Åslaug Helland - Academia.edu (original) (raw)

Papers by Åslaug Helland

Clinical and Translational Radiation Oncology, Jun 1, 2017

To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deo... more To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (18 F-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 18 F-FDG PET before, during, and after treatment. A total of 57 18 F-FDG PET scans were analyzed. Pulmonary 18 F-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 (SUV 0) and a response slope (DSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung 18 F-FDG dose response parameters were further investigated. Results: From the dose response analysis, SUV 0 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, SUV 0 at posttherapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in DSUV were seen with treatments or time. SUV 0 was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine CC motif ligand 21 (CCL21) for patients receiving RT + erlotinib. Conclusions: Concomitant RT and erlotinib causes an elevation in pulmonary 18 F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions.

Acta Oncologica, Aug 29, 2017

Background: 18 F-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG-PET) may be used fo... more 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 (l) and standard deviation (r) maps were calculated based on cubes in the lung (3 Â 3 Â 3 voxels), where the spread in pre-therapy l and r was characterized by a covariance ellipse in a sub-volume of 3 Â 3 Â 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 (DS) and mean difference maps (Dl) were calculated by subtracting pre-therapy maps from maps at mid-and post-therapy. Corresponding maps based on CT images were also generated. Results: DS identified new areas of interest in the lung compared to conventional Dl maps. DS 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 DS between pre-and post-therapy for 18 F-FDG-PET was the only parameter significantly associated with local lung dose (p ¼ .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.

Radiotherapy and Oncology, 2014

Molecular Imaging and Biology, Jun 18, 2018

Purpose: To map functional bone marrow (BM) by 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) pos... more Purpose: To map functional bone marrow (BM) by 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]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 [ 18 F]FDG PET before, during, and after treatment. A total of 61 [ 18 F]FDG PET scans were analyzed. Vertebral column BM [ 18 F]FDG standardized uptake value normalized to the liver (SUV BMLR) was used as uptake measure. Wilcoxon signed-rank test was used to assess changes in BM uptake of [ 18 F]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 [ 18 F]FDG was observed within the vertebral column prior to treatment. Mean SUV BMLR (± 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 SUV BMLR was observed from pre-to both mid-and post-therapy (p G 0.05). Mean SUV BMLR was significantly higher at post-therapy compared to midtherapy for patients receiving erlotinib in addition to RT (p G 0.05). Conclusions: RT reduces BM [ 18 F]FDG uptake in the vertebral column, especially in the highdose region. Concomitant erlotinib may stimulate a recovery in BM [ 18 F]FDG uptake from mid-to post-therapy. Trial registration: NCT02714530. Registered 10 September 2015.

Advances in radiation oncology, Apr 1, 2018

Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tiss... more 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 (18 F-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

Journal of Cancer Survivorship

Purpose Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related... more Purpose Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related quality of life of survivors. Knowledge on long-term late effects after radiotherapy (RT) and potential underlying biological mechanisms is lacking. We assessed the prevalence of xerostomia, dysphagia, and chronic fatigue (CF) in HNC survivors ≥ 5 years post-RT, and examined associations between pro-inflammatory cytokines and late effects. Methods In a cross-sectional study, 263 HNC survivors treated between 2007 and 2013 were enrolled. They completed validated questionnaires assessing xerostomia and dysphagia (the EORTC QLQ-H&N35), and CF (the Fatigue Questionnaire), and underwent blood sampling and clinical examination. Pro-inflammatory cytokines were analyzed in 262 survivors and 100 healthy age- and gender-matched controls. Results Median time since treatment was 8.5 years. The proportions of survivors reporting xerostomia, dysphagia, and CF were 58%, 31%, and 33%, respectively, wit...

Cancer Research Communications

Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognost... more Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry–based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium–specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM modul...

BMC Cancer, 2021

Background Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutation... more Background Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes. Methods Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, a...

Scandinavian Journal of Immunology, 2020

The analysis of tumour‐associated macrophages (TAMs) has a high potential to predict cancer recur... more The analysis of tumour‐associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan‐macrophage markers (CD14 and CD68) as well as some suggested markers for tumour‐promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non–small cell lung cancer (NSCLC). Tumour, non‐cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan‐macrophage marker although careful selection of antibody was found to be critical. The widely used anti‐CD68 antibody clone KP‐1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane ...

Radiotherapy and Oncology, 2019

Journal of Thoracic Oncology, 2018

Molecular oncology, Jan 15, 2018

B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in se... more B-cell translocation gene 2 (BTG2) is a tumour suppressor protein 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 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour 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, 1.51-2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correl...

British Journal of Cancer, 1998

Several studies have focused on the role of p53 inactivation in cervical cancer, either by inacti... more Several studies have focused on the role of p53 inactivation in cervical cancer, either by inactivating mutations in the TP53 gene or by degradation of the p53 protein by human papillomavirus (HPV). In this study, primary cervical carcinomas from 365 patients were analysed for presence of HPV using both consensus primer-sets and type-specific primer-sets. Nineteen samples were determined to have no or low virus load, and were selected for further analyses: mutation screening of the TP53 gene using constant denaturant gel electrophoresis (CDGE) followed by sequencing, and protein expression of p53, MDM2 and p21 using immunohistochemistry (IHC). Mutations in the TP53 gene were found in eight samples (42%0/). Elevated p53 protein expression was significantty associated with presence of a mutation (P < 0.007). P21 protein expression was detected in 16 of the 19 carcinomas. No p21 expression was seen in normal cervical tissue. Two samples, both with wild-type p53, had elevated MDM2 expression. Compared with a previous study from our group, of mainly HPV-positive cervical carcinomas, in which only one sample was found to contain a TP53 mutation, a significantly higher mutation frequency (P < 0.001) was found among the carcinomas with no or low virus load. Although p53 inactivation pathways are not detected in every tumour, our study supports the hypothesis that p53 inactivation, either by binding to cellular or viral proteins or by mutation, is essential in the development of cervical carcinomas.

Oncotarget, Jan 30, 2016

Breast cancer patients with Luminal A disease generally have a good prognosis, but among this pat... more Breast cancer patients with Luminal A disease generally have a good prognosis, but among this patient group are patients with good prognosis that are currently overtreated with adjuvant chemotherapy, and also patients that have a bad prognosis and should be given more aggressive treatment. There is no available method for subclassification of this patient group. Here we present a DNA methylation signature (SAM40) that segregates Luminal A patients based on prognosis, and identify one good prognosis group and one bad prognosis group. The prognostic impact of SAM40 was validated in four independent patient cohorts. Being able to subdivide the Luminal A patients may give the two-sided benefit of identifying one subgroup that may benefit from a more aggressive treatment than what is given today, and importantly, identifying a subgroup that may benefit from less treatment.

International journal of cancer, Sep 15, 2016

Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast ca... more Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary in order to identify relevant and robust signatures of invasive disease. We have identified miRNA alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings. We analysed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed. We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include dow...

British Journal of Cancer, 1995

Primary carcinomas from 46 patients were screened for TP53 alterations. Immunohistochemistry demo... more Primary carcinomas from 46 patients were screened for TP53 alterations. Immunohistochemistry demonstrated nuclear TPS3 protein accumulation in 22 (48%) cases using the polyclonal CM1 antiserum, whereas 15 (33%) cases showed positive nuclear staining with the mononuclear antibody PAb 1801. Constant denaturant gel electrophoresis (CDGE) was used to screen 27 of the vaginal carcinomas for mutations in the conserved regions of the TP53 gene (exons 5-8). Six of these tumours (22%) contained mutations: four were found in exon 5 and two in exon 8. A total of 50% of the primary vaginal carcinomas carried a TP53 alteration. These results indicate that TP53 abnormalities may be involved in the development of these tumours. However, there was no significant association between TP53 abnormalities and survival.

Clinical Cancer Research, 2015

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, wh... more Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical...

Cell Reports, 2014

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge ... more Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre-and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre-and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

Genome Biology, 2014

Background: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carci... more Background: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.