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• Salamanca, Mar Fernandez; Houdt, Petra J. van; Hompland, Tord; Deręgowska-Cylke, Malgorzata; Leeuwen, Pim J. van & Poel, Henk G. van der [Vis alle 11 forfattere av denne artikkelen] (2025). Hypoxia and cribriform growth in prostate cancer – establishing a link via MRI. BMC Medical Imaging. 26(1). doi: 10.1186/s12880-025-02084-3. Fulltekst i vitenarkiv Vis sammendrag

  Background Prostate Cancer (PCa) is a heterogeneous disease, where hypoxia and cribriform growth have been established as adverse prognostic features. Hypoxia refers to a condition of limited oxygen concentration within the tumor microenvironment, associated with enhanced tumor aggressiveness, resistance to therapy, and poor clinical outcome. Likewise, cribriform growth has also been related to poor prognosis, though the biologic basis remains unclear. Recent pathological studies suggest that there is an association between cribriform growth and tumor hypoxia, but evidence from PCa patient studies are scarce. To fill this knowledge gap, this study aims to investigate the association between hypoxia measured by MR imaging and cribriform growth identified in whole-mount histological specimens. Methods A retrospective cohort of 291 patients with biopsy-confirmed PCa who underwent radical prostatectomy and pre-operative MRI was analyzed. Tumors were graded according to the 2019 ISUP classification, and cribriform growth presence and length were assessed on whole-mount histology. The oxygen consumption and supply based model using apparent diffusion coefficient and fractional blood volume was applied to estimate hypoxia level (HL) and hypoxia fraction (HFDWI). Differences in HL and HFDWI across Gleason patterns and between cribriform growth-positive and -negative tumors were assessed. Furthermore, a linear regression model was used to evaluate the association between cribriform growth and hypoxia after adjusting for confounders. Results Cribriform growth-positive tumors exhibited significantly higher HFDWI values compared to cribriform growth-negative tumors (p < 0.001). Within individual cancer Grade Groups (GG), cribriform growth length was significantly associated with increased HFDWI in pGG 3 tumors. HLmedian values were highest in Gleason Pattern 3 (GP3) regions and lowest in cribriform growth (GP4Crib+) regions, with significant differences observed between GP3 vs. non-cribriform growth GP4 regions (p < 0.001) and GP3 vs. GP4Crib+ (p < 0.001), consistent with more hypoxia in GP4Crib+. Multivariable regression confirmed cribriform growth presence as an independent predictor of increased hypoxia fraction, even after adjusting for tumor volume and GG. Conclusions This study shows an association between cribriform growth and tumor hypoxia using an MRI-based biomarker. These findings provide further biological insights into the aggressive nature of cribriform growth architecture and highlight the potential clinical utility of non-invasive hypoxia quantification for risk stratification in prostate cancer management.

• Skipar, Kjersti Øvrum; Hompland, Tord; Lund, Kjersti Vassmo; Fjeldbo, Christina Sæten; Lindemann, Kristina Yvonne Kathe & Hellebust, Taran Annette Paulsen [Vis alle 8 forfattere av denne artikkelen] (2025). Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: A phase II, randomized study. Acta Oncologica. ISSN 0284-186X. 64, s. 439–447. doi: 10.2340/1651-226X.2025.43045. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: Locally advanced cervical cancer is treated with chemoradiotherapy. The treatment-related morbidity is high. Tumor hypoxia has prognostic impact and represents a valid, interventional target. This phase II study investigated efficacy of the antidiabetic drug metformin to modify hypoxia according to established biomarkers. Preliminary results including tolerability, safety and feasibility are reported here. Patients and methods: Patients were included in a 1:1 randomized, open-label design, comparing standard chemoradiotherapy ± metformin. Metformin 850 mg twice daily was administered 1 week before and during chemoradiotherapy. Magnetic resonance images (MRI) and tumor biopsies were collected at baseline, after 1 week of metformin treatment, and at brachytherapy for biomarker assessments. Tolerability and safety were determined by treatment completion rates and frequency of adverse events (AEs). Safety was further evaluated by possible increase in MRI-based hypoxia during the first week of metformin. Feasibility was determined by proportion of completed study interventions and imaging and biopsy procedures. Results: In total, 18 and 23 patients were allocated to the intervention and control arm, respectively. Eighteen and 15 patients completed metformin treatment for 1 and 5 weeks. Frequency of AEs ≥ grade 3 was not significantly different between study arms. Most AEs were gastrointestinal toxicities. Tumors with increase in hypoxia during the first week were all below the defined safety limit. A total of 98% of scheduled MR series and biopsies were collected with satisfactory quality. Interpretation: Addition of metformin to chemoradiotherapy is tolerable and safe. Serial sampling of MRI and tumor biopsies for hypoxia biomarker assessment is feasible.

• Wang, Ruoyu; Gunesli, Gozde N.; Skingen, Vilde Eide; Valen, Kari-Anne Frikstad; Lyng, Heidi & Young, Lawrence S. [Vis alle 7 forfattere av denne artikkelen] (2025). Deep learning for predicting prognostic consensus molecular subtypes in cervical cancer from histology images. NPJ precision oncology. 9(1). doi: 10.1038/s41698-024-00778-5. Fulltekst i vitenarkiv Vis sammendrag

  Cervical cancer remains the fourth most common cancer among women worldwide. This study proposes an end-to-end deep learning framework to predict consensus molecular subtypes (CMS) in HPV-positive cervical squamous cell carcinoma (CSCC) from H&E-stained histology slides. Analysing three CSCC cohorts (n = 545), we show our Digital-CMS scores significantly stratify patients by both disease-specific (TCGA p = 0.0022, Oslo p = 0.0495) and disease-free (TCGA p = 0.0495, Oslo p = 0.0282) survival. In addition, our extensive tumour microenvironment analysis reveals differences between the two CMS subtypes, with CMS-C1 tumours exhibit increased lymphocyte presence, while CMS-C2 tumours show high nuclear pleomorphism, elevated neutrophil-to-lymphocyte ratio, and higher malignancy, correlating with poor prognosis. This study introduces a potentially clinically advantageous Digital-CMS score derived from digitised WSIs of routine H&E-stained tissue sections, offers new insights into TME differences impacting patient prognosis and potential therapeutic targets, and identifies histological patterns serving as potential surrogate markers of the CMS subtypes for clinical application.

• Lukovic, Jelena; Pintilie, Melania; Han, Kathy; Fyles, Anthony W.; Bruce, Jeffrey P. & Quevedo, Rene [Vis alle 10 forfattere av denne artikkelen] (2024). An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer. Clinical Cancer Research. ISSN 1078-0432. 30(6), s. 1200–1207. doi: 10.1158/1078-0432.CCR-23-2085. Fulltekst i vitenarkiv
• Skingen, Vilde Eide; Salberg, Unn Beate; Hompland, Tord; Fjeldbo, Christina Sæten; Helgeland, Hanna & Frikstad, Kari-Anne [Vis alle 11 forfattere av denne artikkelen] (2024). Spatial analysis of microRNA regulation at defined tumor hypoxia levels reveals biological traits of aggressive prostate cancer. Journal of Pathology. ISSN 0022-3417. 264(3), s. 270–283. doi: 10.1002/path.6344. Fulltekst i vitenarkiv Vis sammendrag

  Mechanisms regulating the gene expression program at different hypoxia severity levels in patient tumors are not understood. We aimed to determine microRNA (miRNA) regulation of this program at defined hypoxia levels from moderate to severe in prostate cancer. Biopsies from 95 patients were used, where 83 patients received the hypoxia marker pimonidazole before prostatectomy. Forty hypoxia levels were extracted from pimonidazole-stained histological sections and correlated with miRNA and gene expression profiles determined by RNA sequencing and Illumina bead arrays. This identified miRNAs associated with moderate (n = 7) and severe (n = 28) hypoxia and predicted their target genes. The scores of miRNAs or target genes showed prognostic significance, as validated in an external cohort of 417 patients. The target genes showed enrichment of gene sets for cell proliferation and MYC activation at all hypoxia levels and PTEN inactivation at severe hypoxia. This was confirmed by RT-qPCR for MYC and PTEN, by Ki67 imm

• Skipar, Kjersti Øvrum; Hompland, Tord; Lund, Kjersti Vassmo; Lindemann, Kristina Yvonne Kathe; Hellebust, Taran Annette Paulsen & Bruheim, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2024). MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy. Radiotherapy and Oncology. ISSN 0167-8140. 195, s. 1–7. doi: 10.1016/j.radonc.2024.110263. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: Improvements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification. Material and methods: Ninety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HFpre) was determined from DCE- and DW-MR images using the consumption and supply-based hypoxia (CSH)-imaging method. Volume regression at brachytherapy was assessed from T2W-MR images and combined with HFpre. In 17 patients with adequate DW-MR images at brachytherapy, the apparent diffusion coefficient (ADC), reflecting tumor cell density, was calculated. C

• Marsilla, Joseph; Weiss, Jessica; Ye, Xiang Y.; Welch, Mattea; Milosevic, Michael & Lyng, Heidi [Vis alle 11 forfattere av denne artikkelen] (2024). A T2-weighted MRI-based radiomic signature for disease-free survival in locally advanced cervical cancer following chemoradiation: An international, multicentre study. Radiotherapy and Oncology. ISSN 0167-8140. 199. doi: 10.1016/j.radonc.2024.110463. Fulltekst i vitenarkiv
• Fackler, Mary Jo; Pleas, Madison; Li, Youran; Soni, Anushri; Xing, Deyin & Cope, Leslie [Vis alle 19 forfattere av denne artikkelen] (2024). Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries. Clinical Epigenetics. 16(1). doi: 10.1186/s13148-024-01669-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically distinguish individuals with neoplasia. We investigated whether a quantitative molecular test that measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. Results Marker discovery was performed in TCGA-CESC Infinium Methylation 450 K Array database and verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation-Specific PCR in tissue sections (N = 252) and cervical smears (N = 244) from the USA, South Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from all three countries showed highly significant differential methylation in squamous cell carcinoma (SCC) with a sensitivity of 100% [95% CI 74.12–100.00], and specificity of 91% [95% CI 62.26–99.53] to 96% [95% CI 79.01–99.78], and receiver operating characteristic area under the curve (ROC AUC) = 1.000 [95% CI 1.00–1.00] compared to benign cervical tissue, and cervical intraepithelial neoplasia 2/3 with sensitivity of 55% [95% CI 37.77–70.84] to 89% [95% CI 67.20–98.03], specificity of 93% [95% CI 84.07–97.38] to 96% [95% CI 79.01–99.78], and a ROC AUC ranging from 0.793 [95% CI 0.68–0.89] to 0.99 [95% CI 0.97–1.00] compared to CIN1. In cervical smears, the marker panel detected SCC with a sensitivity of 87% [95% CI 77.45–92.69], specificity 95% [95% CI 88.64–98.18], and ROC AUC = 0.925 [95% CI 0.878–0.974] compared to normal, and high-grade squamous intraepithelial lesion (HSIL) at a sensitivity of 70% (95% CI 58.11–80.44), specificity of 94% (95% CI 88.30–97.40), and ROC AUC = 0.884 (95% CI 0.822–0.945) compared to low-grade intraepithelial lesion (LSIL)/normal in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. Conclusions This 5-marker panel detected SCC and HSIL in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk HSIL will lead to timely treatment for those in need and prevent unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

• Salamanca, Salamanca Fernandez; Hompland, Tord; Deręgowska-Cylke, M.; Poel, der Van der; Bekers, E. & Guimaraes, M.A.S. [Vis alle 10 forfattere av denne artikkelen] (2024). A DWI-based hypoxia model shows robustness in an external prostatectomy cohort. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1433197. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Prostate cancer hypoxia is a negative prognostic biomarker. A promising MRI-based tool to assess hypoxia is the ‘Consumption and Supply based Hypoxia’ (CSH) model based on diffusion-weighted imaging (DWI). The aim of the study was to validate the association between the CSH hypoxia fraction (HFDWI) with pathological Grade Group (pGG) and pathological T-staging (pTstage) in an external prostatectomy cohort. Methods: Apparent diffusion coefficient (ADC) and fractional blood volume (fBV) maps were assessed from DWI data from 291 prostatectomies and combined by the CSH model. HFDWI was calculated for each lesion after median scaling of ADC and fBV to address differences in acquisition and analysis between centers. The absolute HFDWI values and the associations of HFDWI between pGG < 3 versus ≥ 3, and pTstage = 2 versus = 3 in the Netherlands Cancer Institute (NKI) cohort were compared to the obtained by original cohort (Oslo cohort). Statistical T- and Mann-Whitney tests (p<0.05) were performed. Pearson correlation was determined between HFDWI and individual pGG groups. Results: The HFDWI showed comparable absolute values and similar metric performance as in the original published cohort. Higher HFDWI values were observed for higher pGG (Oslo: 0.27; NKI: 0.24) compared to lower pGG (Oslo: 0.11; NKI: 0.17). Similar results were obtained for pTstage. Furthermore, HFDWI demonstrated a significant positive correlation with pGG groups 1-5 (ρ = 0.41, p<0.001). Conclusion: The CSH model exhibited sufficient robustness in the external cohort, suggesting a plausible reflection of true hypoxia and enabling the use of the HFDWI metric for further research into prostate cancer and hypoxia.

• Gorodetska, Ielizaveta; Offermann, Anne; Püschel, Jakob; Lukiyanchuk, Vasyl; Gaete, Diana & Kurzyukova, Anastasia [Vis alle 25 forfattere av denne artikkelen] (2024). ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. Theranostics. 14(2), s. 714–737. doi: 10.7150/thno.88057. Fulltekst i vitenarkiv Vis sammendrag

  Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.

• Leech, Michelle; Leijenaar, Ralph T.H.; Hompland, Tord; Gaffney, John; Lyng, Heidi & Marignol, Laure (2023). Exploring Hypoxia in Prostate Cancer With T2-weighted Magnetic Resonance Imaging Radiomics and Pimonidazole Scoring. Anticancer Research. ISSN 0250-7005. 43(1), s. 351–357. doi: 10.21873/anticanres.16170. Fulltekst i vitenarkiv
• Skingen, Vilde Eide; Hompland, Tord; Fjeldbo, Christina Sæten; Salberg, Unn Beate; Helgeland, Hanna & Ragnum, Harald Bull [Vis alle 11 forfattere av denne artikkelen] (2023). Prostate cancer radiogenomics reveals proliferative gene expression programs associated with distinct MRI-based hypoxia levels. Radiotherapy and Oncology. ISSN 0167-8140. 188. doi: 10.1016/j.radonc.2023.109875. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: The biology behind individual hypoxia levels in patient tumors is poorly understood. Here, we used radiogenomics to identify associations between magnetic resonance imaging (MRI)-based hypoxia levels and biological processes derived from gene expression data in prostate cancer. Materials and methods: For 85 prostate cancer patients, MRI-based hypoxia images were constructed by combining diffusion-weighted images reflecting oxygen consumption and supply. The ability to differentiate hypoxia levels in these images was verified by comparison with matched biopsy sections stained for the hypoxia marker pimonidazole. For MRI-defined hypoxia levels, corresponding hypoxic fractions were calculated and correlated with biopsy gene expression profiles. Biological processes were predicted by gene set enrichment analysis (GSEA) and validated by immunohistochemistry (Ki67 proliferation marker, reactive stroma grade) and RT-PCR (MYC). Results: Genes with correlation between expression level and hypoxic fraction were identified for 56 MRI-based hypoxia levels. At all levels, GSEA identified proliferation as the predominant biological process enriched among the correlating genes. Two independent proliferative gene signatures were developed. The Peak1 signature, upregulated at moderate/severe hypoxia, reflected MYC upregulation and high Ki67-proliferation index of cancer cells in pimonidazole-positive regions. The Peak2 signature, upregulated at mild to non-hypoxic levels, was associated with fibroblast gene signature and reactive stroma grade. High scores of both Peak1 and Peak2 indicated elevated risk of biochemical recurrence in multiple cohorts. Conclusion: Radiogenomics identified two gene expression programs activated at different hypoxia levels, reflecting proliferation of cancer cells and stroma cells. Genes involved in these programs could be candidate targets for intervention.

• Skipar, Kjersti Øvrum; Hompland, Tord; Lund, Kjersti Vassmo; Løndalen, Ayca; Malinen, Eirik & Kristensen, Gunnar S Balle [Vis alle 10 forfattere av denne artikkelen] (2022). Risk of recurrence after chemoradiotherapy identified by multimodal MRI and 18F-FDG-PET/CT in locally advanced cervical cancer. Radiotherapy and Oncology. ISSN 0167-8140. 176, s. 17–24. doi: 10.1016/j.radonc.2022.09.002. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: MRI, applying dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) sequences, and 18F-fluorodeoxyglucose (18F-FDG) PET/CT provide information about tumor aggressiveness that is unexploited in treatment of locally advanced cervical cancer (LACC). We investigated the potential of a multimodal combination of imaging parameters for classifying patients according to their risk of recurrence. Materials and methods: Eighty-two LACC patients with diagnostic MRI and FDG-PET/CT, treated with chemoradiotherapy, were collected. Thirty-eight patients with MRI only were included for validation of MRI results. Endpoints were survival (disease-free, cancer-specific, overall) and tumor control (local, locoregional, distant). Ktrans, reflecting vascular function, apparent diffusion coefficient (ADC), reflecting cellularity, and standardized uptake value (SUV), reflecting glucose uptake,were extracted from DCE-MR, DW-MR and FDG-PET images, respectively. By applying an oxygen consumption and supply-based method, ADC and Ktrans parametric maps were voxel-wise combined into hypoxia images that were used to determine hypoxic fraction (HF). Results: HF showed a stronger association with outcome than the single modality parameters. This association was confirmed in the validation cohort.Low HF identified low-risk patients with 95 % precision. Based on the 50th SUV-percentile (SUV50), patients with high HF were divided into an intermediate- and high-risk group with high and low SUV50, respectively. This defined a multimodality biomarker, HF/SUV50. HF/SUV50 increased the precision of detecting high-risk patients from 41% (HF alone) to 57% and showed prognostic significance in multivariable analysis for all endpoints. Conclusion: Multimodal combination of MR- and FDG-PET/CT-images improves classification of LACC patients compared to single modality images and clinical factors.

• Nilsen, Anja; Hillestad, Tiril; Skingen, Vilde Eide; Aarnes, Eva-Katrine; Fjeldbo, Christina Sæten & Hompland, Tord [Vis alle 11 forfattere av denne artikkelen] (2022). miR-200a/b/-429 downregulation is a candidate biomarker of tumor radioresistance and independent of hypoxia in locally advanced cervical cancer. Molecular Oncology. ISSN 1574-7891. 16(6), s. 1402–1419. doi: 10.1002/1878-0261.13184. Fulltekst i vitenarkiv Vis sammendrag

  Many patients with locally advanced cervical cancer experience recurrence within the radiation field after chemoradiotherapy. Biomarkers of tumor radioresistance are required to identify patients in need of intensified treatment. Here, the biomarker potential of miR-200 family members was investigated in this disease. Also, involvement of tumor hypoxia in the radioresistance mechanism was determined, using a previously defined 6-gene hypoxia classifier. miR-200 expression was measured in pretreatment tumor biopsies of an explorative cohort (n = 90) and validation cohort 1 (n = 110) by RNA sequencing. Publicly available miR-200 data of 79 patients were included for the validation of prognostic significance. A score based on expression of the miR-200a/b/-429 (miR-200a, miR-200b, and miR-429) cluster showed prognostic significance in all cohorts. The score was significant in multivariate analysis of central pelvic recurrence. No association with distant recurrence or hypoxia status was found. Potential miRNA target genes were identified from gene expression profiles and showed enrichment of genes in extracellular matrix organization and cell adhesion. miR-200a/b/-429 overexpression had a pronounced radiosensitizing effect in tumor xenografts, whereas the effect was minor in vitro. In conclusion, miR-200a/b/-429 downregulation is a candidate biomarker of central pelvic recurrence and seems to predict cell adhesion-mediated tumor radioresistance independent of clinical markers and hypoxia.

• Salberg, Unn Beate; Skingen, Vilde Eide; Fjeldbo, Christina Sæten; Hompland, Tord; Ragnum, Harald Bull & Vlatkovic, Ljiljana [Vis alle 9 forfattere av denne artikkelen] (2022). A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients. British Journal of Cancer. ISSN 0007-0920. 127, s. 321–328. doi: 10.1038/s41416-022-01782-x. Fulltekst i vitenarkiv Vis sammendrag

  Background: Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer. Methods: The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia. Results: The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts. Conclusions: Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

• Chakravarthy, Ankur; Reddin, Ian; Henderson, Stephen; Dong, Cindy; Kirkwood, Nerissa & Jeyakumar, Maxmilan [Vis alle 29 forfattere av denne artikkelen] (2022). Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance. Nature Communications. 13:5818, s. 1–17. doi: 10.1038/s41467-022-33544-x. Fulltekst i vitenarkiv Vis sammendrag

  Human papillomavirus (HPV)-associated cervical cancer is a leading cause of cancer deaths in women. Here we present an integrated multi-omic analysis of 643 cervical squamous cell carcinomas (CSCC, the most common histological variant of cervical cancer), representing patient populations from the USA, Europe and Sub-Saharan Africa and identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 and C2 tumours can be driven by either of the two most common HPV types in cervical cancer (16 and 18) and while HPV16 and HPV18 are overrepresented among C1 and C2 tumours respectively, the prognostic difference between groups is not due to HPV type. C2 tumours, which comprise approximately 20% of CSCCs across these cohorts, display distinct genomic alterations, including loss or mutation of the STK11 tumour suppressor gene, increased expression of several immune checkpoint genes and differences in the tumour immune microenvironment that may explain the shorter survival associated with this group. In conclusion, we identify two therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.

• Hompland, Tord; Fjeldbo, Christina Sæten & Lyng, Heidi (2021). Tumor hypoxia as a barrier in cancer therapy: Why levels matter. Cancers. 13:499(3), s. 1–23. doi: 10.3390/cancers13030499. Fulltekst i vitenarkiv Vis sammendrag

  Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.

• Tulipan, Andreas Julius; Salberg, Unn Beate; Hole, Knut Håkon; Vlatkovic, Ljiljana; Aarnes, Eva-Katrine & Rootwelt-Revheim, Mona Elisabeth [Vis alle 8 forfattere av denne artikkelen] (2021). Amino acid transporter expression and 18F-FACBC uptake at PET in primary prostate cancer. The American Journal of Nuclear Medicine and Molecular Imaging (AJNMMI). 11(4), s. 250–259. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Little is known about the transport mechanism of anti-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC) into prostate tumors. Because of the structural similarity to natural amino acids, FACBC is anticipated to cross the cell membrane via amino acid transporters, and preclinical studies have suggested that ASCT2, LAT1 and SNAT2 are involved. In 16 patients with intermediate or high-risk prostate cancer we matched the FACBC uptake from clinical PET to the location of punch biopsies from resected prostatectomy specimens and compared maximum standardized uptake value (SUVmax) with the gene expression of 40 amino acid transporters. The study also included immunohistochemistry for the three amino acid transporters ASCT2, LAT1 and SNAT2. Furthermore, we performed global gene expression analysis of the biopsies to investigate biological processes associated with FACBC uptake. Several amino acid transporters had a higher gene expression level than the others, but we found no significant correlations between SUVmax and the gene expression levels of any of 40 different amino acid transporters. In the immunohistochemical analyses, ASCT2 and SNAT2 were highly expressed, but not correlated to SUVmax. LAT1 had low gene- and protein expression. Global gene expression analyses identified 153 unique genes that were positively correlated to SUVmax. These genes were found to be associated with gene sets reflecting intracellular transport and high metabolic activity. Based on the study findings we propose that the uptake mechanism of FACBC is more complex than mediated by a few amino acid transporters.

• Fjeldbo, Christina Sæten; Hompland, Tord; Hillestad, Tiril; Aarnes, Eva-Katrine; Günther, Clara-Cecilie & Kristensen, Gunnar S Balle [Vis alle 8 forfattere av denne artikkelen] (2020). Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity. EBioMedicine. 57. doi: 10.1016/j.ebiom.2020.102841. Fulltekst i vitenarkiv Vis sammendrag

  Background Emerging biomarkers from medical imaging or molecular characterization of tumour biopsies open up for combining the two and exploiting their synergy in treatment planning of cancer patients. We generated a paired data set of imaging- and gene-based hypoxia biomarkers in cervical cancer, appraised the influence of intratumour heterogeneity in patient classification, and investigated the benefit of combining the methodologies in prediction of chemoradiotherapy failure. Methods Hypoxic fraction from dynamic contrast enhanced (DCE)-MR images and an expression signature of six hypoxia-responsive genes were assessed as imaging- and gene-based biomarker, respectively in 118 patients. Findings Dichotomous biomarker cutoff to yield similar hypoxia status by imaging and genes was defined in 41 patients, and the association was validated in the remaining 77 patients. The two biomarkers classified 75% of 118 patients with the same hypoxia status, and inconsistent classification was not related to imaging-defined intratumour heterogeneity in hypoxia. Gene-based hypoxia was independent on tumour cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumours. Combining imaging- and gene-based classification gave a significantly better prediction of PFS than one biomarker alone. A combined dichotomous biomarker optimized in 77 patients showed a large separation in PFS between more and less hypoxic tumours, and separated the remaining 41 patients with different PFS. The combined biomarker showed prognostic value together with tumour stage in multivariate analysis. Interpretation Combining imaging- and gene-based biomarkers may enable more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer.

• Hillestad, Tiril; Hompland, Tord; Fjeldbo, Christina Sæten; Skingen, Vilde Eide; Salberg, Unn Beate & Aarnes, Eva-Katrine [Vis alle 12 forfattere av denne artikkelen] (2020). MRI distinguishes tumor hypoxia levels of different prognostic and biological significance in cervical cancer. Cancer Research. ISSN 0008-5472. 80(18), s. 3993–4003. doi: 10.1158/0008-5472.can-20-0950. Fulltekst i vitenarkiv
• Pitman, Kathinka; Alluri, Santosh Reddy; Kristian, Alexandr; Aarnes, Eva-Katrine; Lyng, Heidi & Riss, Patrick [Vis alle 7 forfattere av denne artikkelen] (2019). Influx rate of 18F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts. European Journal of Nuclear Medicine and Molecular Imaging. ISSN 1619-7070. 46(10), s. 2190–2198. doi: 10.1007/s00259-019-04375-8. Fulltekst i vitenarkiv
• Jonsson, Marte; Fjeldbo, Christina Sæten; Holm, Ruth; Stokke, Trond; Kristensen, Gunnar S Balle & Lyng, Heidi (2019). Mitochondrial Function of CKS2 Oncoprotein Links Oxidative Phosphorylation with Cell Division in Chemoradioresistant Cervical Cancer. Neoplasia. ISSN 1522-8002. 21(4), s. 353–362. doi: 10.1016/j.neo.2019.01.002. Fulltekst i vitenarkiv
• Nilsen, Anja; Jonsson, Marte; Aarnes, Eva-Katrine; Kristensen, Gunnar S Balle & Lyng, Heidi (2019). Reference MicroRNAs for RT-qPCR Assays in Cervical Cancer Patients and Their Application to Studies of HPV16 and Hypoxia Biomarkers. Translational Oncology. ISSN 1944-7124. 12(3), s. 576–584. doi: 10.1016/j.tranon.2018.12.010. Fulltekst i vitenarkiv Vis sammendrag

  MicroRNA (miRNA) expressions in tumor biopsies have shown potential as biomarkers in cervical cancer, but suitable reference RNAs for normalization of reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays in patient cohorts with different clinicopathological characteristics are not available. We aimed to identify the optimal reference miRNAs and apply these to investigate the potential of miR-9-5p as human papilloma virus (HPV) 16 biomarker and miR-210-3p as hypoxia biomarker in cervical cancer. Candidate reference miRNAs were preselected in sequencing data of 90 patients and ranked in a stability analysis by RefFinder. A selection of the most stable miRNAs was evaluated by geNorm and NormFinder analyses of RT-qPCR data of 29 patients. U6 small nuclear RNA (RNU6) was also included in the evaluation. MiR-9-5p and miR-210-3p expression was assessed by RT-qPCR in 45 and 65 patients, respectively. Nine candidates were preselected in the sequencing data after excluding those associated with clinical markers, HPV type, hypoxia status, suboptimal expression levels, and low stability. In RT-qPCR assays, the combination of miR-151-5p, miR-152-3p, and miR-423-3p was identified as the most stable normalization factor across clinical markers, HPV type, and hypoxia status. RNU6 showed poor stability. By applying the optimal reference miRNAs, higher miR-9-5p expression in HPV16- than HPV18-positive tumors and higher miR-210-3p expression in more hypoxic than less hypoxic tumors were found in accordance with the sequencing data. MiR-210-3p was associated with poor outcome by both sequencing and RT-qPCR assays. In conclusion, miR-151-5p, miR-152-3p, and miR-423-3p are suitable reference miRNAs in cervical cancer. MiR-9-5p and miR-210-3p are promising HPV16 and hypoxia biomarkers, respectively.

• Switlyk, Marta Daniela; Salberg, Unn Beate; Geier, Oliver; Vlatkovic, Ljiljana; Lilleby, Wolfgang & Lyng, Heidi [Vis alle 7 forfattere av denne artikkelen] (2019). PTEN Expression in Prostate Cancer: Relationship with Clinicopathological Features and Multiparametric MRI Findings. American Journal of Roentgenology. ISSN 0361-803X. 212(6), s. 1206–1214. doi: 10.2214/AJR.18.20743. Fulltekst i vitenarkiv
• Mikalsen, Stine Gyland; Mikalsen, Lars Tore G; Sandvik, Joe Alexander; Aarnes, Eva-Katrine; Fenne, Siri & Flatmark, Kjersti [Vis alle 9 forfattere av denne artikkelen] (2018). Low dose-rate irradiation with [3H]-labelled valine to selectively target hypoxic cells in a human colorectal cancer xenograft model. Acta Oncologica. ISSN 0284-186X. 57(9), s. 1216–1224. doi: 10.1080/0284186X.2018.1457223. Fulltekst i vitenarkiv
• Hompland, Tord; Hole, Knut Håkon; Ragnum, Harald Bull; Aarnes, Eva-Katrine; Vlatkovic, Ljiljana & Lie, Agnes Kathrine [Vis alle 10 forfattere av denne artikkelen] (2018). Combined MR imaging of oxygen consumption and supply reveals tumor hypoxia and aggressiveness in prostate cancer patients. Cancer Research. ISSN 0008-5472. 78(16), s. 4774–4785. doi: 10.1158/0008-5472.CAN-17-3806. Fulltekst i vitenarkiv
• Lam, Khiem Chi; Vyshenska, Dariia; Hu, Jialu; Rodrigues, Richard Rosario; Nilsen, Anja & Zielke, Ryszard A. [Vis alle 12 forfattere av denne artikkelen] (2018). Transkingdom network reveals bacterial players associated with cervical cancer gene expression program. PeerJ. 6:e5590(9), s. 1–21. doi: 10.7717/peerj.5590. Fulltekst i vitenarkiv
• Leibfarth, Sara; Winter, René M.; Lyng, Heidi; Zips, Daniel & Thorwarth, Daniela (2018). Potentials and challenges of diffusion-weighted magnetic resonance imaging in radiotherapy. Clinical and Translational Radiation Oncology. 13, s. 29–37. doi: 10.1016/j.ctro.2018.09.002. Fulltekst i vitenarkiv Vis sammendrag

  Purpose To review the potential and challenges of integrating diffusion weighted magnetic resonance imaging (DWI) into radiotherapy (RT). Content Details related to image acquisition of DWI for RT purposes are discussed, along with the challenges with respect to geometric accuracy and the robustness of quantitative parameter extraction. An overview of diffusion- and perfusion-related parameters derived from mono- and bi-exponential models is provided, and their role as potential RT biomarkers is discussed. Recent studies demonstrating potential of DWI in different tumor sites such as the head and neck, rectum, cervix, prostate, and brain, are reviewed in detail. Conclusion DWI has shown promise for RT outcome prediction, response assessment, as well as for tumor delineation and characterization in several cancer types. Geometric and quantification robustness is challenging and has to be addressed adequately. Evaluation in larger clinical trials with well designed imaging protocol and advanced analysis models is needed to develop the optimal strategy for integrating DWI in RT.

• Li, Anna; Andersen, Erlend K F; Lervåg, Christoffer; Julin, Cathinka H.; Lyng, Heidi & Hellebust, Taran Paulsen [Vis alle 7 forfattere av denne artikkelen] (2017). Dynamic contrast enhanced magnetic resonance imaging for hypoxia mapping and potential for brachytherapy targeting. Physics and imaging in radiation oncology (PIRO). 2(1), s. 1–6. doi: 10.1016/j.phro.2017.03.002. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Hole, Knut Håkon; Lund, Kjersti Vassmo; Indahl, Ulf Geir & Lyng, Heidi [Vis alle 8 forfattere av denne artikkelen] (2017). Autodelineation of cervical cancers using multiparametric magnetic resonance imaging and machine learning. Acta Oncologica. ISSN 0284-186X. 56(6), s. 806–812. doi: 10.1080/0284186X.2017.1285499. Fulltekst i vitenarkiv
• Lyng, Heidi & Malinen, Eirik (2017). Hypoxia in cervical cancer: from biology to imaging. Clinical and translational imaging. ISSN 2281-5872. 5(4), s. 373–388. doi: 10.1007/s40336-017-0238-7. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Grøndahl, Aurora Rosvoll; Andersen, Erlend K F; Lyng, Heidi; Malinen, Eirik & Kvaal, Knut [Vis alle 7 forfattere av denne artikkelen] (2016). Cluster analysis of dynamic contrast enhanced MRI reveals tumor subregions related to locoregional relapse for cervical cancer patients. Acta Oncologica. ISSN 0284-186X. 55(11), s. 1294–1298. doi: 10.1080/0284186X.2016.1189091. Fulltekst i vitenarkiv
• Wilting, Saskia M.; Miok, Viktorian; Jaspers, Annelieke; Boon, Debby; Sørgård, Hanne Kristine & Lando, Malin [Vis alle 12 forfattere av denne artikkelen] (2016). Aberrant methylation-mediated silencing of microRNAs contributes to HPV-induced anchorage independence. OncoTarget. 7(28), s. 43805–43819. doi: 10.18632/oncotarget.9698. Fulltekst i vitenarkiv
• Fjeldbo, Christina Sæten; Aarnes, Eva-Katrine; Malinen, Eirik; Kristensen, Gunnar S Balle & Lyng, Heidi (2016). Identification and validation of reference genes for RT-qPCR studies of hypoxia in squamous cervical cancer patients. PLOS ONE. 11(5). doi: 10.1371/journal.pone.0156259. Fulltekst i vitenarkiv Vis sammendrag

  Hypoxia is an adverse factor in cervical cancer, and hypoxia-related gene expression could be a powerful biomarker for identifying the aggressive hypoxic tumors. Reverse transcription quantitative PCR (RT-qPCR) is a valuable method for gene expression studies, but suitable reference genes for data normalization that are independent of hypoxia status and clinical parameters of cervical tumors are lacking. In the present work, we aimed to identify reference genes for RT-qPCR studies of hypoxia in squamous cervical cancer. From 422 candidate reference genes selected from the literature, we used Illumina array-based expression profiles to identify 182 genes not affected by hypoxia in cervical cancer, i.e. genes regulated by hypoxia in eight cervical cancer cell lines or correlating with the hypoxia-associated dynamic contrast-enhanced magnetic resonance imaging parameter ABrix in 42 patients, were excluded. Among the 182 genes, nine candidates (CHCHD1, GNB2L1, IPO8, LASP1, RPL27A, RPS12, SOD1, SRSF9, TMBIM6) that were not associated with tumor volume, stage, lymph node involvement or disease progression in array data of 150 patients, were selected for further testing by RT-qPCR. geNorm and NormFinder analyses of RT-qPCR data of 74 patients identified CHCHD1, SRSF9 and TMBIM6 as the optimal set of reference genes, with stable expression both overall and across patient subgroups with different hypoxia status (ABrix) and clinical parameters. The suitability of the three reference genes were validated in studies of the hypoxia-induced genes DDIT3, ERO1A, and STC2. After normalization, the RT-qPCR data of these genes showed a significant correlation with Illumina expression (P<0.001, n = 74) and ABrix (P<0.05, n = 32), and the STC2 data were associated with clinical outcome, in accordance with the Illumina data. Thus, CHCHD1, SRSF9 and TMBIM6 seem to be suitable reference genes for studying hypoxia-related gene expression in squamous cervical cancer samples by RT-qPCR. Moreover, STC2 is a promising prognostic hypoxia biomarker in cervical cancer.

• Fjeldbo, Christina Sæten; Julin, Cathinka Halle; Lando, Malin; Forsberg, Malin Forårsveen; Aarnes, Eva-Katrine & Alsner, Jan [Vis alle 9 forfattere av denne artikkelen] (2016). Integrative analysis of DCE-MRI and gene expression profiles in construction of a gene classifier for assessment of hypoxia-related risk of chemoradiotherapy failure in cervical cancer. Clinical Cancer Research. ISSN 1078-0432. 22(16), s. 4067–4076. doi: 10.1158/1078-0432.CCR-15-2322. Fulltekst i vitenarkiv
• Hasvold, Grete; Lund-Andersen, Christin; Lando, Malin; Patzke, Sebastian; Hauge, Sissel & Suo, Zhenhe [Vis alle 8 forfattere av denne artikkelen] (2016). Hypoxia-induced alterations of G2 checkpoint regulators. Molecular Oncology. ISSN 1574-7891. 10(5), s. 764–773. doi: 10.1016/j.molonc.2015.12.015. Fulltekst i vitenarkiv
• Jonsson, Marte; Ragnum, Harald Bull; Halle, Cathinka Lønning; Yeramian, Andree; Clancy, Trevor & Frikstad, Kari-Anne [Vis alle 12 forfattere av denne artikkelen] (2016). Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition. British Journal of Cancer. ISSN 0007-0920. 115(8), s. 929–939. doi: 10.1038/bjc.2016.278. Fulltekst i vitenarkiv
• Ragnum, Harald Bull; Vlatkovic, Ljiljana; Lie, Kathrine; Axcrona, Eugen Jan Karol; Halle, Cathinka Lønning & Frikstad, Kari-Anne [Vis alle 9 forfattere av denne artikkelen] (2015). The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. British Journal of Cancer. ISSN 0007-0920. 112, s. 382–390. doi: 10.1038/bjc.2014.604. Fulltekst i vitenarkiv
• Pettersen, Erik O; Ebbesen, Peter; Gieling, RG; Williams, KJ; Dubois, Ludwig & Lambin, Philippe [Vis alle 47 forfattere av denne artikkelen] (2015). Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium. Journal of Enzyme Inhibition and Medicinal Chemistry. ISSN 1475-6366. 30(5), s. 689–721. doi: 10.3109/14756366.2014.966704. Fulltekst i vitenarkiv
• Lando, Malin; Fjeldbo, Christina Sæten; Wilting, Saskia M.; Snoek, Barbara C.; Aarnes, Eva-Katrine & Forsberg, Malin [Vis alle 9 forfattere av denne artikkelen] (2015). Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer. Epigenetics. ISSN 1559-2294. 10(10), s. 970–980. doi: 10.1080/15592294.2015.1085140. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Kvaal, Knut; Lyng, Heidi; Indahl, Ulf Geir & Andersen, Erlend K F [Vis alle 7 forfattere av denne artikkelen] (2014). Classification of dynamic contrast enhanced MR images of cervical cancers using texture analysis and support vector machines. IEEE Transactions on Medical Imaging. ISSN 0278-0062. 33(8), s. 1648–1656. doi: 10.1109/TMI.2014.2321024. Fulltekst i vitenarkiv
• Shulzhenko, Natalia; Lyng, Heidi; Sanson, Gerdine F. & Morgun, Andrey (2014). Ménage à trois: An evolutionary interplay between human papillomavirus, a tumor, and a woman. Trends in Microbiology. ISSN 0966-842X. 22(6), s. 345–353. doi: 10.1016/j.tim.2014.02.009. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Hole, Knut Håkon; Lund, Kjersti Vassmo; Sundfør, Kolbein; Kristensen, Gunnar S Balle & Lyng, Heidi [Vis alle 7 forfattere av denne artikkelen] (2013). Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome. Radiotherapy and Oncology. ISSN 0167-8140. 107(1), s. 117–122. doi: 10.1016/j.radonc.2012.11.007. Fulltekst i vitenarkiv
• Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn M & Aarnes, Eva-Katrine [Vis alle 11 forfattere av denne artikkelen] (2013). Hypoxia-independent downregulation of hypoxia-inducible factor 1 targets by androgen deprivation therapy in prostate cancer. International Journal of Radiation Oncology, Biology, Physics. ISSN 0360-3016. 87(4), s. 753–760. doi: 10.1016/j.ijrobp.2013.07.023. Fulltekst i vitenarkiv
• Mine, Karina L.; Shulzhenko, Natalia; Yambartsev, Anatoly; Rochman, Mark; Sanson, Gerdine F.O. & Lando, Malin [Vis alle 19 forfattere av denne artikkelen] (2013). Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. Nature Communications. 4. doi: 10.1038/ncomms2693. Fulltekst i vitenarkiv
• Lando, Malin; Wilting, Saskia M.; Snipstad, Kristin; Clancy, Trevor; Bierkens, Mariska & Aarnes, Eva-Katrine [Vis alle 13 forfattere av denne artikkelen] (2013). Identification of eight candidate target genes of the recurrent 3p12p14 loss in cervical cancer by integrative genomic profiling. Journal of Pathology. ISSN 0022-3417. 230(1), s. 59–69. doi: 10.1002/path.4168. Fulltekst i vitenarkiv Vis sammendrag

  The pathogenetic role, including its target genes, of the recurrent 3p12–p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high-grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down-regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down-regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight-gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12–p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets.

• Røe, Kathrine; Mikalsen, Lars Tore G; Kogel, Albert van der; Bussink, Johan; Lyng, Heidi & Ree, Anne Hansen [Vis alle 8 forfattere av denne artikkelen] (2012). Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer. Radiation Oncology. 7. doi: 10.1186/1748-717X-7-75. Fulltekst i vitenarkiv Vis sammendrag

  Background: Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC. Methods: Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI. Results: Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density ( VD), and vessel area fraction ( VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores ( AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve ( AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size ( VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such modeling also detected tumor necrosis very strongly. Conclusions: DCE MRI reliably allows non-invasive assessment of tumors’ vascular function. The findings of increased tumor vascularization after ADT encourage further studies into whether these changes are beneficial for combined RT, or if treatment with anti-angiogenic therapy may be a strategy to improve the therapeutic efficacy of ADT in advanced PC.

• Andersen, Erlend K F; Hole, Knut Håkon; Lund, Kjersti Vassmo; Sundfør, Kolbein; Kristensen, Gunnar S Balle & Lyng, Heidi [Vis alle 7 forfattere av denne artikkelen] (2012). Dynamic Contrast-Enhanced MRI of Cervical Cancers: Temporal Percentile Screening of Contrast Enhancement Identifies Parameters for Prediction of Chemoradioresistance. International Journal of Radiation Oncology, Biology, Physics. ISSN 0360-3016. 82(3), s. E485–E492. doi: 10.1016/j.ijrobp.2011.05.050. Fulltekst i vitenarkiv
• Halle, Cathinka Lønning; Andersen, Erlend K F; Lando, Malin; Aarnes, Eva-Katrine; Hasvold, Grete & Holden, Marit [Vis alle 12 forfattere av denne artikkelen] (2012). Hypoxia-induced gene expression in chemoradioresistant cervical cancer revealed by dynamic contrast enhanced MRI. Cancer Research. ISSN 0008-5472. 72(20), s. 5285–5295. doi: 10.1158/0008-5472.CAN-12-1085. Fulltekst i vitenarkiv Vis sammendrag

  Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrast-enhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter ABrix by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low ABrix appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between ABrix and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1α) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low ABrix was associated with upregulation of HIF1α protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low ABrix was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance.

• Halle, Cathinka Lønning; Lando, Malin; Sundfør, Kolbein; Kristensen, Gunnar S Balle; Holm, Ruth & Lyng, Heidi (2011). Phosphorylation of EGFR measured with in situ proximity ligation assay: relationship to EGFR protein level and gene dosage in cervical cancer. Radiotherapy and Oncology. ISSN 0167-8140. 101(1), s. 152–157. doi: 10.1016/j.radonc.2011.05.052. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Kristensen, Gunnar S Balle; Lyng, Heidi & Malinen, Eirik (2011). Pharmacokinetic analysis and k-means clustering of DCEMR images for radiotherapy outcome prediction of advanced cervical cancers. Acta Oncologica. ISSN 0284-186X. 50(6), s. 859–865. doi: 10.3109/0284186X.2011.578586. Fulltekst i vitenarkiv
• Landsverk, Kirsti; Patzke, Sebastian; Rein, Idun Dale; Stokke, Caroline; Lyng, Heidi & Angelis, Paula De [Vis alle 7 forfattere av denne artikkelen] (2011). Three independent mechanisms for arrest in G(2) after ionizing radiation. Cell Cycle. ISSN 1538-4101. 10(5), s. 819–829. doi: 10.4161/cc.10.5.14968. Fulltekst i vitenarkiv
• Bergersen, Linn Cecilie; Glad, Ingrid Kristine & Lyng, Heidi (2011). Weighted Lasso with Data Integration. Statistical Applications in Genetics and Molecular Biology. 10(1). doi: 10.2202/1544-6115.1703. Fulltekst i vitenarkiv
• Halle, Cathinka Lønning; Lando, Malin; Svendsrud, Debbie Hege; Clancy, Trevor; Holden, Marit & Sundfør, Kolbein [Vis alle 9 forfattere av denne artikkelen] (2011). Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node-Negative Cervical Cancer. Clinical Cancer Research. ISSN 1078-0432. 17(16), s. 5501–5512. doi: 10.1158/1078-0432.CCR-11-0297. Fulltekst i vitenarkiv
• Lando, M; Holden, Marit; Bergersen, LC; Glad, Ingrid K; Kristensen, GB & Lyng, H [Vis alle 9 forfattere av denne artikkelen] (2009). Gene Dosage, Expression, and Ontology Analysis Identifies Driver Genes in the Carcinogenesis and Chemoradioresistance of Cervical Cancer. PLoS Genetics. ISSN 1553-7390. 5(11). doi: 10.1371/journal.pgen.1000719. Fulltekst i vitenarkiv Vis sammendrag

  Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q) associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1) and 13q (FAM48A, MED4) correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers.

• Ferkingstad, Egil; Frigessi, Arnoldo & Lyng, Heidi (2008). Indirect genomic effects on survival from gene expression data. Genome Biology. ISSN 1465-6906. 9. Fulltekst i vitenarkiv
• Nygaard, V; Liu, Fang; Holden, Marit; Kuo, Winston P.; Trimarchi, Jeff & Ohno-Machado, Lucila [Vis alle 12 forfattere av denne artikkelen] (2008). Validation of oligoarrays for quantitative exploration of the transcriptome. BMC Genomics. 9. doi: 10.1186/1471-2164-9-258. Fulltekst i vitenarkiv Vis sammendrag

  Background Oligoarrays have become an accessible technique for exploring the transcriptome, but it is presently unclear how absolute transcript data from this technique compare to the data achieved with tag-based quantitative techniques, such as massively parallel signature sequencing (MPSS) and serial analysis of gene expression (SAGE). By use of the TransCount method we calculated absolute transcript concentrations from spotted oligoarray intensities, enabling direct comparisons with tag counts obtained with MPSS and SAGE. The tag counts were converted to number of transcripts per cell by assuming that the sum of all transcripts in a single cell was 5·105. Our aim was to investigate whether the less resource demanding and more widespread oligoarray technique could provide data that were correlated to and had the same absolute scale as those obtained with MPSS and SAGE. Results A number of 1,777 unique transcripts were detected in common for the three technologies and served as the basis for our analyses. The correlations involving the oligoarray data were not weaker than, but, similar to the correlation between the MPSS and SAGE data, both when the entire concentration range was considered and at high concentrations. The data sets were more strongly correlated at high transcript concentrations than at low concentrations. On an absolute scale, the number of transcripts per cell and gene was generally higher based on oligoarrays than on MPSS and SAGE, and ranged from 1.6 to 9,705 for the 1,777 overlapping genes. The MPSS data were on same scale as the SAGE data, ranging from 0.5 to 3,180 (MPSS) and 9 to1,268 (SAGE) transcripts per cell and gene. The sum of all transcripts per cell for these genes was 3.8·105 (oligoarrays), 1.1·105 (MPSS) and 7.6·104 (SAGE), whereas the corresponding sum for all detected transcripts was 1.1·106 (oligoarrays), 2.8·105 (MPSS) and 3.8·105 (SAGE). Conclusion The oligoarrays and TransCount provide quantitative transcript concentrations that are correlated to MPSS and SAGE data, but, the absolute scale of the measurements differs across the technologies. The discrepancy questions whether the sum of all transcripts within a single cell might be higher than the number of 5·105 suggested in the literature and used to convert tag counts to transcripts per cell. If so, this may explain the apparent higher transcript detection efficiency of the oligoarrays, and has to be clarified before absolute transcript concentrations can be interchanged across the technologies. The ability to obtain transcript concentrations from oligoarrays opens up the possibility of efficient generation of universal transcript databases with low resource demands.

• Lyng, Heidi; Brøvig, Runar S; Svendsrud, Debbie H.; Holm, Ruth; Kaalhus, Olav & Knutstad, Kjetil [Vis alle 10 forfattere av denne artikkelen] (2006). Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics. 7, s. 268–268. doi: 10.1186/1471-2164-7-268. Fulltekst i vitenarkiv Vis sammendrag

  Background A better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies. This study was conducted to identify gene expressions associated with metastatic phenotypes of locally advanced cervical carcinomas and investigate whether gains or losses of these genes could play a role in regulation of the transcripts. Gene expressions and copy number changes were determined in primary tumors from 29 patients with and 19 without diagnosed lymph node metastases by use of cDNA and genomic microarray techniques, respectively. Results Thirty-one genes that differed in expression between the node positive and negative tumors were identified. Expressions of eight of these genes (MRPL11, CKS2, PDK2, MRPS23, MSN, TBX3, KLF3, LSM3) correlated with progression free survival in univariate analysis and were therefore more strongly associated with metastatic phenotypes than the others. Immunohistochemistry data of CKS2 and MSN showed similar relationships to survival. The prognostic genes clustered into two groups, suggesting two major metastatic phenotypes. One group was associated with rapid proliferation, oxidative phosphorylation, invasiveness, and tumor size (MRPS23, MRPL11, CKS2, LSM3, TBX3, MSN) and another with hypoxia tolerance, anaerobic metabolism, and high lactate content (PDK2, KLF3). Multivariate analysis identified tumor volume and PDK2 expression as independent prognostic variables. Gene copy number changes of the differentially expressed genes were not frequent, but correlated with the expression level for seven genes, including MRPS23, MSN, and LSM3. Conclusion Gene expressions associated with known metastatic phenotypes of cervical cancers were identified. Our findings may indicate molecular mechanisms underlying development of these phenotypes and be useful as markers of cancer spread. Gains or losses of the genes may be involved in development of the metastatic phenotypes in some cases, but other mechanisms for transcriptional regulation are probably important in the majority of tumors.

• Wiel, Mark van de; Holden, Marit; Glad, Ingrid Kristine; Lyng, Heidi & Frigessi, Arnoldo (2006). Bayesian process-based modeling of two-channel microarray experiments estimating absolute mRNA concentrations. I Do, Kim-Anh; Müller, Peter & Vannucci, M. (Red.), Bayesian Inference for Gene Expression and Proteomics. Cambridge University Press. ISSN 9780521860925. s. 75–97. Fulltekst i vitenarkiv
• Scheel, Ida; Aldrin, Magne; Glad, Ingrid Kristine; Sorum, Ragnhild; Lyng, Heidi & Frigessi, Arnoldo (2005). The influence of missing value imputation on detection of differentially expressed genes from microarray data. Bioinformatics. ISSN 1367-4803. 21(23), s. 4272–4279. Fulltekst i vitenarkiv
• Frigessi, Arnoldo; Wiel, Mark van de; Holden, Marit; Svendsrud, Debbie H.; Glad, Ingrid Kristine & Lyng, Heidi (2005). Genome-wide estimation of transcript concentrations from spotted cDNA microarray data. Nucleic Acids Research (NAR). ISSN 0305-1048. 33(17). doi: 10.1093/nar/gni141. Fulltekst i vitenarkiv Vis sammendrag

  A method providing absolute transcript concentrations from spotted microarray intensity data is presented. Number of transcripts per µg total RNA, mRNA or per cell, are obtained for each gene, enabling comparisons of transcript levels within and between tissues. The method is based on Bayesian statistical modelling incorporating available information about the experiment from target preparation to image analysis, leading to realistically large confidence intervals for estimated concentrations. The method was validated in experiments using transcripts at known concentrations, showing accuracy and reproducibility of estimated concentrations, which were also in excellent agreement with results from quantitative real-time PCR. We determined the concentration for 10 157 genes in cervix cancers and a pool of cancer cell lines and found values in the range of 105–1010 transcripts per µg total RNA. The precision of our estimates was sufficiently high to detect significant concentration differences between two tumours and between different genes within the same tumour, comparisons that are not possible with standard intensity ratios. Our method can be used to explore the regulation of pathways and to develop individualized therapies, based on absolute transcript concentrations. It can be applied broadly, facilitating the construction of the transcriptome, continuously updating it by integrating future data.

• Lyng, Heidi; Landsverk, Kirsti; Kristiansen, Elin; Angelis, Paula de; Ree, Anne Hansen & Myklebost, Ola [Vis alle 8 forfattere av denne artikkelen] (2004). The response of malignant B lymphocytes to ionizing radiation: Geneexpression and genotype. International Journal of Cancer. ISSN 0020-7136. 115(6), s. 935–942. Fulltekst i vitenarkiv Vis sammendrag

  The human malignant B-lymphocyte cell lines Reh and U698 show arrest in G2 phase after ionizing radiation (IR), but only Reh cells arrest in G1 phase and die by apoptosis. We have used cDNA microarrays to measure changes in gene expression at 2, 4 and 6 hr after irradiation of Reh and U698 cells with 0.5 and 4 Gy in order to begin exploring the molecular mechanisms underlying the phenotypic changes. We also investigated whether gene expression changes could be caused by possible aberrations of genes, as measured by comparative genomic hybridization. Reh cells showed upregulation of CDKN1A that likely mediated the G1 arrest. In contrast, U698 cells have impaired function of TP53 protein and no activation of CDKN1A, suppressing the arrest in G1. The G2 arrest in both cell lines was likely due to repression of PLK1 and/or CCNF. IR-induced apoptosis in Reh cells was probably mediated by TP53 and CDKN1A, whereas a high expression level of MCL1, caused by gene amplification, and activation of the NFKB pathway may have suppressed the apoptotic response in U698 cells. Genes suggested to be involved in apoptosis were activated long before this phenotype was detectable and showed the same temporal expression profiles as genes involved in cell cycle arrest. Our results suggest that differences in functionality and/or copy number of several genes involved in IR-regulated pathways contributed to the phenotypic differences between Reh and U698 cells after IR, and that multiple molecular factors control the radiation response of malignant B lymphocytes.

• Lyng, Heidi; Badiee, Azadeh; Svendsrud, Debbie H.; Hovig, Eivind; Myklebost, Ola & Stokke, Trond (2004). Profound influence of microarray scanner characteristics on gene expression ratios: analysis and procedure for correction. BMC Genomics. 5, s. 10–10. Fulltekst i vitenarkiv
• Landsverk, Kirsti; Lyng, Heidi & Stokke, Trond (2004). The response of malignant B lymphocytes to ionizing radiation: cell cycle arrest, apoptosis and protection against the cytotoxic effects of the mitotic inhibitor nocodazole. Radiation Research. ISSN 0033-7587. 162(4), s. 405–415. Fulltekst i vitenarkiv
• Lyng, Heidi; Beigi, Marzieh; Svendsrud, Debbie H.; Brustugun, Odd Terje; Stokke, Trond & Kristensen, Gunnar S Balle [Vis alle 9 forfattere av denne artikkelen] (2004). Intratumor chromosomal heterogeneity in advanced carcinomas of the uterine cervix. International Journal of Cancer. ISSN 0020-7136. 111(3), s. 358–366. doi: 10.1002/ijc.20258. Fulltekst i vitenarkiv

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• Lyng, Heidi; Skipar, Kjersti Øvrum & Hompland, Tord (2022). Targeted Therapy on the Screen: Do We Hit the Target? Clinical Cancer Research. ISSN 1078-0432. 28(24), s. 5233–5234. doi: 10.1158/1078-0432.CCR-22-2707. Fulltekst i vitenarkiv
• Fjeldbo, Christina Sæten; Hompland, Tord; Hillestad, Tiril; Aarnes, Eva-Katrine; Kristensen, Gunnar S Balle & Malinen, Eirik [Vis alle 7 forfattere av denne artikkelen] (2019). Treatment decision support by imaging- and gene-based hypoxia classification in cervical cancer. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Hole, Knut Håkon; Lund, Kjersti Vassmo; Indahl, Ulf Geir & Kvaal, Knut [Vis alle 8 forfattere av denne artikkelen] (2017). Autodelineation of cervical cancers using multiparametric MRI and machine learning. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Grøndahl, Aurora R.; Andersen, Erlend K F; Lyng, Heidi; Malinen, Eirik & Kvaal, Knut [Vis alle 7 forfattere av denne artikkelen] (2016). Cluster analysis of DCE MRI reveals tumor subregions related to relapse of cervical cancers. Radiotherapy and Oncology. ISSN 0167-8140. 119, s. 195–195. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Hole, Knut Håkon; Lund, Kjersti Vassmo; Indahl, Ulf Geir & Kvaal, Knut [Vis alle 8 forfattere av denne artikkelen] (2015). Cervical tumour segmentation using multi-sequence MRI and linear discriminant analysis. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Grøndahl, Aurora R.; Andersen, Erlend K F; Kvaal, Knut; Lyng, Heidi & Malinen, Eirik [Vis alle 7 forfattere av denne artikkelen] (2015). Cluster analysis of DCE-MRI pharmacokinetic parameter maps is related to locoregional and metastatic relapse for cervical cancer patients. Fulltekst i vitenarkiv
• Fjeldbo, Christina Sæten; Julin, Cathinka; Lando, Malin; Forsberg, MF; Alsner, Jan & Kristensen, Gunnar S Balle [Vis alle 8 forfattere av denne artikkelen] (2015). Construction of a prognostic hypoxia gene classifier in cervical cancer that is reflected in dynamic contrast-enhanced (DCE) MR images. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Indahl, Ulf Geir; Lyng, Heidi; Kvaal, Knut & Futsæther, Cecilia Marie (2015). Cervical tumour segmentation using multi-sequence MRI and linear discriminant analysis. Radiotherapy and Oncology. ISSN 0167-8140. 115, s. 827–827. Fulltekst i vitenarkiv
• Li, Anna; Andersen, Erlend K F; Lervåg, Christoffer; Julin, Cathinka; Lyng, Heidi & Hellebust, Taran Paulsen [Vis alle 7 forfattere av denne artikkelen] (2015). Hypoxia imaging with dynamic contrast enhanced MRI and focal brachytherapy of cervical cancers. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Indahl, Ulf Geir; Kvaal, Knut; Lyng, Heidi & Futsæther, Cecilia Marie (2014). Tumour segmentation using pattern recognition techniques. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Malinen, Eirik; Kvaal, Knut; Lyng, Heidi; Indahl, Ulf Geir & Andersen, Erlend K F [Vis alle 7 forfattere av denne artikkelen] (2013). Classification of cervical cancers using texture analysis and support vector machines. Fulltekst i vitenarkiv
• Futsæther, Cecilia Marie; Torheim, Turid K Gjerstad; Malinen, Eirik & Lyng, Heidi (2013). Strålebehandling ikke like effektivt for alle med livmorhalskreft. [Internet]. forskning.no. Fulltekst i vitenarkiv
• Hellebust, Taran Paulsen; Li, Anna; Andersen, Erlend K F; Lervåg, Christoffer; Lyng, Heidi & Malinen, Eirik (2013). Hypoxia guided brachytherapy of cervical cancers using dynamic contrast enhanced MRI. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Kallehauge, Jesper; Jurgenliemk-Schulz, Ina; Tanderup, Kari; Lyng, Heidi & Malinen, Eirik (2013). Cross-institutional comparison of pharmacokinetic parameters from DCEMRI of cervical cancers: initial results. Radiotherapy and Oncology. ISSN 0167-8140. 106, s. 330–330. Fulltekst i vitenarkiv
• Li, Anna; Andersen, Erlend K F; Lervåg, Christoffer; Lyng, Heidi; Hellebust, Taran Paulsen & Malinen, Eirik (2013). Biological image guided brachytherapy of hypoxic cervical cancers. Radiotherapy and Oncology. ISSN 0167-8140. 106, s. 57–57. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Andersen, Erlend K. F.; Futsæther, Cecilia Marie; Indahl, Ulf Geir; Kvaal, Knut & Lyng, Heidi [Vis alle 7 forfattere av denne artikkelen] (2012). Classification of DCE-MR images using texture analysis and support vector machines. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Andersen, Erlend K. F.; Futsæther, Cecilia Marie; Indahl, Ulf Geir; Kruse, Ole Mathis Opstad & Kvaal, Knut [Vis alle 8 forfattere av denne artikkelen] (2012). Multivariate analysis of DCE-MRI images of cervical cancer tumours. Fulltekst i vitenarkiv
• Torheim, Turid K Gjerstad; Andersen, Erlend K. F.; Futsæther, Cecilia Marie; Indahl, Ulf Geir; Kvaal, Knut & Lyng, Heidi [Vis alle 7 forfattere av denne artikkelen] (2012). Classification of cervical cancer tumors from DCE-MRI using texture analysis and support vector machines. Fulltekst i vitenarkiv
• Redalen, Kathrine Røe; Mikalsen, Lars Tore G; Kogel, Albert van der; Bussink, Johan; Lyng, Heidi & Ree, Anne Hansen [Vis alle 8 forfattere av denne artikkelen] (2012). DCEMRI IN ASSESSMENT OF TUMOR NEOVASCULARIZATION AFTER ANDROGEN-DEPRIVATION IN EXPERIMENTAL PROSTATE CANCER: CORRELATION TO QUANTITATIVE IMMUNOHISTOCHEMISTRY. Radiotherapy and Oncology. ISSN 0167-8140. 102, s. S68–S68. doi: 10.1016/S0167-8140(12)70119-6. Fulltekst i vitenarkiv
• Ragnum, Harald Bull; Seierstad, Therese; Redalen, Kathrine Røe; Nesland, Jahn M; Holm, Ruth & Lilleby, Wolfgang [Vis alle 7 forfattere av denne artikkelen] (2012). ANDROGEN DEPRIVATION THERAPY PRIOR TO IRRADIATION OF PROSTATE CANCER: EXPRESSION OF HYPOXIA-INDUCED PROTEINS AND CHANGES IN DIFFUSION WEIGHTED MRI PARAMETERS. Radiotherapy and Oncology. ISSN 0167-8140. 102, s. S93–S94. doi: 10.1016/S0167-8140(12)70165-2. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Hole, Knut Håkon; Lund, Kjersti Vassmo; Kristensen, Gunnar S Balle; Lyng, Heidi & Malinen, Eirik (2012). IMPACT OF TUMOR DELINEATION ERRORS ON OUTCOME PREDICTION BASED ON DCE-MRI OF CERVICAL CANCER PATIENTS RECEIVING RT. Radiotherapy and Oncology. ISSN 0167-8140. 103, s. 72–72. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Kristensen, Gunnar S Balle; Lyng, Heidi & Malinen, Eirik (2011). SEGMENTATION OF DCEMR IMAGES OF CERVICAL CANCERS USING K-MEANS CLUSTERING FOR OUTCOME PREDICTION. Radiotherapy and Oncology. ISSN 0167-8140. 99, s. 128–128. Fulltekst i vitenarkiv
• Andersen, Erlend K F; Kristensen, Gunnar S Balle; Lyng, Heidi & Malinen, Eirik (2011). Clustering analysis of DCEMRI for prediction of radiotherapy outcome. Fulltekst i vitenarkiv
• Halle, Cathinka Lønning; Holm, Ruth; Lando, Malin; Kristensen, Gunnar S Balle & Lyng, Heidi (2010). Prognostic value of EGFR phosphorylation and short isoforms in cervical cancer patients receiving chemoradiotherapy. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 213–214. Fulltekst i vitenarkiv
• Ferkingstad, Egil; Frigessi, Arnoldo & Lyng, Heidi (2010). Indirect genomic effects on survival from gene expression data. Fulltekst i vitenarkiv
• Lando, Malin; Holm, Ruth; Kristensen, Gunnar S Balle & Lyng, Heidi (2010). The RYBP apoptosis pathway is deactivated in cervical cancer patients with 3p-loss. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 213–213. Fulltekst i vitenarkiv
• Ferkingstad, Egil; Frigessi, Arnoldo & Lyng, Heidi (2009). Indirect genomic effects on survival from gene expression data. Fulltekst i vitenarkiv
• Frigessi, Arnoldo; Wiel, Mark A. van de; Holden, Marit; Svendsrud, Debbie H.; Glad, Ingrid K. & Lyng, Heidi (2005). Absolute mRNA concentrations from MA-data. Fulltekst i vitenarkiv
• Redalen, Kathrine Røe; Olsen, Dag Rune; Ree, Anne Hansen & Lyng, Heidi (2012). Treatment response evaluation in experimental prostate cancer by functional magnetic resonance imaging and molecular profiling. Unipub forlag. ISSN 9788282642729. Fulltekst i vitenarkiv
• Frigessi, Arnoldo; Wiel, Mark Van der; Holden, Marit; Glad, Ingrid Kristine; Lyng, Heidi & Wiel, Mark A. van de [Vis alle 7 forfattere av denne artikkelen] (2004). Model-based estimation of transcript concentrations from spotted microarray data. Norsk Regnesentral. ISSN 9788253905075. Fulltekst i vitenarkiv Vis sammendrag

  In this paper a bootstrap algorithm Much data from spotted microarrays remain unused because obtained with different protocols, platforms or designs, making comparisons across experiments impossible. We have developed a model-based method, which provides absolute transcript levels. Transcript levels are universal, and can be included in further analyses with similar estimates obtained with different techniques in other laboratories. It is a first step both towards genuine meta-analyses, including comparisons across different organisms, and the building of data bases of transcript levels in cells. Our method is based on statistical modelling incorporating all available information about the experiment, from target preparation to image analysis, coherently propagating uncertainties from data to estimates. It requires some genes spotted in replicates, their number being related to the levels of experimental factors included in the model, but not to the number of spotted genes. No uncertainty in the estimates caused by decimated data sets, indirect comparisons, normalisation or imputation of missing values, is introduced, leading to a far more precise analysis of microarray data than provided by conventional methods. Using a flexible Bayesian technique we estimate the highly multivariate joint posterior distribution of all transcripts, which enables extended exploitation of the data. In the present work we apply our method to cervical cancer data. We show that the estimated transcript concentrations are accurate and reproducible, and demonstrate improved statistical tools for selecting genes based on their concentration in highly unbalanced experimental settings.

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