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Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.

4 min 25 sek siden
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Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.

Lancet Oncol. 2017 Sep 08;:

Authors: Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, Giannone V, D'Amelio AM, Zhang P, Mookerjee B, Johnson BE

Abstract
BACKGROUND: BRAF(V600E) mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAF(V600E)-mutant metastatic NSCLC.
METHODS: In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAF(V600E)-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634.
FINDINGS: Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).
INTERPRETATION: Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF(V600E)-mutant NSCLC.
FUNDING: Novartis.

PMID: 28919011 [PubMed - as supplied by publisher]

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

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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 - indexed for MEDLINE]

Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.

tir, 09/19/2017 - 09:30
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Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.

Nat Genet. 2017 Jan;49(1):65-74

Authors: Weischenfeldt J, Dubash T, Drainas AP, Mardin BR, Chen Y, Stütz AM, Waszak SM, Bosco G, Halvorsen AR, Raeder B, Efthymiopoulos T, Erkek S, Siegl C, Brenner H, Brustugun OT, Dieter SM, Northcott PA, Petersen I, Pfister SM, Schneider M, Solberg SK, Thunissen E, Weichert W, Zichner T, Thomas R, Peifer M, Helland A, Ball CR, Jechlinger M, Sotillo R, Glimm H, Korbel JO

Abstract
Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

PMID: 27869826 [PubMed - indexed for MEDLINE]

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

fre, 09/08/2017 - 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 Jul 01;141(1):184-190

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 untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined 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.

PMID: 28387924 [PubMed - indexed for MEDLINE]

A new method to assess pulmonary changes using (18)F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

tor, 09/07/2017 - 09:30

A new method to assess pulmonary changes using (18)F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

Acta Oncol. 2017 Aug 29;:1-7

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

Abstract
BACKGROUND: (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on (18)F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients.
MATERIAL AND METHODS: Sixteen patients with lung cancer undergoing fractionated RT were examined by (18)F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (μ) and standard deviation (σ) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy μ and σ was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (ΔS) and mean difference maps (Δμ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated.
RESULTS: ΔS identified new areas of interest in the lung compared to conventional Δμ maps. ΔS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that ΔS between pre- and post-therapy for (18)F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04).
CONCLUSIONS: The new method using local structures on (18)F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity.

PMID: 28849707 [PubMed - as supplied by publisher]

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.

ons, 08/30/2017 - 09:30
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The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.

PLoS One. 2017;12(7):e0181527

Authors: Al-Saad S, Richardsen E, Kilvaer TK, Donnem T, Andersen S, Khanehkenari M, Bremnes RM, Busund LT

Abstract
INTRODUCTION: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.
MATERIALS AND METHODS: Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.
RESULTS: In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).
CONCLUSION: MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

PMID: 28742836 [PubMed - in process]

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

ons, 07/26/2017 - 09:30

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]

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]