of All Ages and Exposure Types: A HUNT Study.

tir, 04/24/2018 - 09:30
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A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of All Ages and Exposure Types: A HUNT Study.

EBioMedicine. 2018 Mar 30;:

Authors: Markaki M, Tsamardinos I, Langhammer A, Lagani V, Hveem K, Røe OD

Abstract
Lung cancer causes >1·6 million deaths annually, with early diagnosis being paramount to effective treatment. Here we present a validated risk assessment model for lung cancer screening. The prospective HUNT2 population study in Norway examined 65,237 people aged >20years in 1995-97. After a median of 15·2years, 583 lung cancer cases had been diagnosed; 552 (94·7%) ever-smokers and 31 (5·3%) never-smokers. We performed multivariable analyses of 36 candidate risk predictors, using multiple imputation of missing data and backwards feature selection with Cox regression. The resulting model was validated in an independent Norwegian prospective dataset of 45,341 ever-smokers, in which 675 lung cancers had been diagnosed after a median follow-up of 11·6years. Our final HUNT Lung Cancer Model included age, pack-years, smoking intensity, years since smoking cessation, body mass index, daily cough, and hours of daily indoors exposure to smoke. External validation showed a 0·879 concordance index (95% CI [0·866-0·891]) with an area under the curve of 0·87 (95% CI [0·85-0·89]) within 6years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6years. Our model of seven variables is simple, accurate, and useful for screening selection.

PMID: 29678673 [PubMed - as supplied by publisher]

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

søn, 04/22/2018 - 09:30
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Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

Ann Oncol. 2018 Apr 14;:

Authors: Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J

Abstract
Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib.
Patients and methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2:1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary endpoint was investigator-assessed progression-free survival (PFS).
Results: Altogether, 107 patients were randomized (alectinib, n=72; chemotherapy, n=35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months (95% confidence interval [CI]: 6.9-12.2) with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy (hazard ratio 0.15 [95% CI: 0.08-0.29]; P<0.001). Independent Review Committee-assessed PFS was also significantly longer with alectinib (HR 0.32 [95% CI: 0.17-0.59]; median PFS was 7.1 months [95% CI: 6.3-10.8] with alectinib and 1.6 months [95% CI: 1.3-4.1] with chemotherapy). In patients with measurable baseline central nervous system (CNS) disease (alectinib, n=24; chemotherapy, n=16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P<0.001). Grade ≥3 adverse events (AEs) were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 versus 6.0 weeks).
Conclusion: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.
Trial registration: ClinicalTrials.gov NCT02604342; Roche study MO29750.

PMID: 29668860 [PubMed - as supplied by publisher]

A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer.

tor, 04/19/2018 - 09:30

A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer.

Mol Oncol. 2018 Apr 15;:

Authors: Shen S, Zhang R, Guo Y, Loehrer E, Wei Y, Zhu Y, Yuan Q, Moran S, Fleischer T, Bjaanaes MM, Karlsson A, Planck M, Staaf J, Helland Å, Esteller M, Su L, Chen F, Christiani DC

Abstract
B-cell translocation gene 2 (BTG2) is a tumor suppressor protein and is known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1,230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3,038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumor tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51 to 2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression positively correlated with survival in each cohort (HR range, 0.28 to 0.68), which we confirmed with meta-analysis (HR = 0.61, 95%CI: 0.54-0.68). The three CpG probes all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.

PMID: 29656435 [PubMed - as supplied by publisher]

Expression of Estrogen Receptor-α and Survival in Advanced-stage Non-small Cell Lung Cancer.

man, 04/16/2018 - 11:30
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Expression of Estrogen Receptor-α and Survival in Advanced-stage Non-small Cell Lung Cancer.

Anticancer Res. 2018 04;38(4):2261-2269

Authors: Lund-Iversen M, Scott H, Strøm EH, Theiss N, Brustugun OT, Grønberg BH

Abstract
BACKGROUND/AIM: The favorable prognosis of women with non-small-cell lung cancer (NSCLC) compared to men might be explained by sex hormone-related mechanisms. We investigated whether this observation could be explained by the expression of estrogen receptor-alpha (ER-α) in tumor tissue.
MATERIALS AND METHODS: Archived, formalin fixed, paraffin embedded tumor tissue samples were retrospectively analyzed for nuclear expression of ER-α with immunohistochemistry.
RESULTS: Biopsies from 222 patients were analyzed. Twenty-three percent were ER-α positive. Fifty-four percent of the patients were men and 46% of the tumors were adenocarcinomas. One hundred-nine (49%) patients received pemetrexed and carboplatin and 113 (51%) received gemcitabine and carboplatin. Females with ER-α positive tumors who received PC had a substantial survival benefit over all other groups (20 vs. 4.6 months; p=0.003).
CONCLUSION: ER-α is an independent prognostic factor in advanced NSCLC and might also be a predictive factor for response to pemetrexed/carboplatin in women.

PMID: 29599348 [PubMed - indexed for MEDLINE]

Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

fre, 04/13/2018 - 08:30
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Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

Clin Epigenetics. 2018;10:41

Authors: Wei Y, Liang J, Zhang R, Guo Y, Shen S, Su L, Lin X, Moran S, Helland Å, Bjaanæs MM, Karlsson A, Planck M, Esteller M, Fleischer T, Staaf J, Zhao Y, Chen F, Christiani DC

Abstract
Background: KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival.
Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.
Results: DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50, P = 1.1 × 10-4; HRcg26662347 = 1.88, 95%CI, 1.37-2.60, P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 for KDM2A, P = 1.3 × 10-10; cg26662347 for KDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.
Conclusions: These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

PMID: 29619118 [PubMed - in process]

Implementation of lung cancer CT screening in the Nordic countries.

fre, 04/06/2018 - 14:00
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Implementation of lung cancer CT screening in the Nordic countries.

Acta Oncol. 2017 Oct;56(10):1249-1257

Authors: Pedersen JH, Sørensen JB, Saghir Z, Fløtten Ø, Brustugun OT, Ashraf H, Strand TE, Friesland S, Koyi H, Ek L, Nyrén S, Bergman P, Jekunen A, Nieminen EM, Gudbjartsson T

Abstract
INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries.
MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening.
RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

PMID: 28571524 [PubMed - indexed for MEDLINE]

Assessment of pulmonary 18F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

lør, 03/31/2018 - 09:30
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Assessment of pulmonary 18F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

Clin Transl Radiat Oncol. 2017 Jun;4:57-63

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

Abstract
Purpose: To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) during and after treatment of non-small cell lung cancer (NSCLC) and to identify associations between serum cytokine levels and lung glucose uptake.
Material and methods: Twenty-seven patients with advanced NSCLC, receiving RT alone or concomitant RT and erlotinib therapy, were examined by 18F-FDG PET before, during, and after treatment. A total of 57 18F-FDG PET scans were analyzed. Pulmonary 18F-FDG uptake and radiotherapy dose mapping were used to acquire dose-response curves for each patient, where subsequent linear regression gave a glucose uptake level in the un-irradiated parts of the lungs (SUV0) and a response slope (ΔSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung 18F-FDG dose response parameters were further investigated.
Results: From the dose response analysis, SUV0 at post-therapy was significantly higher (P < 0.001) than at mid- and pre-therapy (45% and 58%, respectively) for the group receiving RT + erlotinib. Also, SUV0 at post-therapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in ΔSUV were seen with treatments or time. SUV0 was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine C-C motif ligand 21 (CCL21) for patients receiving RT + erlotinib.
Conclusions: Concomitant RT and erlotinib causes an elevation in pulmonary 18F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions.

PMID: 29594209 [PubMed]