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

59 min 43 sek siden
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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]

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

fre, 03/30/2018 - 09:30

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

Sci Rep. 2018 Mar 22;8(1):5059

Authors: Kiselev Y, Andersen S, Johannessen C, Fjukstad B, Standahl Olsen K, Stenvold H, Al-Saad S, Donnem T, Richardsen E, Bremnes RM, Rasmussen Busund LT

Abstract
Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC.

PMID: 29568088 [PubMed - in process]

The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

lør, 03/24/2018 - 08:30
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The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

J Thorac Oncol. 2017 Jul;12(7):1109-1121

Authors: Chansky K, Detterbeck FC, Nicholson AG, Rusch VW, Vallières E, Groome P, Kennedy C, Krasnik M, Peake M, Shemanski L, Bolejack V, Crowley JJ, Asamura H, Rami-Porta R, IASLC Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions

Abstract
INTRODUCTION: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons.
METHODS: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases.
RESULTS: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage.
CONCLUSIONS: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.

PMID: 28461257 [PubMed - indexed for MEDLINE]

Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer.

ons, 03/21/2018 - 09:00
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Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer.

PLoS One. 2018;13(2):e0192157

Authors: Kilvaer TK, Rakaee M, Hellevik T, Østman A, Strell C, Bremnes RM, Busund LT, Dønnem T, Martinez-Zubiaurre I

Abstract
OBJECTIVES: Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.
METHODS: Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.
RESULTS: Fibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.
CONCLUSIONS: The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.

PMID: 29415055 [PubMed - indexed for MEDLINE]

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

tir, 03/20/2018 - 15:00
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A new method to assess pulmonary changes using 18F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

Acta Oncol. 2017 Nov;56(11):1597-1603

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

Abstract
BACKGROUND: 18F-fluoro-2-deoxyglucose positron emission tomography (18F-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 18F-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 18F-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 18F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04).
CONCLUSIONS: The new method using local structures on 18F-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 - indexed for MEDLINE]

Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer.

lør, 03/03/2018 - 10:30
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Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer.

Oncotarget. 2016 11 01;7(44):72184-72196

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

Abstract
Recent data indicate that tumor-associated neutrophils (TANs) serve a dual role in tumor progression and regression. CD66b is a neutrophil marker and has been associated with patient outcome in various cancers. However, its clinical impact in non-small cell lung cancer (NSCLC) remains controversial. 536 NSCLC patients, of which 172 harbored lymph node metastases, were included in this study. Tissue microarrays were constructed and multiplexed immunohistochemistry of CD66b, CD34 and pan-keratin was performed to evaluate the localization and quantity of CD66b+ TANs. High intratumoral CD66b+ TANs density in squamous cell carcinoma (SCC) subgroup was an independent positive prognosticator for disease-specific survival (P = 0.038). In contrast, high intratumoral TANs density was an independent negative prognostic factor in the adenocarcinoma (ADC) subgroup (P= 0.032). Likewise, in ADC patients with lymph node metastases, high level of intratumoral TANs was associated with poor prognosis (P = 0.003). Stromal CD66b+ TANs were not associated with outcome of NSCLC patients. In conclusion, CD66b+ TANs show diverging prognostic effect in NSCLC patients according to histological subgroups. The presence of CD66b+ TANs could prove pivotal for development of an immunoscore in ADC NSCLC patients.

PMID: 27708229 [PubMed - indexed for MEDLINE]