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CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases.

20 min 22 sek siden

CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases.

Cancer Immunol Immunother. 2017 Jul 13;:

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

Abstract
The immune checkpoint receptor CTLA-4 plays a crucial part in negatively regulating T cell activation and maintaining self-tolerance. It is frequently overexpressed in a variety of malignancies, yet its prognostic impact in non-small cell lung cancer (NSCLC) remains unclear. We constructed tissue microarrays from tumor tissue samples and evaluated the immunohistochemical expression of CTLA-4 in 536 patients with primary resected stage I-IIIA NSCLC. Expression of CTLA-4 was analyzed in tumor and stromal primary tumor tissue and in locoregional metastatic lymph nodes. CTLA-4 expression in neither tumor epithelial cells (T-CTLA-4) nor stromal cells (S-CTLA-4) of primary tumors was significantly associated with disease-specific survival (DSS) in all patients. However, high S-CTLA-4 expression independently predicted significantly improved DSS in the squamous cell carcinoma subgroup (HR 0.62, 95% CI 0.41-0.93, P = 0.021). In contrast, there was an independent negative prognostic impact of T-CTLA-4 expression in metastatic lymph nodes (HR 1.65, 95% CI 1.03-2.65, P = 0.039). Our results indicate that the expression of CTLA-4 has diverging prognostic impacts in metastatic NSCLC lymph nodes versus primary tumors. The presented results highlight important differences in the tumor microenvironments of primary and metastatic NSCLC tissues, and have potential to guide treatment and clinical sampling strategies.

PMID: 28707078 [PubMed - as supplied by publisher]

NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors.

lør, 07/15/2017 - 09:30
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NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors.

Genes Cancer. 2017 Mar;8(3-4):497-504

Authors: McGowan M, Kleinberg L, Halvorsen AR, Helland Å, Brustugun OT

Abstract
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes. YAP was localized in the nucleus, indicative of active protein. siRNA-mediated silencing of YAP resulted in re-sensitizing the drug-resistant cells to EGFR TKI compared to the negative siRNA controls (p = <0.05). These results suggest YAP is a potential mechanism of EGFR-TKI resistance in NSCLC and may presents itself as a viable therapeutic target.

PMID: 28680534 [PubMed - in process]

Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer.

fre, 07/07/2017 - 09:30
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Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer.

Steroids. 2016 Sep;113:5-13

Authors: Skjefstad K, Grindstad T, Khanehkenari MR, Richardsen E, Donnem T, Kilvaer T, Andersen S, Bremnes RM, Busund LT, Al-Saad S

Abstract
Sex steroids and their receptors are important in the fetal development of normal lung tissue. In addition emerging evidence reveals their significance in lung cancer pathogenesis. This encourages the exploitation of hormone receptors as treatment targets in lung cancer, as it has been successfully used in breast cancer. This study investigates the prognostic impact of estrogen receptor (ER) α and β and the aromatase (AR) enzyme in non-small cell lung cancer (NSCLC) patients. Tumor tissue from 335 NSCLC patients was collected and tissue microarrays (TMAs) were constructed. Immunohistochemical analyses were performed to evaluate the expression of ERα, ERβ and AR in the cytoplasme and nuclei of cells in the tumor epithelial and stromal compartment. By use of survival statistics we investigated the markers impact on disease-specific survival (DSS). Nuclear ERβ expression in tumor epithelial cells in female patients (HR 3.03; 95% CI 1.39-6.61) and tumor cell AR expression in all patients (HR 1.55; 95% CI 1.08-2.23) were significant negative prognostic markers of disease-specific survival in our cohort. High ERβ expression correlates with worse outcome in female patients. Further, patients with high AR expression had an unfavorable prognostic outcome compared with patients expressing low AR levels. These results emphasize the importance of sex steroids role in NSCLC, and, as anti-hormonal drugs are widely available, could lead to the development of novel palliative or even adjuvant treatment strategies in this patient population.

PMID: 27234503 [PubMed - indexed for MEDLINE]

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

tor, 07/06/2017 - 09:30

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Nat Genet. 2017 Jun 12;:

Authors: McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, Caporaso NE, Johansson M, Xiao X, Li Y, Byun J, Dunning A, Pooley KA, Qian DC, Ji X, Liu G, Timofeeva MN, Bojesen SE, Wu X, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, 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 CA, Wilkens LR, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden HFM, 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 JA, Barnett MP, Chen C, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Wichmann HE, Manz J, Muley TR, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd FA, 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 RS, McLaughlin J, Stevens VL, Joubert P, Lamontagne M, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Kachuri L, Artigas MS, Tobin MD, Wain LV, SpiroMeta Consortium, Rafnar T, Thorgeirsson TE, Reginsson GW, Stefansson K, Hancock DB, Bierut LJ, Spitz MR, Gaddis NC, Lutz SM, Gu F, Johnson EO, Kamal A, Pikielny C, Zhu D, Lindströem S, Jiang X, Tyndale RF, Chenevix-Trench G, Beesley J, Bossé Y, Chanock S, Brennan P, Landi MT, Amos CI

Abstract
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

PMID: 28604730 [PubMed - as supplied by publisher]

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

tir, 06/13/2017 - 09:30
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Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

PLoS One. 2017;12(6):e0177875

Authors: Carreras-Torres R, Johansson M, Haycock PC, Wade KH, Relton CL, Martin RM, Davey Smith G, Albanes D, Aldrich MC, Andrew A, Arnold SM, Bickeböller H, Bojesen SE, Brunnström H, Manjer J, Brüske I, Caporaso NE, Chen C, Christiani DC, Christian WJ, Doherty JA, Duell EJ, Field JK, Davies MPA, Marcus MW, Goodman GE, Grankvist K, Haugen A, Hong YC, Kiemeney LA, van der Heijden EHFM, Kraft P, Johansson MB, Lam S, Landi MT, Lazarus P, Le Marchand L, Liu G, Melander O, Park SL, Rennert G, Risch A, Haura EB, Scelo G, Zaridze D, Mukeriya A, Savić M, Lissowska J, Swiatkowska B, Janout V, Holcatova I, Mates D, Schabath MB, Shen H, Tardon A, Teare MD, Woll P, Tsao MS, Wu X, Yuan JM, Hung RJ, Amos CI, McKay J, Brennan P

Abstract
BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.
METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results.
CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

PMID: 28594918 [PubMed - in process]

Implementation of lung cancer CT screening in the Nordic countries.

fre, 06/09/2017 - 09:30
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Implementation of lung cancer CT screening in the Nordic countries.

Acta Oncol. 2017 Jun 01;:1-9

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 - as supplied by publisher]

The presence of intraepithelial CD45RO+ cells in resected lymph nodes with metastases from NSCLC patients is an independent predictor of disease-specific survival.

fre, 06/09/2017 - 09:30
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The presence of intraepithelial CD45RO+ cells in resected lymph nodes with metastases from NSCLC patients is an independent predictor of disease-specific survival.

Br J Cancer. 2016 May 10;114(10):1145-51

Authors: Kilvaer TK, Paulsen EE, Khanehkenari MR, Al-Saad S, Johansen RM, Al-Shibli K, Bremnes RM, Busund LT, Donnem T

Abstract
BACKGROUND: Operable non-small cell lung cancer (NSCLC) patients whose tumours have spread to regional or central lymph nodes at the time of diagnosis have dismal prognoses compared with those who have limited disease. The current TNM staging system for NSCLC poorly distinguishes patients with lymph-node metastases who will succumb to, and those who will eventually be cured from, their disease. This novel study: (1) evaluates the presence of different subsets of intraepithelial tumour-infiltrating lymphocytes (TILs) in lymph nodes with metastases from NSCLC patients; (2) explores the impact of intraepithelial TILs in lymph nodes on survival; (3) correlates their presence with both intraepithelial and stromal TILs in their corresponding primary tumours.
METHODS: Metastatic lymph-node tissue from 143N+ NSCLC patients was collected and tissue microarrays were constructed. Immunohistochemistry was used to evaluate the presence of intraepithelial CD3+, CD4+, CD8+, CD20+ and CD45RO+ TILs and their impact on survival.
RESULTS: A high level of intraepithelial CD45RO+ TILs in lymph-node metastases from N+ NSCLC patients was an independent positive prognostic factor for disease-specific survival in all patients (HR=0.58, P=0.029) and in squamous cell carcinoma (HR=0.31, P=0.006), but not in adenocarcinoma patients.
CONCLUSIONS: The presence of intraepithelial CD45RO+ cells in lymph-node metastases from N+ NSCLC patients predicts favourable disease-specific survival and outperforms the established TNM staging system in the SCC subgroup.

PMID: 27167450 [PubMed - indexed for MEDLINE]

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

lør, 06/03/2017 - 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 May 10;:

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 (cm(2) /m(2) ) 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 cm(2) /m(2) in men (n = 420) and 39.6 cm(2) /m(2) 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 cm(2) /m(2) for men and 37-40 cm(2) /m(2) 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 - as supplied by publisher]

Trajectory of sleep disturbances in patients undergoing lung cancer surgery: a prospective study.

fre, 05/12/2017 - 09:30
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Trajectory of sleep disturbances in patients undergoing lung cancer surgery: a prospective study.

Interact Cardiovasc Thorac Surg. 2017 May 08;:

Authors: Halle IH, Westgaard TK, Wahba A, Oksholm T, Rustøen T, Gjeilo KH

Abstract
OBJECTIVES: Patients with lung cancer report sleep difficulties to be frequent and bothersome symptoms. This study describes the trajectory of sleep from before and up to 12 months after surgery for lung cancer. Further, it investigates possible associations between sleep disturbance, demographic and clinical characteristics before surgery.
METHODS: This study is part of a longitudinal multicentre study. Sleep disturbance was measured by The General Sleep Disturbance Scale (GSDS) that investigates frequencies of sleep difficulties (21 items) and a total sum score ≥43 indicates a clinically meaningful level of sleep disturbance (score range 0-147). Linear mixed models were used to study changes in sleep from baseline to 1, 5, 9 and 12 months after surgery.
RESULTS: The percentage of patients ( n  = 264) reporting sleep disturbances was 60.9% at baseline, 68.5% at Month 1, 55.4% at Month 5, 51.3% at Month 9 and 49.7% at Month 12. The increase to and decrease from Month 1 was the only significant alteration in the occurrence of sleep disturbance. The patients reported most problems within the subscales sleep quantity, early awakenings and sleep quality. Factors associated with sleep disturbance were lower age, use of pain medication and psychotropic medication and higher comorbidity score.
CONCLUSIONS: Lung cancer patients sleep poorly, before as well as after surgery. There is a need to address sleeping disturbance routinely in clinical practice and screening for sleeping problems is indicated. Further studies are warranted concerning factors that contribute to sleep disturbance and how they best can be treated.

PMID: 28486702 [PubMed - as supplied by publisher]

Transfer Between Hospitals Is a Risk Situation for Patients After Lung Cancer Surgery.

ons, 05/10/2017 - 09:30
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Transfer Between Hospitals Is a Risk Situation for Patients After Lung Cancer Surgery.

Cancer Nurs. 2017 Apr 20;:

Authors: Oksholm T, Rustoen T, Ekstedt M

Abstract
BACKGROUND: Patients with lung cancer often undergo surgery shortly after diagnosis. Despite undergoing extensive operation, many patients are transferred to a local hospital a few days after surgery. Transitions between different levels of care are risky due to common medication and follow-up errors.
OBJECTIVE: The study purpose was to explore patients' experiences of transfer between hospitals after lung cancer surgery. The study aim was to improve the quality of transitional care.
METHODS: In-depth interviews with 14 patients with lung cancer (6 men, 8 women) were conducted in the patients' homes. Interviews were audiotaped, transcribed, and analyzed using the hermeneutic analysis method.
RESULTS: Patients' experience of transfer between hospitals after lung cancer surgery is one of being in a caregiver gap characterized by feeling unprepared and uncertain, feeling unprotected and not being cared for, and suffering because of inadequate organization. Patients are vulnerable and at risk of injury before and during transfer, as well as after arrival at local hospitals.
CONCLUSIONS: Study findings highlight a rarely considered risk of inadequate care before, during, and after hospital transfer of vulnerable patients. Transition between hospitals after lung cancer surgery is a part of patient care for which there are no policies or care plans and a time during which the borders of responsibility between caregivers are unclear.
IMPLICATIONS FOR PRACTICE: It is important to develop guidelines for clearly defined responsibilities during transfer between hospitals. Healthcare providers need to plan transfers with the same rigor as they do hospital care.

PMID: 28426541 [PubMed - as supplied by publisher]

Copy number variation, increased gene expression and molecular mechanisms of Neurofascin in lung cancer.

fre, 04/21/2017 - 08:30

Copy number variation, increased gene expression and molecular mechanisms of Neurofascin in lung cancer.

Mol Carcinog. 2017 Apr 18;:

Authors: Erdem JS, Arnoldussen YJ, Skaug V, Haugen A, Zienolddiny S

Abstract
Metastasis and cell adhesion are key aspects of cancer progression. Neurofascin (NFASC) is a member of the immunoglobulin superfamily of adhesion molecules and, while studies on NFASC are inadequate, other members have been indicated pivotal roles in cancer progression and metastasis. This study aimed at increasing the knowledge on the involvement of adhesion molecules in lung cancer progression by studying the regulation and role of NFASC in non-small cell lung cancer (NSCLC). Here, copy number variations in the NFASC gene were analyzed in tumor and non-tumorous lung tissues of 204 NSCLC patients. Frequent gene amplifications (OR = 4.50, 95% CI: 2.27-8.92, P ≤ 0.001) and increased expression of NFASC (P = 0.034) were identified in tumors of NSCLC patients. Furthermore, molecular mechanisms of NFASC in lung cancer progression were evaluated by investigating the effects of NFASC silencing on cell proliferation, viability, migration and invasion using siRNA technology in four NSCLC cell lines. Silencing of NFASC did not affect cell proliferation or viability but rather decreased NCSLC cell migration (P ≤ 0.001) and led to morphological changes, rearrangements in the actin cytoskeleton and changes in F-actin networks in migrating NSCLC cell lines. This study is the first to report frequent copy number gain and increased expression of NFASC in NCSLC. Moreover, these data suggest that NFASC is a novel regulator of NSCLC cell motility and support a role of NFASC in the regulation of NSCLC progression. This article is protected by copyright. All rights reserved.

PMID: 28418179 [PubMed - as supplied by publisher]

High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.

ons, 04/19/2017 - 09:30
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High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.

Int J Cancer. 2017 Apr 07;:

Authors: Helland Å, Brustugun OT, Nakken S, Halvorsen AR, Dønnem T, Bremnes R, Busund LT, Sun J, Lorenz S, Solberg SK, Jørgensen LH, Vodak D, Myklebost O, Hovig E, Meza-Zepeda LA

Abstract
Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and UTRs of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined by using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (P<0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations. This article is protected by copyright. All rights reserved.

PMID: 28387924 [PubMed - as supplied by publisher]

Real-world data on nivolumab treatment of non-small cell lung cancer.

ons, 04/19/2017 - 09:30
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Real-world data on nivolumab treatment of non-small cell lung cancer.

Acta Oncol. 2017 Mar;56(3):438-440

Authors: Brustugun OT, Sprauten M, Helland Å

Abstract
BACKGROUND: Checkpoint inhibitors have proven effectiveness in clinical trials for non-small cell lung cancer (NSCLC) patients, but if this is congruent with routine patient care is discussed. We present real-world experience with the PD1-inhibitor nivolumab in NSCLC.
PATIENTS AND METHODS: Patients with NSCLC were considered eligible for nivolumab treatment after one or more lines of chemotherapy, and when in reasonable performance status (PS) [Eastern Cooperative Oncology Group (ECOG) < 3]. Treatment was given according to guidelines in the two phase III studies, CA209017 and CA209057. Response evaluation was done according to Recist 1.1, and treatment given until unequivocal progression or intolerable toxicity.
RESULTS: Fifty-eight patients (30 females) commenced therapy in the period June-August 2015. Median age was 64.6 years (range 32.3-88.2). Twenty-four patients had squamous cell carcinoma and 32 adenocarcinoma, 38 had received two or more prior lines of therapy. Fourteen cases (24%) were in ECOG PS 2. After a medium observation time of 14.3 months, 13 (22%) are still in treatment. Median time to treatment failure (TTF) was 4.0 months, 34% were off treatment during the first two months. Median overall survival (OS) is 11.7 months. There was no difference in TTF or OS among patients with squamous versus non-squamous histology or between 1 versus >1 prior line of therapy. Four patients (7%) were off treatment due to toxicity, none were grade 4 or 5.
CONCLUSION: Nivolumab treatment outside clinical trials seems to perform as expected.

PMID: 27892773 [PubMed - indexed for MEDLINE]

Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells.

lør, 04/08/2017 - 09:30
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Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells.

Toxicol In Vitro. 2016 Sep;35:55-65

Authors: Bersaas A, Arnoldussen YJ, Sjøberg M, Haugen A, Mollerup S

Abstract
Lung cancer is largely an environmentally caused disease with poor prognosis. An in vitro transformation model of human bronchial epithelial cells (HBEC) was used to study long-term effects of tobacco smoke carcinogens on epithelial-mesenchymal transition (EMT) and the forkhead box transcription factors FOXA1 and FOXA2. CDK4 and hTERT immortalized HBEC2 and HBEC12 cell lines were exposed weekly to either cigarette smoke condensate (CSC), benzo[a]pyrene, or methylnitrosourea. Transformed cell lines were established from soft-agar colonies after 12weeks of exposure. HBEC12 was transformed by all exposures while HBEC2 was only transformed by CSC. Untransformed HBEC2 showed little invasive capacity, whereas transformed cell lines completely closed the gap in a matrigel scratch wound assay. CDH1 was down-regulated in all of the transformed cell lines. In contrast, CDH2 was up-regulated in both HBEC2 and one of the HBEC12 transformed cell lines. Furthermore, transformed cells showed activation of EMT markers including SNAI1, ZEB1, VIM, and MMP2. All transformed cell lines had significant down-regulation of FOXA1 and FOXA2, indicating a possible role in cell transformation and EMT. ChIP analysis showed increased binding of Histone-H3 and macroH2A in FOXA1 and FOXA2 in the transformed HBEC2 cell lines, indicating a compact chromatin. In conclusion, long-term carcinogen exposure lead to down-regulation of FOXA1 and FOXA2 concomitantly with the occurrence of EMT and in vitro transformation in HBEC cells.

PMID: 27221058 [PubMed - indexed for MEDLINE]

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

ons, 04/05/2017 - 09:30
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Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

EBioMedicine. 2016 Sep;11:219-226

Authors: Chen LS, Baker T, Hung RJ, Horton A, Culverhouse R, Hartz S, Saccone N, Cheng I, Deng B, Han Y, Hansen HM, Horsman J, Kim C, Rosenberger A, Aben KK, Andrew AS, Chang SC, Saum KU, Dienemann H, Hatsukami DK, Johnson EO, Pande M, Wrensch MR, McLaughlin J, Skaug V, van der Heijden EH, Wampfler J, Wenzlaff A, Woll P, Zienolddiny S, Bickeböller H, Brenner H, Duell EJ, Haugen A, Brüske I, Kiemeney LA, Lazarus P, Le Marchand L, Liu G, Mayordomo J, Risch A, Schwartz AG, Teare MD, Wu X, Wiencke JK, Yang P, Zhang ZF, Spitz MR, Amos CI, Bierut LJ

Abstract
BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not.
METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium.
RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10(-10)). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype.
CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

PMID: 27543155 [PubMed - indexed for MEDLINE]