Arild Nesbakken

• Bruun J, Kryeziu K, Eide PW, Moosavi SH, Eilertsen IA, Langerud J, Røsok BI, Totland MZ, Brunsell TH, Pellinen T, Saarela J, Bergsland CH, Palmer HG, Brudvik KW, Guren T, Dienstmann R, Guren MG, Nesbakken A, Bjørnbeth BA, Sveen A, Lothe RA. Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity.  Clin Cancer Res. 2020 Apr 16. [Epub ahead of print]
• Skrede OJ, De Raedt S, Kleppe A, Hveem TS, Liestøl K, Maddison J, Askautrud HA, Pradhan M, Nesheim JA, Albregtsen F, Farstad IN, Domingo E, Church DN, Nesbakken A, Shepherd NA, Tomlinson I, Kerr R, Novelli M, Kerr DJ, Danielsen HE.  Deep learning for prediction of colorectal cancer outcome: a discovery and validation study. Lancet. 2020; 395 (10221):350-360.
• Smeby J, Sveen A, Bergsland CH, Eilertsen IA, Danielsen SA, Eide PW, Hektoen M, Guren MG, Nesbakken A, Bruun J, Lothe RA.. Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer. ESMO Open. 2019 Jun 24;4(3):e000523
• Brunsell TH, Sveen A, Bjørnbeth BA, Røsok BI, Danielsen SA, Brudvik KW, Berg KCG, Johannessen B, Cengija V, Abildgaard A, Guren MG, Nesbakken A, Lothe RA. High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases.   Clin Colorectal Cancer. 2020;19:e26-e47
• Brunsell TH, Cengija V, Sveen A, Bjørnbeth BA, Røsok BI, Brudvik KW, Guren MG, Lothe RA, Abildgaard A, Nesbakken A. Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases. Eur J Surg Oncol. 2019; 45:2340-2346.
• Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol. 2019; 30:1622-1629.
• Smeby J, Sveen A, Merok MA, Danielsen SA, Eilertsen IA, Guren MG, Dienstmann R, Nesbakken A, Lothe RA.  CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Ann Oncol. 2018; 29:1227-1234
• Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumägi A, Arjama M, Danielsen SA, Kryeziu K, Elez E, Tabernero J, Guinney J, Palmer HG, Nesbakken A, Kallioniemi O, Dienstmann R, Lothe RA.  Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies  Clin Cancer Res. 2018; 24:794-806
• Joranger P, Nesbakken A, Sorbye H, Hoff G, Oshaug A, Aas E. Survival and costs of colorectal cancer treatment and effects of changing treatment strategies: a model approach. Eur J Health Econ. 2020; 21: 321-334
• Ommundsen N, Wyller TB, Nesbakken A, Bakka AO, Jordhøy MS, Skovlund E, Rostoft S. Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial. Colorectal Dis. 2018; 20: 16-25
• Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol. 2019; 30: 1622-1629.
• Dienstmann R, Mason MJ, Sinicrope FA, Phipps AI, Tejpar S, Nesbakken A, Danielsen SA, Sveen A, Buchanan DD, Clendenning M, Rosty C, Bot B, Alberts SR, Milburn Jessup J, Lothe RA, Delorenzi M, Newcomb PA, Sargent D, Guinney J.  Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol. 2017; 28: 1023-1031
• Labori KJ, Guren MG, Brudvik KW, Røsok BI, Waage A, Nesbakken A, Larsen S, Dueland S, Edwin B, Bjørnbeth BA.  Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short term surgical outcomes, overall and recurrence free survivals. Colorectal Dis. 2017; 19: 731-8
• Kristjansson SR, Nesbakken A, Jordhøy MS, Skovlund E, Audisio RA, Johannessen HO, Bakka A, Wyller TB.  Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study.  Crit Rev Oncol Hematol. 2010; 76: 208-17
• Lind GE, Danielsen SA, Ahlquist T, Merok MA, Andresen K, Skotheim RI, Hektoen M, Rognum TO, Meling GI, Hoff G, Bretthauer M, Thiis-Evensen E, Nesbakken A, Lothe RA.  Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas  Mol Cancer. 2011; 10: 85

• Nunes, Luis; Nesbakken, Arild; Lothe, Ragnhild Adelheid & Sveen, Anita (2026). Temporal Trends in Cancer Mortality Among People Younger Than 50 Years in Norway. JAMA Network Open. 9(8), s. e2629437–e2629437. doi: 10.1001/jamanetworkopen.2026.29437. Fulltekst i vitenarkiv
• Kryeziu, Kushtrim; Klokkerud, Solveig Knoph; Totland, Max Zachrisson; Moosavi, Hossein; Reims, Henrik Mikael & Bergsland, Christian Holst [Vis alle 17 forfattere av denne artikkelen] (2026). Patient-derived organoids from metastatic colorectal cancer mirror tumor heterogeneity and predict patient survival and drug sensitivity. Cell Reports Medicine. 7(6). doi: 10.1016/j.xcrm.2026.102840. Fulltekst i vitenarkiv Vis sammendrag

  This study reports the pharmacogenomic analysis of tumor heterogeneity in a living biobank of 213 organoids derived from liver metastases of 102 patients with metastatic colorectal cancer. Successful organoid establishment reflects poorer chemosensitivity and patient survival. Molecular fidelity is confirmed in tumor-organoid pairs, and multi-modal phenotypes are defined based on organoid morphology. Cystic morphology associates with intestinal stem cell markers and greater drug sensitivity, while solid morphology is linked to markers of plasticity and aggressiveness. The potential to identify treatments less affected by tumor heterogeneity is supported by multi-lesion analyses in 65 patients. Clinical translation is illustrated in two prospective cases of pharmacogenomics-guided treatment, including successful chemotherapy rechallenge and targeted therapy resistance in cancers with low and high heterogeneity. All pharmacogenomic data are openly available as a functional oncology resource to support interpretation of ex vivo drug sensitivities into clinical “actionability.”

• Skrede, Ole-Johan; Pradhan, Manohar; Isaksen, Maria; Hveem, Tarjei Sveinsgjerd; Vlatkovic, Ljiljana & Nesbakken, Arild [Vis alle 23 forfattere av denne artikkelen] (2026). Generalisation of automatic tumour segmentation in histopathological whole-slide images across multiple cancer types. NPJ precision oncology. 10. doi: 10.1038/s41698-026-01311-6. Fulltekst i vitenarkiv Vis sammendrag

  Deep learning is expected to aid pathologists in tasks such as tumour segmentation. We developed a general tumour segmentation model for histopathological images and examined its performance in different cancer types. The model was developed using over 20,000 whole-slide images from over 4000 patients with colorectal, endometrial, lung, or prostate carcinoma. Performance was validated in pre-planned analyses on external cohorts with over 3000 patients across six cancer types. Exploratory analyses included over 1500 additional patients from The Cancer Genome Atlas. Average Dice coefficient was over 80% in all validation cohorts with en bloc resection specimens and in The Cancer Genome Atlas cohorts. No performance loss was observed when comparing the general model with single-cancer models specialised in cancer types from the development set. In conclusion, extensive and rigorous evaluations demonstrate that generic tumour segmentation by a single model is possible across cancer types, patient populations, sample preparations and slide scanners.

• Viktil, Ellen; Hanekamp, Bettina Andrea; Nesbakken, Arild; Sjo, Ole Helmer; Negård, Anne & Dormagen, Johann Baptist [Vis alle 7 forfattere av denne artikkelen] (2025). Bisacodyl micro-enema before MRI of rectal tumors: effects on rectum, image quality and patient acceptance. European Radiology. ISSN 0938-7994. doi: 10.1007/s00330-025-11996-1. Fulltekst i vitenarkiv
• Viktil, Ellen; Hanekamp, Bettina; Nesbakken, Arild; Løberg, Else Marit; Sjo, Ole Helmer & Negård, Anne [Vis alle 8 forfattere av denne artikkelen] (2024). Early rectal cancer: The diagnostic performance of MRI supplemented with a rectal micro-enema and a modified staging system to identify tumors eligible for local excision. Acta Radiologica Open. 13(5). doi: 10.1177/20584601241241523. Fulltekst i vitenarkiv Vis sammendrag

  Background In staging early rectal cancers (ERC), submucosal tumor depth is one of the most important features determining the possibility of local excision (LE). The micro-enema (Bisacodyl) induces submucosal edema and may hypothetically improve the visualization of tumor depth. Purpose To test the diagnostic performance of MRI to identify ERC suitable for LE when adding a pre-procedural micro-enema and concurrent use of a modified classification system. Material and Methods In this prospective study, we consecutively included 73 patients with newly diagnosed rectal tumors. Two experienced radiologists independently interpreted the MRI examinations, and diagnostic performance was calculated for local tumors eligible for LE (Tis-T1sm2, n = 43) and non-local tumors too advanced for LE (T1sm3-T3b, n = 30). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were registered for each reader. Inter- and intra-reader agreements were assessed by kappa statistics. Lymph node status was derived from the clinical MRI reports. Results Reader1/reader2 achieved sensitivities of 93%/86%, specificities of 90%/83%, PPV of 93%/88%, and NPV of 90%/81%, respectively, for identifying tumors eligible for LE. Rates of overstaging of local tumors were 7% and 14% for the two readers, and kappa values for the inter- and intra-reader agreement were 0.69 and 0.80, respectively. For tumors ≤T2, all metastatic lymph nodes were smaller than 3 mm on histopathology. Conclusion MRI after a rectal micro-enema and concurrent use of a modified staging system achieved good diagnostic performance to identify tumors suitable for LE. The rate of overstaging of local tumors was comparable to results reported in previous endorectal ultrasound (ERUS) studies.

• Viktil, Ellen; Hanekamp, Bettina; Nesbakken, Arild; Løberg, Else Marit; Sjo, Ole Helmer & Negård, Anne [Vis alle 8 forfattere av denne artikkelen] (2024). MRI of early rectal cancer; bisacodyl micro-enema increases submucosal width, reader confidence, and tumor conspicuity. Abdominal Radiology. ISSN 2366-004X. 00(0), s. 1–13. doi: 10.1007/s00261-024-04701-1. Fulltekst i vitenarkiv Vis sammendrag

  Purpose To investigate the influence of a micro-enema on diagnostic performance, submucosal width, reader confidence, and tumor conspicuity using MRI to stage early rectal cancers (ERC). Methods In this single-center study, we consecutively included 50 participants with assumed ERC who all completed MRI with (MRin) and without (MRex) a micro-enema. The diagnostic performance was recorded for two experienced radiologists using histopathology as the gold standard. In addition, the width of the submucosa in the tumor-bearing wall, reader confidence for T-staging, and tumor conspicuity were assessed. Significance levels were calculated using McNemar’s test (diagnostic performance) and Wilcoxon’s signed-rank test (reader confidence, submucosal width, and conspicuity). Interreader agreement was assessed using kappa statistics. Results Sensitivity/specificity were for Reader1 91%/87% for both MRex and MRin and for Reader2 74%/87% and 89%/87%, both readers p > 0.05. The micro-enema induced a significant widening of the submucosa, p < 0.001, with a mean increase of 2.2/2.8 mm measured by Reader1/Reader2. Reader confidence in T-staging and tumor conspicuity increased for both readers, p < 0.005. The proportion of tumors with both correct staging and high reader confidence increased from 58% (29/50) to 80% (40/50) (p = 0.04) for Reader1 and from 42% (21/50) to 72% (36/50) (p = 0.002) for Reader2. Interreader agreement increased from moderate (kappa 0.58) to good (kappa 0.68). Conclusion The micro-enema significantly increased the submucosal width in the tumor-bearing wall, reader confidence, and tumor conspicuity and improved interreader agreement from moderate to good. Sensitivity and specificity in T-staging did not improve, but there was a significant increase in the proportion of tumors staged with both high confidence and correct T-stage.

• Majid, Umair; Bergsland, Christian Holst; Sveen, Anita; Bruun, Jarle; Eilertsen, Ina Andrassy & Bækkevold, Espen Sønderaal [Vis alle 10 forfattere av denne artikkelen] (2024). The prognostic effect of tumor-associated macrophages in stage I-III colorectal cancer depends on T cell infiltration. Cellular Oncology. ISSN 2211-3428. 47(4), s. 1267–1276. doi: 10.1007/s13402-024-00926-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Tumor-associated macrophages (TAMs) are associated with unfavorable patient prognosis in many cancer types. However, TAMs are a heterogeneous cell population and subsets have been shown to activate tumor-infiltrating T cells and confer a good patient prognosis. Data on the prognostic value of TAMs in colorectal cancer are conflicting. We investigated the prognostic effect of TAMs in relation to tumor-infiltrating T cells in colorectal cancers. Methods The TAM markers CD68 and CD163 were analyzed by multiplex fluorescence immunohistochemistry and digital image analysis on tissue microarrays of 1720 primary colorectal cancers. TAM density in the tumor stroma was scored in relation to T cell density (stromal CD3+ and epithelial CD8+ cells) and analyzed in Cox proportional hazards models of 5-year relapse-free survival. Multivariable survival models included clinicopathological factors, MSI status and BRAFV600E mutation status. Results High TAM density was associated with a favorable 5-year relapse-free survival in a multivariable model of patients with stage I–III tumors (p = 0.004, hazard ratio 0.94, 95% confidence interval 0.90–0.98). However, the prognostic effect was dependent on tumoral T-cell density. High TAM density was associated with a good prognosis in patients who also had high T-cell levels in their tumors, while high TAM density was associated with poorer prognosis in patients with low T-cell levels (pinteraction = 0.0006). This prognostic heterogeneity was found for microsatellite stable tumors separately. Conclusions This study supported a phenotypic heterogeneity of TAMs in colorectal cancer, and showed that combined tumor immunophenotyping of multiple immune cell types improved the prediction of patient prognosis.

• Langerud, Jonas; Eilertsen, Ina Andrassy; Moosavi, Hossein; Klokkerud, Solveig Margrete Knoph; Reims, Henrik Mikael & Backe, Ingeborg Flåten [Vis alle 13 forfattere av denne artikkelen] (2024). Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer. Nature Communications. 15(1). doi: 10.1038/s41467-024-48706-2. Fulltekst i vitenarkiv Vis sammendrag

  Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.

• Rostoft, Siri; Thomas, Michael; Jordhøy, Marit Slaaen; Møller, Bjørn; Nesbakken, Arild & Syse, Astri (2023). Hospital use and cancer treatment by age and socioeconomic status in the last year of life: A Norwegian population-based study of patients dying of cancer. Journal of Geriatric Oncology. ISSN 1879-4068. 15(2). doi: 10.1016/j.jgo.2023.101683. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Cancer is the leading cause of death in Norway. In this nationwide study we describe the number and causes of hospital admissions and treatment in the final year of life for patients who died of cancer, as well as the associations to age and socioeconomic status (SES). Materials and Methods From nationwide registries covering 2010–2014, we identified all patients who were diagnosed with cancer 12–60 months before death and had cancer as their reported cause of death. We examined the number of overnight hospital stays, causes of admission, and treatment (chemotherapy, radiotherapy, surgical procedures) offered during the last year of life by individual (age, sex, comorbidity), cancer (type, stage, months since diagnosis), and socioeconomic variables (co-residential status, income, education). Results The analytical sample included 17,669 patients; 8,247 (47%) were female, mean age was 71.7 years (standard deviation 13.7). At diagnosis, 31% had metastatic disease, while 29% had an intermediate or high comorbidity burden. Altogether, 94% were hospitalized during their final year, 82% at least twice, and 33% six times or more. Patients spent a median of 23 days in hospital (interquartile range 11–41), and altogether 38% died there. Younger age, bladder and ovarian cancer, not living alone, and higher income were associated with having ≥6 hospitalizations. Cancer-related diagnoses were the main causes of hospitalizations (65%), followed by infections (11%). Around 51% had ≥1 chemotherapy episode, with large variations according to patient age and SES; patients who were younger, did not live alone, had high education, and high income received more chemotherapy. Radiotherapy was received by 15% and declined with age, and the variation according to SES characteristics was minor. Of the 12,940 patients with a cancer type where surgery is a main treatment modality, only 835 (6%) underwent surgical procedures for their primary tumor in the last year of life. Discussion Most patients who die of cancer are hospitalized multiple times during the last year of life. Hospitalizations and treatment decline with advancing age. Living alone and having low income is associated with fewer hospitalizations and less chemotherapy treatment. Whether this indicates over- or undertreatment across various groups warrants further exploration.

• Kleppe, Andreas; Skrede, Ole-Johan; Raedt, Sepp De; Hveem, Tarjei Sveinsgjerd; Askautrud, Hanne Arenberg & Jacobsen, Jørn E. [Vis alle 14 forfattere av denne artikkelen] (2022). A clinical decision support system optimising adjuvant chemotherapy for colorectal cancers by integrating deep learning and pathological staging markers: a development and validation study. The Lancet Oncology. ISSN 1470-2045. 23(9), s. 1221–1232. doi: 10.1016/S1470-2045(22)00391-6. Fulltekst i vitenarkiv Vis sammendrag

  The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment. Methods We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival. Findings The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39–17·93; p<0·0001) for high-risk versus low-risk patients and 3·06 (1·73–5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1–98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7–96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1–82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients). Interpretation Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs.

• Bergsland, Christian Holst; Jeanmougin, Marine; Moosavi, Seyed Hossein; Svindland, Aud; Bruun, Jarle & Nesbakken, Arild [Vis alle 8 forfattere av denne artikkelen] (2022). Spatial analysis and CD25-expression identify regulatory T cells as predictors of a poor prognosis in colorectal cancer. Modern Pathology. ISSN 0893-3952. 35, s. 1236–1246. doi: 10.1038/s41379-022-01086-8. Fulltekst i vitenarkiv Vis sammendrag

  Regulatory T cells (Tregs) are a heterogeneous cell population that can either suppress or stimulate immune responses. Tumor-infiltrating Tregs are associated with an adverse outcome from most cancer types, but have generally been found to be associated with a good prognosis in colorectal cancer (CRC). We investigated the prognostic heterogeneity of Tregs in CRC by co-expression patterns and spatial analyses with diverse T cell markers, using multiplex fluorescence immunohistochemistry and digital image analysis in two consecutive series of primary CRCs (total n = 1720). Treg infiltration in tumors, scored as FOXP3+ or CD4+/CD25+/FOXP3+ (triple-positive) cells, was strongly correlated to the overall amount of CD3+ and CD8+ T cells, and consequently associated with a favorable 5-year relapse-free survival rate among patients with stage I–III CRC who underwent complete tumor resection. However, high relative expression of the activation marker CD25 in triple-positive Tregs was independently associated with an adverse outcome in a multivariable model incorporating clinicopathological and known molecular prognostic markers (hazard ratio = 1.35, p = 0.028). Furthermore, spatial marker analysis based on Voronoi diagrams and permutation testing of cellular neighborhoods revealed a statistically significant proximity between Tregs and CD8+-cells in 18% of patients, and this was independently associated with a poor survival (multivariable hazard ratio = 1.36, p = 0.017). These results show prognostic heterogeneity of different Treg populations in primary CRC, and highlight the importance of multi-marker and spatial analyses for accurate immunophenotyping of tumors in relation to patient outcome.

• Sveen, Anita; Johannessen, Bjarne; Eilertsen, Ina Andrassy; Røsok, Bård Ingvald; Gulla, Marie & Eide, Peter Andreas Wold [Vis alle 14 forfattere av denne artikkelen] (2021). The expressed mutational landscape of microsatellite stable colorectal cancers. Genome Medicine. 13. doi: 10.1186/s13073-021-00955-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Colorectal cancer is the 2nd leading cause of cancer-related deaths with few patients benefiting from biomarker-guided therapy. Mutation expression is essential for accurate interpretation of mutations as biomarkers, but surprisingly, little has been done to analyze somatic cancer mutations on the expression level. We report a large-scale analysis of allele-specific mutation expression. Methods Whole-exome and total RNA sequencing was performed on 137 samples from 121 microsatellite stable colorectal cancers, including multiregional samples of primary and metastatic tumors from 4 patients. Data were integrated with allele-specific resolution. Results were validated in an independent set of 241 colon cancers. Therapeutic associations were explored by pharmacogenomic profiling of 15 cell lines or patient-derived organoids. Results The median proportion of expressed mutations per tumor was 34%. Cancer-critical mutations had the highest expression frequency (gene-wise mean of 58%), independent of frequent allelic imbalance. Systematic deviation from the general pattern of expression levels according to allelic frequencies was detected, including preferential expression of mutated alleles dependent on the mutation type and target gene. Translational relevance was suggested by correlations of KRAS/NRAS or TP53 mutation expression levels with downstream oncogenic signatures (p < 0.03), overall survival among patients with stage II and III cancer (KRAS/NRAS: hazard ratio 6.1, p = 0.0070), and targeted drug sensitivity. The latter was demonstrated for EGFR and MDM2 inhibition in pre-clinical models. Conclusions Only a subset of mutations in microsatellite stable colorectal cancers were expressed, and the “expressed mutation dose” may provide an opportunity for more fine-tuned biomarker interpretations.

• Eide, Peter Andreas Wold; Moosavi, Seyed Hossein; Eilertsen, Ina Andrassy; Brunsell, Tuva Høst; Langerud, Jonas & Berg, Kaja Christine Graue [Vis alle 11 forfattere av denne artikkelen] (2021). Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer. NPJ GENOMIC MEDICINE. 6:59, s. 1–9. doi: 10.1038/s41525-021-00223-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Gene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set ( n  = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

• Kleive, Dyre; Aas, Eline; Angelsen, Jon-Helge; Bringeland, Erling Audun; Nesbakken, Arild & Nymo, Linn Såve [Vis alle 9 forfattere av denne artikkelen] (2021). Simultaneous Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: Contemporary Practice, Evidence and Knowledge Gaps. Oncology and Therapy. ISSN 2366-1070. 9(1), s. 111–120. doi: 10.1007/s40487-021-00148-2. Fulltekst i vitenarkiv Vis sammendrag

  The timing of surgical resection of synchronous liver metastases from colorectal cancer has been debated for decades. Several strategies have been proposed, but high-level evidence remains scarce. Simultaneous resection of the primary tumour and liver metastases has been described in numerous retrospective audits and meta-analyses. The potential benefits of simultaneous resections are the eradication of the tumour burden in one procedure, overall shorter procedure time, reduced hospital stay with the likely benefits on quality of life and an expected reduction in the use of health care services compared to staged procedures. However, concerns about accumulating complications and oncological outcomes remain and the optimal selection criteria for whom simultaneous resections are beneficial remains undetermined. Based on the current level of evidence, simultaneous resection should be restricted to patients with a limited liver tumour burden. More high-level evidence studies are needed to evaluate the quality of life, complication burden, oncological outcomes, as well as overall health care implications for simultaneous resections.

• Kryeziu, Kushtrim; Moosavi, Seyed Hossein; Bergsland, Christian Holst; Guren, Marianne; Eide, Peter Andreas Wold & Totland, Max [Vis alle 11 forfattere av denne artikkelen] (2021). Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases. Journal of Translational Medicine. 19:384, s. 1–11. doi: 10.1186/s12967-021-03062-3. Fulltekst i vitenarkiv Vis sammendrag

  Tumor heterogeneity is a primary cause of treatment failure. However, changes in drug sensitivity over time are not well mapped in cancer. Patient-derived organoids (PDOs) may predict clinical drug responses ex vivo and ofer an opportunity to evaluate novel treatment strategies in a personalized fashion. Here we have evaluated spatio-temporal functional and molecular dynamics of fve PDO models established after hepatic re-resections and neoadjuvant combination chemotherapies in a patient with microsatellite stable and KRAS mutated metastatic rectal cancer. Histopathological diferentiation phenotypes of the PDOs corresponded with the liver metastases, and ex vivo drug sensitivities generally refected clinical responses and selection pressure, assessed in comparison to a reference data set of PDOs from metastatic colorectal cancers. PDOs from the initial versus the two recurrent metastatic settings showed heterogeneous cell morphologies, protein marker expression, and drug sensitivities. Exploratory analyses of a drug screen library of 33 investigational anticancer agents showed the strongest ex vivo sensitivity to the SMAC mimetic LCL161 in PDOs of recurrent disease compared to those of the initial metastasis. Functional analyses confrmed target inhibition and apoptosis induction in the LCL161 sensitive PDOs from the recurrent metastases. Gene expression analyses indicated an association between LCL161 sensitivity and tumor necrosis factor alpha signaling and RIPK1 gene expression. In conclusion, LCL161 was identifed as a possible experimental therapy of a metastatic rectal cancer that relapsed after hepatic resection and standard systemic treatment.

• Bruun, Jarle; Eide, Peter Andreas Wold; Bergsland, Christian Holst; Brück, Oscar; Svindland, Aud & Arjama, Mariliina [Vis alle 13 forfattere av denne artikkelen] (2021). E-cadherin is a robust prognostic biomarker in colorectal cancer and low expression is associated with sensitivity to inhibitors of topoisomerase, aurora, and HSP90 in preclinical models. Molecular Oncology. ISSN 1574-7891. 00, s. 1–18. doi: 10.1002/1878-0261.13159. Fulltekst i vitenarkiv Vis sammendrag

  Cell–cell and cell–matrix adhesion proteins that have been implicated in colorectal epithelial integrity and epithelial-to-mesenchymal transition could be robust prognostic and potential predictive biomarkers for standard and novel therapies. We analyzed in situ protein expression of E-cadherin (ECAD), integrin β4 (ITGB4), zonula occludens 1 (ZO-1), and cytokeratins in a single-hospital series of Norwegian patients with colorectal cancer (CRC) stages I–IV (n = 922) using multiplex fluorescence-based immunohistochemistry (mfIHC) on tissue microarrays. Pharmacoproteomic associations were explored in 35 CRC cell lines annotated with drug sensitivity data on > 400 approved and investigational drugs. ECAD, ITGB4, and ZO-1 were positively associated with survival, while cytokeratins were negatively associated with survival. Only ECAD showed independent prognostic value in multivariable Cox models. Clinical and molecular associations for ECAD were technically validated on a different mfIHC platform, and the prognostic value was validated in another Norwegian series (n = 798). In preclinical models, low and high ECAD expression differentially associated with sensitivity to topoisomerase, aurora, and HSP90 inhibitors, and EGFR inhibitors. E-cadherin protein expression is a robust prognostic biomarker with potential clinical utility in CRC.

• Moosavi, Seyed Hossein; Eide, Peter Andreas Wold; Eilertsen, Ina Andrassy; Brunsell, Tuva Høst; Berg, Kaja Christine Graue & Røsok, Bård Ingvald [Vis alle 12 forfattere av denne artikkelen] (2021). De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity. Genome Medicine. 13, s. 143–143. doi: 10.1186/s13073-021-00956-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework. Methods In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients. Results Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1. Conclusions We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing.

• Slørdahl, Kathinka; Klotz, Dagmar; Olsen, Jan Åge; Skovlund, Eva; Undseth, Christine & Abildgaard, Heidi L. [Vis alle 17 forfattere av denne artikkelen] (2021). Treatment outcomes and prognostic factors after chemoradiotherapy for anal cancer. Acta Oncologica. ISSN 0284-186X. 60(7), s. 921–930. doi: 10.1080/0284186X.2021.1918763. Fulltekst i vitenarkiv Vis sammendrag

  Background Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with rising incidence, associated with human papilloma virus (HPV). Chemoradiotherapy (CRT) is the preferred treatment. The purpose was to investigate treatment failure, survival and prognostic factors after CRT. Material and methods In this prospective observational study from a large regional centre, 141 patients were included from 2013 to 2017, and 132 were eligible for analysis. The main inclusion criteria were SCCA, planned radiotherapy, and performance status (ECOG) ≤2. Patient characteristics, disease stage, treatment, and treatment response were prospectively registered. Disease-free survival (DFS), overall survival (OS), and locoregional treatment failure after CRT were analysed. Hazard ratios (HRs) were estimated with Cox`s proportional hazards model. Results Median follow-up was 54 (range 6–71) months. Eighteen patients (14%) had treatment failures after CRT; of these 10 (8%) had residual tumour, and 8 (6%) relapse as first failure. The first treatment failure was locoregional (11 patients), distant (5 patients), and both (2 patients). Salvage abdomino-perineal resection was performed in 10 patients, 2 had resections of metastases, and 3 both. DFS was 85% at 3 years and 78% at 5 years. OS was 93% at 3 years and 86% at 5 years. In analyses adjusted for age and gender, HPV negative tumours (HR 2.5, p = 0.024), N3 disease (HR 2.6, p = 0.024), and tumour size ≥4 cm (HR 2.4, p = 0.038) were negative prognostic factors for DFS. Conclusion State-of-the-art chemoradiotherapy for SCCA resulted in excellent outcomes, and improved survival compared with previous national data, with <15% treatment failures and a 3-year DFS of >80%.

• Smeby, Jørgen; Kryeziu, Kushtrim; Berg, Kaja Christine Graue; Eilertsen, Ina Andrassy; Eide, Peter Andreas Wold & Johannessen, Bjarne [Vis alle 11 forfattere av denne artikkelen] (2020). Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMedicine. 59:102923, s. 1–13. doi: 10.1016/j.ebiom.2020.102923. Fulltekst i vitenarkiv Vis sammendrag

  Background PARP inhibitors are active in various tumour types beyond BRCA-mutant cancers, but their activity and molecular correlates in colorectal cancer (CRC) are not well studied. Methods Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP inhibitor sensitive and resistant cell lines. Findings A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition. Interpretation PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.

• Skrede, Ole-Johan; Raedt, Sepp De; Kleppe, Andreas; Hveem, Tarjei Sveinsgjerd; Liestøl, Knut & Maddison, John [Vis alle 20 forfattere av denne artikkelen] (2020). Deep learning for prediction of colorectal cancer outcome: a discovery and validation study. The Lancet. ISSN 0140-6736. 395:10221, s. 350–360. doi: 10.1016/S0140-6736(19)32998-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. Methods More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. Findings 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72–5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07–4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion. Interpretation A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes.

• Berg, Kaja Christine Graue; Brunsell, Tuva Høst; Sveen, Anita; Alagaratnam, Sharmini; Bjørnslett, Merete Pauline & Hektoen, Merete [Vis alle 11 forfattere av denne artikkelen] (2020). Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co-mutated resectable colorectal liver metastases. Molecular Oncology. ISSN 1574-7891. s. 1–16. doi: 10.1002/1878-0261.12885. Fulltekst i vitenarkiv Vis sammendrag

  Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAFV600, and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high‐level amplifications of cancer‐critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAFV600E and TP53 co‐mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome‐wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAFV600E/TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co‐mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, P = 0.013; co‐mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co‐mutated RAS/BRAFV600E/TP53.

• Bergsland, Christian Holst; Bruun, Jarle; Guren, Marianne; Svindland, Aud; Bjørnslett, Merete Pauline & Smeby, Jørgen [Vis alle 16 forfattere av denne artikkelen] (2020). Prediction of relapse-free survival according to adjuvant chemotherapy and regulator of chromosome condensation 2 (RCC2) expression in colorectal cancer. ESMO Open. 5:e001040(6), s. 1–12. doi: 10.1136/esmoopen-2020-001040. Fulltekst i vitenarkiv Vis sammendrag

  Background There is a need for improved selection of patients for adjuvant chemotherapy after resection of non-metastatic colorectal cancer (CRC). Regulator of chromosome condensation 2 (RCC2) is a potential prognostic biomarker. We report on the establishment of a robust protocol for RCC2 expression analysis and prognostic tumour biomarker evaluation in patients who did and did not receive adjuvant chemotherapy. Materials and methods RCC2 was analysed in 2916 primary CRCs from the QUASAR2 randomised trial and two single-hospital Norwegian series. A new protocol using fluorescent antibody staining and digital image analysis was optimised. Biomarker value for 5-year relapse-free survival was analysed in relation to tumour stage, adjuvant chemotherapy and the molecular markers microsatellite instability, KRAS/BRAFV600E/TP53 mutations and CDX2 expression. Results Low RCC2 expression was scored in 41% of 2696 evaluable samples. Among patients with stage I–III CRC who had not received adjuvant chemotherapy, low RCC2 expression was an independent marker of inferior 5-year relapse-free survival in multivariable Cox models including clinicopathological factors and molecular markers (HR 1.45, 95% CI 1.09 to 1.94, p=0.012, N=521). RCC2 was not prognostic in patients who had received adjuvant chemotherapy, neither in QUASAR2 nor the pooled Norwegian series. The interaction between RCC2 and adjuvant chemotherapy for prediction of patient outcome was significant in stage III, and strongest among patients with microsatellite stable tumours (pinteraction=0.028). Conclusions Low expression of RCC2 is a biomarker for poor prognosis in patients with stage I–III CRC and seems to be a predictive biomarker for effect of adjuvant chemotherapy.

• Gallo, Gaetano; Pata, Francesco; Vennix, S.; Laurberg, S.; Morton, D. & Rubbini, M. [Vis alle 1 087 forfattere av denne artikkelen] (2020). Predictors for anastomotic leak, postoperative complications, and mortality after right colectomy for cancer: Results from an international snapshot audit. Diseases of the Colon & Rectum. ISSN 0012-3706. 63(5), s. 606–618. doi: 10.1097/DCR.0000000000001590. Fulltekst i vitenarkiv
• Bruun, Jarle; Kryeziu, Kushtrim; Eide, Peter Andreas Wold; Moosavi, Seyed Hossein; Eilertsen, Ina Andrassy & Røsok, Bård Ingvald [Vis alle 21 forfattere av denne artikkelen] (2020). Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity. Clinical Cancer Research. ISSN 1078-0432. 26(15), s. 4107–4119. doi: 10.1158/1078-0432.CCR-19-3637. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients. Results: Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression. Conclusions: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.

• Glaire, Mark A; Domingo, Enric; Sveen, Anita; Bruun, Jarle; Nesbakken, Arild & Nicholson, George [Vis alle 16 forfattere av denne artikkelen] (2019). Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage. British Journal of Cancer. ISSN 0007-0920. 121, s. 474–482. doi: 10.1038/s41416-019-0540-4. Fulltekst i vitenarkiv
• Brunsell, Tuva Høst; Sveen, Anita; Bjørnbeth, Bjørn Atle; Røsok, Bård Ingvald; Danielsen, Stine Aske & Brudvik, Kristoffer Watten [Vis alle 13 forfattere av denne artikkelen] (2019). High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases. Clinical colorectal cancer. ISSN 1533-0028. 19(1), s. 26–47. doi: 10.1016/j.clcc.2019.09.003. Fulltekst i vitenarkiv Vis sammendrag

  Background The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF, and PIK3CA and their prognostic impact. Patients and Methods We analyzed the mutation status among 372 liver metastases and 78 primary tumors from 106 patients by methods used in clinical routine testing, by Sanger sequencing, by next-generation sequencing (NGS), and/or by droplet digital polymerase chain reaction. The 3-year cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. Results Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14 of 97 patients (14%), almost all cases were refuted by high-sensitive NGS. Also, heterogeneity among metastatic deposits was concluded only for PIK3CA in 2 patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8 of 78 patients (10%) using Sanger sequencing but for only 2 patients after NGS, showing the emergence of 1 KRAS and 1 PIK3CA mutation in the metastatic lesions. KRAS mutations were present in 53 of 106 patients (50%) and were associated with poorer 3-year CSS after liver resection (37% vs. 61% for KRAS wild-type; P = .004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations compared with triple wild-type (P = .002). Conclusion Intra-patient mutation heterogeneity was virtually undetected, both between the primary tumor and the liver metastases and among the metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with poor patient survival after partial liver resection.

• Eilertsen, Ina Andrassy; Moosavi, Seyed Hossein; Strømme, Jonas Meier; Nesbakken, Arild; Johannessen, Bjarne & Lothe, Ragnhild A [Vis alle 7 forfattere av denne artikkelen] (2019). Technical differences between sequencing and microarray platforms impact transcriptomic subtyping of colorectal cancer. Cancer Letters. ISSN 0304-3835. 469, s. 246–255. doi: 10.1016/j.canlet.2019.10.040. Fulltekst i vitenarkiv Vis sammendrag

  Gene expression profiling has increasing relevance in the molecular screening of patients with colorectal cancer (CRC). We investigated potential platform-specific effects on transcriptomic subtyping according to established frameworks by comparisons of expression profiles from RNA sequencing and exon-resolution microarrays in 126 primary microsatellite stable CRCs. There was a strong platform correspondence in global gene expression levels, albeit with systematic technical bias likely attributed to few sequencing reads covering short (<2000 nucleotides) and/or lowly expressed genes (<1 FPKM), as well as over-saturation of highly expressed genes on microarrays. Classification concordances according to both the consensus molecular subtypes and CRC intrinsic subtypes (CRIS) were also strong, but with disproportionate subtype distributions between platforms caused by frequent disagreements in adherence to sample classification thresholds. Subtypes defined largely by genes expressed at low levels, including the CRIS-D subtype and the estimated level of tumor-infiltrating cytotoxic lymphocytes, had a weaker correspondence in classification metrics between platforms. In conclusion, even subtle differences between platforms suggest that clinical translation of transcriptomic CRC subtyping frameworks is dependent on assay standardization, and systematic technical biases reinforce the need for careful selection of classifier genes.

• Smeby, Jørgen; Sveen, Anita; Bergsland, Christian Holst; Eilertsen, Ina Andrassy; Danielsen, Stine Aske & Eide, Peter Andreas Wold [Vis alle 11 forfattere av denne artikkelen] (2019). Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer. ESMO Open. 4:e000523(3), s. 1–10. doi: 10.1136/esmoopen-2019-000523. Fulltekst i vitenarkiv Vis sammendrag

  Accumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC).Materials and methodsIn a single-hospital series of 401 stage I–IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582). mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2−4&gt;0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028).Integration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation.

• Berg, Kaja Christine Graue; Sveen, Anita; Høland, Maren; Alagaratnam, Sharmini; Rasmussen, Marianne Berg & Danielsen, Stine Aske [Vis alle 9 forfattere av denne artikkelen] (2019). Gene expression profiles of CMS2-epithelial/canonical colorectal cancers are largely driven by DNA copy number gains. Oncogene. ISSN 0950-9232. 38(33), s. 6109–6122. doi: 10.1038/s41388-019-0868-5. Fulltekst i vitenarkiv Vis sammendrag

  About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an integral part of aggressive malignancy development, but the importance of specific copy number aberrations (CNAs) in modulating gene expression, particularly within the framework of clinically relevant molecular subtypes, remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV primary CRCs and integrative gene expression analysis in 151 microsatellite stable (MSS) tumors, focusing on high-level amplifications and the effect of CNAs on the characteristics of the gene expression-based consensus molecular subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel recurrent high-level amplifications (≥15 additional copies) with a major impact on gene expression were found for TOX3 (16q) at 1.5% frequency, as well as for CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known targets ERBB2 (17q) and MYC (8q). Focal amplifications with ≥15 or ≥5 additional copies of at least one of these regions were associated with a poor overall survival among patients with stage I-III MSS CRCs (multivariable hazard ratio ≥3.2, p ≤ 0.01). All high-level amplifications were focal and had a more consistent relationship with gene expression than lower amplitude and/or broad-range amplifications, suggesting specific targeting during carcinogenesis. Genome-wide, copy number driven gene expression was enriched for pathways characteristic of the CMS2-epithelial/canonical subtype, including DNA repair and cell cycle progression. Furthermore, 50% of upregulated genes in CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared with the other CMS groups, and associated with the stronger correspondence between CNAs and gene expression in malignant epithelial cells than in the cells of the tumor microenvironment (fibroblasts, endothelial cells, leukocytes). In conclusion, we identify novel recurrent amplifications with impact on gene expression in CRC and provide the first evidence that CMS2 may have a stronger copy-number related genetic basis than subtypes more heavily influenced by gene expression signals from the tumor microenvironment.

• Smeby, Jørgen; Sveen, Anita; Eilertsen, Ina Andrassy; Danielsen, Stine Aske; Hoff, Andreas Midbøe & Eide, Peter Andreas Wold [Vis alle 12 forfattere av denne artikkelen] (2019). Transcriptional and functional consequences of TP53 splice mutations in colorectal cancer. Oncogenesis. 8:35(6), s. 1–8. doi: 10.1038/s41389-019-0141-3. Fulltekst i vitenarkiv Vis sammendrag

  TP53 mutations are common in colorectal cancer (CRC). Most TP53 sequencing studies have been restricted to coding regions, but recent studies have revealed that splice mutations can generate transcript variants with distinct tumorigenic and prognostic properties. Here, we performed unrestricted sequencing of all coding sequences and splice regions of TP53 in a single-hospital series of 401 primary CRCs. TP53 splice mutations were detected in 4% of the cases (N = 16), considerably more frequent than reported in major databases, and they were mutually exclusive to exon mutations. RNA sequencing revealed high-level expression of aberrant transcript variants in the majority of splice mutated tumors (75%). Most variants were predicted to produce truncated TP53 proteins, including one sample expressing the potentially oncogenic and druggable p53ψ isoform. Despite heterogeneous transcript structures, downstream transcriptional profiling revealed that TP53 splice mutations had similar effects on TP53 target gene expression and pathway activity as exonic mutations. Intriguingly, TP53 splice mutations were associated with worse 5-year relapse-free survival in stage II disease, compared to both TP53 wild-type and exon mutations (P = 0.007). These data highlight the importance of including splice regions when examining the biological and clinical consequences of TP53 mutations in CRC.

• Lopes, Nair Susana da Costa Florim Ribeiro; Bergsland, Christian Holst; Bjørnslett, Merete Pauline; Pellinen, Teijo Severi; Svindland, Aud & Nesbakken, Arild [Vis alle 10 forfattere av denne artikkelen] (2019). Digital image analysis of multiplex fluorescence IHC in colorectal cancer recognizes the prognostic value of CDX2 and its negative correlation with SOX2. Laboratory Investigation. ISSN 0023-6837. 100(1), s. 120–134. doi: 10.1038/s41374-019-0336-4. Fulltekst i vitenarkiv Vis sammendrag

  Flourescence-based multiplex immunohistochemistry (mIHC) combined with multispectral imaging and digital image analysis (DIA) is a quantitative high-resolution method for determination of protein expression in tissue. We applied this method for five biomarkers (CDX2, SOX2, SOX9, E-cadherin, and β-catenin) using tissue microarrays of a Norwegian unselected series of primary colorectal cancer. The data were compared with previously obtained chromogenic IHC data of the same tissue cores, visually assessed by the Allred method. We found comparable results between the methods, although confirmed that DIA offered improved resolution to differentiate cases with high and low protein expression. However, we experienced inherent challenges with digital image analysis of membrane staining, which was better assessed visually. DIA and mIHC enabled quantitative analysis of biomarker coexpression on the same tissue section at the single-cell level, revealing a strong negative correlation between the differentiation markers CDX2 and SOX2. Both methods confirmed known prognostic associations for CDX2, but DIA improved data visualization and detection of clinicopathological and biological associations. In summary, mIHC combined with DIA is an efficient and reliable method to evaluate protein expression in tissue, here shown to recapitulate and improve detection of known clinicopathological and survival associations for the emerging biomarker CDX2, and is therefore a candidate approach to standardize CDX2 detection in pathology laboratories.

• Joranger, Pål; Nesbakken, Arild; Sorbye, Halfdan; Hoff, Geir; Oshaug, Arne & Aas, Eline (2019). Survival and costs of colorectal cancer treatment and effects of changing treatment strategies: a model approach. European Journal of Health Economics. ISSN 1618-7598. s. 1–14. doi: 10.1007/s10198-019-01130-6. Fulltekst i vitenarkiv Vis sammendrag

  New and emerging advances in colorectal cancer (CRC) treatment combined with limited healthcare resources highlight the need for detailed decision-analytic models to evaluate costs, survival and quality-adjusted life years. The objectives of this article were to estimate the expected lifetime treatment cost of CRC for an average 70-year-old patient and to test the applicability and flexibility of a model in predicting survival and costs of changing treatment scenarios. The analyses were based on a validated semi-Markov model using data from a Norwegian observational study (2049 CRC patients) to estimate transition probabilities and the proportion resected. In addition, inputs from the Norwegian Patient Registry, guidelines, literature, and expert opinions were used to estimate resource use. We found that the expected lifetime treatment cost for a 70-year-old CRC patient was €47,300 (CRC stage I €26,630, II €38,130, III €56,800, and IV €69,890). Altered use of palliative chemotherapy would increase the costs by up to 29%. A 5% point reduction in recurrence rate for stages I-III would reduce the costs by 5.3% and increase overall survival by 8.2 months. Given the Norwegian willingness to pay threshold per QALY gained, society's willingness to pay for interventions that could result in such a reduction was on average €28,540 per CRC patient. The life years gained by CRC treatment were 6.05 years. The overall CRC treatment costs appear to be low compared to the health gain, and the use of palliative chemotherapy can have a major impact on cost. The model was found to be flexible and applicable for estimating the cost and survival of several CRC treatment scenarios.

• Brunsell, Tuva Høst; Cengija, Vanja; Sveen, Anita; Bjørnbeth, Bjørn Atle; Røsok, Bård Ingvald & Brudvik, Kristoffer Watten [Vis alle 10 forfattere av denne artikkelen] (2019). Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases. European Journal of Surgical Oncology. ISSN 0748-7983. s. 1–7. doi: 10.1016/j.ejso.2019.07.017. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Surgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy. Materials and Methods Radiological response to treatment was evaluated in a lesion-specific manner in 2–5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient. Results In total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4–5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant. Conclusion A subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.

• Dienstmann, Rodrigo; Villacampa, Guillermo; Sveen, Anita; Mason, Michael J.; Niedzwiecki, Donna & Nesbakken, Arild [Vis alle 10 forfattere av denne artikkelen] (2019). Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Annals of Oncology. ISSN 0923-7534. 30(10), s. 1622–1629. doi: 10.1093/annonc/mdz287. Fulltekst i vitenarkiv Vis sammendrag

  Background It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor–node–metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). Patients and methods We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). Results In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6–0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). Conclusions Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

• Eilertsen, Ina Andrassy; Sveen, Anita; Strømme, Jonas Meier; Skotheim, Rolf I.; Nesbakken, Arild & Lothe, Ragnhild A (2018). Alternative splicing expands the prognostic impact of KRAS in microsatellite stable primary colorectal cancer. International Journal of Cancer. ISSN 0020-7136. 144(4), s. 841–847. doi: 10.1002/ijc.31809. Fulltekst i vitenarkiv Vis sammendrag

  KRAS mutation is a well‐known marker for poor response to targeted treatment and patient prognosis in microsatellite stable (MSS) colorectal cancer (CRC). However, variation in clinical outcomes among patients wild‐type for KRAS underlines that this is not a homogeneous population. Here, we evaluated the prognostic impact of KRAS alternative splicing in relation to mutation status in a single‐hospital series of primary MSS CRCs (N = 258). Using splicing‐sensitive microarrays and RNA sequencing, the relative expression of KRAS‐4A versus KRAS‐4B transcript variants was confirmed to be down‐regulated in CRC compared to normal colonic mucosa (N = 41; p ≤ 0.001). This was independent of mutation status, however, gene set enrichment analysis revealed that the effect of splicing on KRAS signaling was specific to the KRAS wild‐type subgroup, in which low relative KRAS‐4A expression was associated with a higher level of KRAS signaling (p = 0.005). In concordance, the prognostic value of KRAS splicing was also dependent on mutation status, and for patients with Stage I–III KRAS wild‐type MSS CRC, low relative KRAS‐4A expression was associated with inferior overall survival (HR: 2.36, 95% CI: 1.07–5.18, p = 0.033), a result not found in mutant cases (pinteraction = 0.026). The prognostic association in the wild‐type subgroup was independent of clinicopathological factors, including cancer stage in multivariable analysis (HR: 2.68, 95% CI: 1.18–6.09, p = 0.018). This suggests that KRAS has prognostic value beyond mutation status in MSS CRC, and highlights the importance of molecular heterogeneity in the clinically relevant KRAS wild‐type subgroup.

• Danielsen, Håvard Emil; Hveem, Tarjei Sveinsgjerd; Domingo, Enric; Pradhan, Manohar; Kleppe, Andreas & Syvertsen, Rolf Anders [Vis alle 18 forfattere av denne artikkelen] (2018). Prognostic markers for colorectal cancer: Estimating ploidy and stroma. Annals of Oncology. ISSN 0923-7534. 29(3), s. 616–623. doi: 10.1093/annonc/mdx794. Fulltekst i vitenarkiv
• Gleditsch, Dagfinn; Wexels, Wilhelm Andreas & Nesbakken, Arild (2018). Surgical options and trends in treating rectal prolapse: long-term results in a 19-year follow-up study. Langenbeck's Archives of Surgery. ISSN 1435-2443. s. 1–8. doi: 10.1007/s00423-018-1728-4. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Many different operations have been proposed for treating rectal prolapse, with varying recurrence rates and functional outcome. The main purpose of this study was to assess long-term results of surgery for prolapse of the rectum. Methods: We carried out a retrospective study to evaluate changing trends in surgical strategies and outcome in all patients treated in our hospital over 19 years. Results: Ninety-three patients were operated and 30 (32%) experienced recurrence of external prolapse during a median (range) follow-up time of 82 (2–231) months. There were 37 reoperations for recurrence, bringing the total number of operations to 130. From 1998 to 2010, laparoscopic posterior suture rectopexy was the preferred abdominal procedure with Delorme’s operation as the perineal alternative. Observed recurrence rates were 15/49 (31%) and 8/15 (53%) during a median observation time of 84 and 9 months, respectively. From 2011 to 2017, these procedures were replaced by ventral mesh rectopexy and Altemeier’s rectosigmoidectomy. The observed recurrence rate for ventral mesh rectopexy was 3/22 (14%) during a median observation time of 29 months. The 30-day mortality rate was 3% and complication rate 14%. Conclusions: The recurrence rates were high after all procedures, with no significant difference between posterior suture rectopexy and ventral mesh rectopexy, but the short observation time for the latter procedure is a limitation of the study. Both procedures had low complication rates, and ventral mesh rectopexy had no mortality.

• El-Hussuna, Alaa; Pinkney, Thomas; Zmora, Oded; Frasson, Murili Zomer; Bhangu, Aneel & Battersby, Nicholas J. [Vis alle 24 forfattere av denne artikkelen] (2018). Risk factors for unfavourable postoperative outcome in patients with Crohn’s disease undergoing right hemicolectomy or ileocaecal resection. An international audit by ESCP and S-ECCO. Colorectal Disease. ISSN 1462-8910. 20(3), s. 219–227. doi: 10.1111/codi.13889. Fulltekst i vitenarkiv
• Kleppe, Andreas; Albregtsen, Fritz; Vlatkovic, Ljiljana; Pradhan, Manohar; Nielsen, Birgitte & Hveem, Tarjei Sveinsgjerd [Vis alle 16 forfattere av denne artikkelen] (2018). Chromatin organisation and cancer prognosis: a pan-cancer study. The Lancet Oncology. ISSN 1470-2045. 19(3), s. 356–369. doi: 10.1016/S1470-2045(17)30899-9. Fulltekst i vitenarkiv Vis sammendrag

  Background: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. Methods Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. Findings: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2–2·5, in the discovery cohort; 1·8, 1·0–3·0, in the Gloucester validation cohort; 2·2, 1·1–4·5, in the QUASAR 2 validation cohort; 3·1, 1·9–5·0, in the ovarian carcinoma cohort; 2·5, 1·8–3·4, in the uterine sarcoma cohort; 2·3, 1·2–4·6, in the prostate carcinoma cohort; and 4·3, 2·8–6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1–2·5, in the discovery cohort; 1·9, 1·1–3·2, in the Gloucester validation cohort; 2·6, 1·2–5·6, in the QUASAR 2 cohort; 1·8, 1·1–3·0, for ovarian carcinoma; 1·6, 1·0–2·4, for uterine sarcoma; 1·43, 0·68–2·99, for prostate carcinoma; and 1·9, 1·1–3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0–8·4) and microsatellite stable (1·8, 1·2–2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7–2·4) or chromatin heterogeneous (0·8, 0·3–2·0) stage II colorectal cancer. Interpretation: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings.

• Smeby, Jørgen; Sveen, Anita; Merok, Marianne Aarstad; Danielsen, Stine Aske; Eilertsen, Ina Andrassy & Guren, Marianne [Vis alle 9 forfattere av denne artikkelen] (2018). CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Annals of Oncology. ISSN 0923-7534. 29(5), s. 1227–1234. doi: 10.1093/annonc/mdy085. Fulltekst i vitenarkiv Vis sammendrag

  Background: The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression–based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods: Totally 1197 primary tumors from a Norwegian series of CRC stage I–IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results: BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. Conclusions: BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.

• Ommundsen, Nina; Nesbakken, Arild; Wyller, Torgeir Bruun; Skovlund, Eva; Bakka, Arne Olav & Jordhøy, Marit Slaaen [Vis alle 7 forfattere av denne artikkelen] (2018). Post-discharge complications in frail older patients after surgery for colorectal cancer. European Journal of Surgical Oncology. ISSN 0748-7983. 44(10), s. 1542–1547. doi: 10.1016/j.ejso.2018.06.024. Fulltekst i vitenarkiv Vis sammendrag

  Background The incidence of postoperative complications after colorectal cancer surgery varies between publications. Complications occurring after discharge from hospital are often not reported. The aims of this study were to investigate the proportion of frail older colorectal cancer patients who developed complications only after discharge, the severity of post-discharge complications, and the time point at which the most frequent complications occurred. Methods Patients were included if they were 65 years and older, screened positively for frailty and were scheduled for colorectal cancer surgery. Included patients were followed prospectively both in hospital and after discharge for 30 days after surgery, and complications were graded according to the Clavien-Dindo classification. Results We included 114 patients. Median age was 79 years. Twenty-two patients (19%) were discharged without complications, but developed complications after discharge. These patients had shorter length of stay (6.5 versus 10 days), were more often discharged to their own home without assistance, and had higher 5-year survival (76% vs 54%) than patients who developed complications in hospital. Post-discharge complications were most frequently grade II. The most common types of complications that occurred late in the postoperative course were urinary tract infections and superficial surgical site infections. Conclusions Complications after colorectal cancer surgery in frail older patients frequently arise after discharge from hospital. Doctors should be aware of this and inform their patients. This is increasingly important as length of stay after surgery decreases. When complications are used as a quality measure, it should be clear whether only in-hospital complications are registered.

• Bruun, Jarle; Sveen, Anita; Barros, Rita; Eide, Peter Andreas Wold; Eilertsen, Ina Andrassy & Kolberg, Matthias [Vis alle 14 forfattere av denne artikkelen] (2018). Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer. Molecular Oncology. ISSN 1574-7891. 12(9), s. 1639–1655. doi: 10.1002/1878-0261.12347. Fulltekst i vitenarkiv Vis sammendrag

  We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

• Vedeld, Hege Marie; Nesbakken, Arild; Lothe, Ragnhild A & Lind, Guro Elisabeth (2018). Re-assessing ZNF331 as a DNA methylation biomarker for colorectal cancer. Clinical Epigenetics. 10(1). doi: 10.1186/s13148-018-0503-2. Fulltekst i vitenarkiv Vis sammendrag

  We have previously shown that aberrant promoter methylation of ZNF331 is a potential biomarker for colorectal cancer detection with high sensitivity (71%) and specificity (98%). This finding was recently confirmed by others, and it was additionally suggested that promoter methylation of ZNF331 was an independent prognostic biomarker for colorectal cancer (n = 146). In the current study, our initial colorectal cancer sample series was extended to include a total of 423 cancer tissue samples. Aberrant promoter methylation was found in 71% of the samples, thus repeatedly suggesting the biomarker potential of ZNF331 for detection of colorectal cancer. Furthermore, multivariate Cox’s analysis indicated a trend towards inferior overall survival for colorectal cancer patients with aberrant methylation of ZNF331.

• Ommundsen, Nina; Wyller, Torgeir Bruun; Nesbakken, Arild; Bakka, Arne Olav; Jordhøy, Marit Slaaen & Skovlund, Eva [Vis alle 7 forfattere av denne artikkelen] (2018). Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial. Colorectal Disease. ISSN 1462-8910. 20(1), s. 16–25. doi: 10.1111/codi.13785. Fulltekst i vitenarkiv
• Sveen, Anita; Bruun, Jarle; Eide, Peter Andreas Wold; Eilertsen, Ina Andrassy; Ramirez, Lorena & Murumagi, Astrid [Vis alle 17 forfattere av denne artikkelen] (2017). Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially targetable cancer cell dependencies. Clinical Cancer Research. ISSN 1078-0432. 24(4), s. 794–806. doi: 10.1158/1078-0432.CCR-17-1234. Fulltekst i vitenarkiv
• Sveen, Anita; Johannessen, Bjarne; Tengs, Torstein; Danielsen, Stine Aske; Eilertsen, Ina Andrassy & Lind, Guro Elisabeth [Vis alle 16 forfattere av denne artikkelen] (2017). Multilevel genomics of colorectal cancers with microsatellite instability – clinical impact of JAK1 mutations and consensus molecular subtype 1. Genome Medicine. 9(1). doi: 10.1186/s13073-017-0434-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. Methods A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling—including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration. Results Novel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10−5), but not with immune cell infiltration—this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05–0.9] and 0.4 [0.2–0.9], respectively, P = 0.03 and 0.02). Conclusions Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9

• Dienstmann, Rodrigo; Mason, M; Sinicrope, FA; Phipps, Alison; Tejpar, S. & Nesbakken, Arild [Vis alle 14 forfattere av denne artikkelen] (2017). Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Annals of Oncology. ISSN 0923-7534. 28(5), s. 1023–1031. doi: 10.1093/annonc/mdx052. Fulltekst i vitenarkiv Vis sammendrag

  Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation. Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)—N0147 (NCT00079274) and PETACC3 (NCT00026273)—was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782). Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61–0.68 in the TNM alone model to 0.63–0.71 in models with added molecular markers, 0.65–0.73 with clinicopathological features and 0.66–0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively. Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

• Sveen, Anita; Bruun, Jarle; Eide, Peter W.; Eilertsen, Ina A.; Ramirez, Lorena & Murumagi, Astrid [Vis alle 17 forfattere av denne artikkelen] (2017). Colorectal cancer consensus molecular subtypes define selective activity of HSP90 inhibitors in preclinical models. Cancer Reports and Reviews. doi: 10.1158/1078-0432.CCR-17-1234. Fulltekst i vitenarkiv
• Labori, Knut Jørgen; Guren, Marianne; Brudvik, Kristoffer Watten; Røsok, Bård Ingvald; Waage, Anne & Nesbakken, Arild [Vis alle 10 forfattere av denne artikkelen] (2017). Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short-term surgical outcomes, overall survival and recurrence-free survival. Colorectal Disease. ISSN 1462-8910. 19(8), s. 731–738. doi: 10.1111/codi.13622. Fulltekst i vitenarkiv
• Vedeld, Hege Marie; Merok, Marianne Aarstad; Jeanmougin, Marine; Danielsen, Stine Aske; Honne, Hilde & Presthus, Gro [Vis alle 13 forfattere av denne artikkelen] (2017). CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers. International Journal of Cancer. ISSN 0020-7136. 141(5), s. 967–976. doi: 10.1002/ijc.30796. Fulltekst i vitenarkiv
• Pedersen, Kjetil Boye; Jacob, Havjin; Frikstad, Kari-Anne; Nesland, Jahn M; Mælandsmo, Gunhild & Dahl, Olav [Vis alle 8 forfattere av denne artikkelen] (2016). Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy. Cancer Medicine. 5(8), s. 1840–1849. doi: 10.1002/cam4.766. Fulltekst i vitenarkiv Vis sammendrag

  Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis-promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population-representative cohort and a randomized phase III study on adjuvant 5-fluorouracil/levamisole. Sensitivity to treatment with 5-fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse-free (P < 0.001 and P = 0.010) and overall survival (P = 0.046 and P = 0.006) in univariate analysis. In multivariate analysis, nuclear S100A4 was a predictor of poor relapse-free survival in the consecutive series (P = 0.002; HR 1.9), but not in the randomized study. Sensitivity to treatment with 5-fluorouracil was not affected by S100A4 expression in in vitro cell culture assays, and there was no indication from subgroup analyses in the randomized study that S100A4 expression was associated with increased benefit of adjuvant treatment with 5-fluorouracil/levamisole. The present study confirms that nuclear S100A4 expression is a negative prognostic biomarker in colorectal cancer, but the clinical utility in selection of patients for adjuvant fluoropyrimidine-based chemotherapy is limited.

• Gleditsch, Dagfinn; Søreide, Ole Kristian & Nesbakken, Arild (2016). Managing Malignant Colorectal Obstruction with Self-Expanding Stents. A Closer Look at Bowel Perforations and Failed Procedures. Journal of Gastrointestinal Surgery. ISSN 1091-255X. s. 1–7. doi: 10.1007/s11605-016-3186-z. Fulltekst i vitenarkiv
• Rønning, Benedicte; Wyller, Torgeir Bruun; Nesbakken, Arild; Skovlund, Eva; Jordhøy, Marit Slaaen & Bakka, Arne Olav [Vis alle 7 forfattere av denne artikkelen] (2016). Quality of life in older and frail patients after surgery for colorectal cancer-A follow-up study. Journal of Geriatric Oncology. ISSN 1879-4068. 7(3), s. 195–200. doi: 10.1016/j.jgo.2016.03.002. Fulltekst i vitenarkiv Vis sammendrag

  Objective The incidence of colorectal cancer is increasing, mainly due to the aging of the population. Frailty, describing a state of increased vulnerability, is common in older patients, but frailty and high age are not necessarily contraindications to surgical treatment. However, limited data describing long-term outcomes after surgery in this patient group exist. In this clinical follow-up study, we aimed to examine long-term health-related quality of life in older surgical patients with colorectal cancer. Materials and Methods Patients were recruited from a prospective multicenter study investigating frailty as a predictor of postoperative complications after surgery for colorectal cancer. A preoperative geriatric assessment was performed, and patients were classified as frail or non-frail. Patients responded to version 3.0 of The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire-C30 before surgery, 3 months postoperatively and at a long-term follow-up 16–28 months (median 22 months) after surgery. One-way repeated-measures analyses of variance were performed to examine changes in scores over time. Results 180 patients with a mean age of 80 years were included at baseline, 138 at 3 months postoperatively, and 84 patients (69% of survivors) at long-term follow-up. A significant improvement in quality of life-scores was present 3 months after surgery, also in the subgroup of frail patients. At long-term follow-up, scores decreased, but to values above baseline. Conclusion Health-related quality of life may be improved in older patients after surgery for colorectal cancer, even in patients who are classified as frail preoperatively.

• Stornes, Tore; Wibe, Arne; Nesbakken, Arild; Myklebust, Tor Åge & Endreseth, Birger Henning (2016). National early rectal cancer treatment revisited. Diseases of the Colon & Rectum. ISSN 0012-3706. 59(7), s. 623–629. doi: 10.1097/DCR.0000000000000591. Fulltekst i vitenarkiv
• Domingo, Enric; Freeman-Mills, Luke; Rayner, Emily; Glaire, Mark; Briggs, Sarah & Vermeulen, Louis [Vis alle 35 forfattere av denne artikkelen] (2016). Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. The Lancet Gastroenterology and Hepatology. ISSN 2468-1253. 1(3), s. 207–216. doi: 10.1016/S2468-1253(16)30014-0. Fulltekst i vitenarkiv
• Guren, Marianne; Kørner, Hartwig; Pfeffer, Frank; Myklebust, Tor Åge; Eriksen, Morten Tandberg & Edna, Tom-Harald [Vis alle 23 forfattere av denne artikkelen] (2015). Nationwide improvement of rectal cancer treatment outcomes in Norway, 1993-2010. Acta Oncologica. ISSN 0284-186X. 54(10), s. 1714–1722. doi: 10.3109/0284186X.2015.1034876. Fulltekst i vitenarkiv
• Joranger, Pål; Nesbakken, Arild; Hoff, Geir; Sorbye, Halfdan; Oshaug, Arne & Aas, Eline (2015). Modeling and Validating the Cost and Clinical Pathway of Colorectal Cancer. Medical decision making. ISSN 0272-989X. 35(2), s. 255–265. doi: 10.1177/0272989X14544749. Fulltekst i vitenarkiv
• Bruun, Jarle; Kolberg, Matthias; Ahlquist, Terje Cruickshank; Røyrvik, Ellen Christine; Nome, Torfinn & Leithe, Edward [Vis alle 18 forfattere av denne artikkelen] (2015). Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. Clinical Cancer Research. ISSN 1078-0432. 21(16), s. 3759–3770. doi: 10.1158/1078-0432.CCR-14-3294. Fulltekst i vitenarkiv
• Danielsen, Stine Aske; Eide, Peter Andreas Wold; Nesbakken, Arild; Guren, Tormod Kyrre; Leithe, Edward & Lothe, Ragnhild A (2015). Portrait of the PI3K/AKT pathway in colorectal cancer. Shengwu huaxue yu shengwu wuli xuebao. ISSN 0582-9879. 1855(1), s. 104–121. doi: 10.1016/j.bbcan.2014.09.008. Fulltekst i vitenarkiv
• Løvf, Marthe; Nome, Torfinn; Bruun, Jarle; Eknæs, Mette; Bakken, Anne Cathrine & Mpindi, John-Patrick [Vis alle 12 forfattere av denne artikkelen] (2014). A novel transcript, VNN1-AB, as a biomarker for colorectal cancer. International Journal of Cancer. ISSN 0020-7136. 135(9), s. 2077–2084. doi: 10.1002/ijc.28855. Fulltekst i vitenarkiv
• Hveem, Tarjei Sveinsgjerd; Merok, Marianne Aarstad; Pretorius, Maria; Novelli, Marco; Silihagen, Mette & Sjo, Ole Helmer [Vis alle 12 forfattere av denne artikkelen] (2014). Prognostic impact of genomic instability in colorectal cancer. British Journal of Cancer. ISSN 0007-0920. 110(8), s. 2159–2164. doi: 10.1038/bjc.2014.133. Fulltekst i vitenarkiv
• Søndenaa, Karl; Quirke, Philip; Hohenberger, Werner; Sugihara, Kenichi; Kobayashi, Hirotoshi & Kessler, Hermann [Vis alle 16 forfattere av denne artikkelen] (2014). The rationale behind complete mesocolic excision (CME) and a central vascular ligation for colon cancer in open and laparoscopic surgery: Proceedings of a consensus conference. International Journal of Colorectal Disease. ISSN 0179-1958. 29(4), s. 419–428. doi: 10.1007/s00384-013-1818-2. Fulltekst i vitenarkiv
• Nome, Torfinn; Hoff, Andreas Midbøe; Bakken, Anne Cathrine; Rognum, Torleiv Ole; Nesbakken, Arild & Skotheim, Rolf Inge (2014). High frequency of fusion transcripts involving TCF7L2 in colorectal cancer: Novel fusion partner and splice variants. PLOS ONE. 9(3). doi: 10.1371/journal.pone.0091264. Fulltekst i vitenarkiv Vis sammendrag

  VTI1A-TCF7L2 was reported as a recurrent fusion gene in colorectal cancer (CRC), found to be expressed in three out of 97 primary cancers, and one cell line, NCI-H508, where a genomic deletion joins the two genes [1]. To investigate this fusion further, we analyzed high-throughput DNA and RNA sequencing data from seven CRC cell lines, and identified the gene RP11-57H14.3 (ENSG00000225292) as a novel fusion partner for TCF7L2. The fusion was discovered from both genome and transcriptome data in the HCT116 cell line. By triplicate nested RT-PCR, we tested both the novel fusion transcript and VTI1A-TCF7L2 for expression in a series of 106 CRC tissues, 21 CRC cell lines, 14 normal colonic mucosa, and 20 normal tissues from miscellaneous anatomical sites. Altogether, 42% and 45% of the CRC samples expressed VTI1A-TCF7L2 and TCF7L2-RP11-57H14.3 fusion transcripts, respectively. The fusion transcripts were both seen in 29% of the normal colonic mucosa samples, and in 25% and 75% of the tested normal tissues from other organs, revealing that the TCF7L2 fusion transcripts are neither specific to cancer nor to the colon and rectum. Seven different splice variants were detected for the VTI1A-TCF7L2 fusion, of which three are novel. Four different splice variants were detected for the TCF7L2-RP11-57H14.3 fusion. In conclusion, we have identified novel variants of VTI1A-TCF7L2 fusion transcripts, including a novel fusion partner gene, RP11-57H14.3, and demonstrated detectable levels in a large fraction of CRC samples, as well as in normal colonic mucosa and other tissue types. We suggest that the fusion transcripts observed in a high frequency of samples are transcription induced chimeras that are expressed at low levels in most samples. The similar fusion transcripts induced by genomic rearrangements observed in individual cancer cell lines may yet have oncogenic potential as suggested in the original study by Bass et al.

• Ommundsen, Nina; Wyller, Torgeir Bruun; Nesbakken, Arild; Jordhøy, Marit; Bakka, Arne Olav & Skovlund, Eva [Vis alle 7 forfattere av denne artikkelen] (2014). Frailty is an independent predictor of survival in older patients with colorectal cancer. The Oncologist. ISSN 1083-7159. 19(12), s. 1268–1275. doi: 10.1634/theoncologist.2014-0237. Fulltekst i vitenarkiv Vis sammendrag

  Background. Colorectal cancer (CRC) is prevalent in the older population. Geriatric assessment (GA) has previously been found to predict treatment tolerance and postoperative complications in older cancer patients. The aim of this study was to explore whether GA also predicts 1-year and 5-year survival after CRC surgery in older patients and to compare the predictive power of GA with that of established prognostic factors such as TNM classification of malignant tumors (TNM) stage and age. Materials and Methods. A cohort of 178 CRC patients aged 70 and older were followed prospectively. All patients went through elective surgery, and GA was performed presurgery. The GA resulted in patients being divided into two groups: frail or nonfrail. All patients were followed for 5 years or until death. Data were analyzed by Kaplan-Meier plots and the Cox proportional hazards model. Results. Seventy-six patients (43%) were frail, and one hundred and two (57%) were nonfrail. Twenty-three patients (13%) died during the first year after surgery. One-year survival was 80% in the frail group and 92% in the nonfrail group. Five-year survival was significantly lower in frail (24%) than nonfrail patients (66%), and this difference was apparent both within the stratums of TNM stages 0–II and TNM stage III. In multivariable analysis adjusting for TNM stage, age, and sex, frailty was an independent prognostic factor for survival. Conclusion. A GA-based frailty assessment predicts 1-year and 5-year survival in older patients after surgery for CRC. In localized and regional disease, the impact of frailty upon 5-year survival is comparable with that of TNM stage.

• Bruun, Jarle; Kolberg, Matthias; Nesland, Jahn M; Svindland, Aud; Nesbakken, Arild & Lothe, Ragnhild A (2014). Prognostic significance of β-catenin, E-cadherin, and SOX9 in colorectal cancer: Results from a large population-representative series. Frontiers in Oncology. 4 MAY. doi: 10.3389/fonc.2014.00118. Fulltekst i vitenarkiv
• Rønning, Benedicte; Wyller, Torgeir Bruun; Jordhøy, Marit Slaaen; Nesbakken, Arild; Bakka, Arne Olav & Seljeflot, Ingebjørg [Vis alle 7 forfattere av denne artikkelen] (2014). Frailty indicators and functional status in older patients after colorectal cancer surgery. Journal of Geriatric Oncology. ISSN 1879-4068. 5(1), s. 26–32. doi: 10.1016/j.jgo.2013.08.001. Fulltekst i vitenarkiv
• Ingebrigtsen, Vibeke Anett; Boye, Kjetil; Nesland, Jahn M; Nesbakken, Arild; Flatmark, Kjersti & Fodstad, Øystein (2014). B7-H3 expression in colorectal cancer: associations with clinicopathological parameters and patient outcome. BMC Cancer. 20(14). doi: 10.1186/1471-2407-14-602. Fulltekst i vitenarkiv Vis sammendrag

  Background We have previously reported overexpression of the immunoregulatory protein B7-H3 in colorectal cancer and that nuclear expression predicted poor outcome in colon cancer patients. The present study was performed to examine the prognostic role of B7-H3 in an independent colorectal cancer cohort. Methods Using tissue microarrays from 731 colorectal cancer patients, tumour B7-H3 expression was assessed by immunohistochemistry. Associations with clinicopathological parameters and patient outcome were investigated. Results Nuclear expression of B7-H3 in cancer cells was present in 27% of the samples in the total study cohort, while cytoplasmic/membrane and stromal expression was seen in 86% and 77% of the samples, respectively. Nuclear B7-H3 had no prognostic relevance in the complete outcome cohort, neither in colon cancer patients. However, nuclear B7-H3 was significantly associated with reduced recurrence-free survival in TNM stage I colorectal cancer patients. Conclusions Overexpression of B7-H3 in colorectal cancer was confirmed, but in contrast to previous results, nuclear B7-H3 was not a strong prognostic biomarker in this cohort. The discrepancy might be related to the use of single-core tissue microarrays for detection of the heterogeneously expressed B7-H3, and the role of B7-H3 in colorectal cancer still needs further examination.

• Vedeld, Hege Marie; Andresen, Kim; Eilertsen, Ina Andrassy; Nesbakken, Arild; Seruca, Raquel & Gladhaug, Ivar Prydz [Vis alle 10 forfattere av denne artikkelen] (2014). The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers. International Journal of Cancer. ISSN 0020-7136. 136(4), s. 844–853. doi: 10.1002/ijc.29039. Fulltekst i vitenarkiv
• Nedrebø, Bjørn Steinar Olden; Søreide, Kjetil; Nesbakken, Arild; Eriksen, Morten Tandberg; Søreide, Jon Arne & Kørner, Hartwig (2013). Risk factors associated with poor lymph node harvest after colon cancer surgery in a national cohort. Colorectal Disease. ISSN 1462-8910. 15(6), s. E301–E308. doi: 10.1111/codi.12245. Fulltekst i vitenarkiv
• Sveen, Anita; Nesbakken, Arild; Ågesen, Trude Holmeide; Guren, Marianne; Tveit, Magne Kjell & Skotheim, Rolf Inge [Vis alle 7 forfattere av denne artikkelen] (2013). Anticipating the Clinical Use of Prognostic Gene Expression-Based Tests for Colon Cancer Stage II and III: Is Godot Finally Arriving? Clinical Cancer Research. ISSN 1078-0432. 19(24), s. 6669–6677. doi: 10.1158/1078-0432.CCR-13-1769. Fulltekst i vitenarkiv
• Merok, Marianne Aarstad; Ahlquist, Terje Cruickshank; Røyrvik, Ellen Christine; Tufteland, Kjersti Forberg; Hektoen, Merete & Sjo, Ole Helmer [Vis alle 10 forfattere av denne artikkelen] (2013). Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Annals of Oncology. ISSN 0923-7534. 24(5), s. 1274–1282. doi: 10.1093/annonc/mds614. Fulltekst i vitenarkiv
• Nome, Torfinn; Thomassen, Gard O Sundby; Bruun, Jarle; Ahlquist, Terje Cruickshank; Bakken, Anne Cathrine & Hoff, Andreas Midbøe [Vis alle 17 forfattere av denne artikkelen] (2013). Common fusion transcripts identified in colorectal cancer cell lines by high throughput RNA sequencing. Translational Oncology. ISSN 1944-7124. 6(5), s. 546–553. doi: 10.1593/tlo.13457. Fulltekst i vitenarkiv
• Kristjansson, Siri Rostoft; Rønning, Benedicte; Hurria, Arti; Skovlund, Eva; Jordhøy, Marit Slaaen & Nesbakken, Arild [Vis alle 7 forfattere av denne artikkelen] (2012). A comparison of two pre-operative frailty measures in older surgical cancer patients. Journal of Geriatric Oncology. ISSN 1879-4068. 3(1), s. 1–7. doi: 10.1016/j.jgo.2011.09.002. Fulltekst i vitenarkiv
• Sveen, Anita; Bakken, Anne Cathrine; Ågesen, Trude Holmeide; Lind, Guro Elisabeth; Nesbakken, Arild & Nordgård, Oddmund [Vis alle 10 forfattere av denne artikkelen] (2012). The exon-level biomarker SLC39A14 has organ-confined cancer-specificity in colorectal cancer. International Journal of Cancer. ISSN 0020-7136. 131(6), s. 1479–1485. doi: 10.1002/ijc.27399. Fulltekst i vitenarkiv
• Sjo, Ole Helmer; Merok, Marianne Aarstad; Svindland, Aud & Nesbakken, Arild (2012). Prognostic Impact of Lymph Node Harvest and Lymph Node Ratio in Patients With Colon Cancer. Diseases of the Colon & Rectum. ISSN 0012-3706. 55(3), s. 307–315. doi: 10.1097/DCR.0b013e3182423f62. Fulltekst i vitenarkiv
• Larssen, Lene; Medhus, Asle Wilhelm; Kørner, Hartwig; Glomsaker, Tom Birger; Søberg, Taran & Gleditsch, Dagfinn [Vis alle 11 forfattere av denne artikkelen] (2012). Long-term outcome of palliative treatment with self-expanding metal stents for malignant obstructions of the GI tract. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 47(12), s. 1505–1514. doi: 10.3109/00365521.2012.711854. Fulltekst i vitenarkiv
• Cekaite, Lina; Rantala, Juha K.; Bruun, Jarle; Guriby, Marianne; Ågesen, Trude Holmeide & Danielsen, Stine Aske [Vis alle 11 forfattere av denne artikkelen] (2012). MiR-9,-31, and-182 Deregulation Promote Proliferation and Tumor Cell Survival in Colon Cancer. Neoplasia. ISSN 1522-8002. 14(9), s. 868–U126. doi: 10.1593/neo.121094. Fulltekst i vitenarkiv
• Ågesen, Trude Holmeide; Sveen, Anita; Merok, Marianne Aarstad; Lind, Guro Elisabeth; Nesbakken, Arild & Skotheim, Rolf Inge [Vis alle 7 forfattere av denne artikkelen] (2012). ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis. Gut. ISSN 0017-5749. 61(11), s. 1560–1567. doi: 10.1136/gutjnl-2011-301179. Fulltekst i vitenarkiv
• Ahmed, Deeqa; Danielsen, Stine Aske; Ågesen, Trude Holmeide; Bretthauer, Michael; Thiis-Evensen, Espen & Hoff, Geir [Vis alle 10 forfattere av denne artikkelen] (2012). A tissue-based comparative effectiveness analysis of biomarkers for early detection of colorectal tumors. Clinical and Translational Gastroenterology. 3. doi: 10.1038/ctg.2012.21. Fulltekst i vitenarkiv
• Sirnes, Solveig; Bruun, Jarle; Kolberg, Matthias; Kjenseth, Ane Hansen; Lind, Guro Elisabeth & Svindland, Aud [Vis alle 11 forfattere av denne artikkelen] (2012). Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome. International Journal of Cancer. ISSN 0020-7136. 131(3), s. 570–581. doi: 10.1002/ijc.26392. Fulltekst i vitenarkiv
• Sveen, Anita; Ågesen, Trude Holmeide; Nesbakken, Arild; Meling, Gunn Iren; Rognum, Torleiv Ole & Liestøl, Knut [Vis alle 8 forfattere av denne artikkelen] (2012). ColoGuidePro: A Prognostic 7-Gene Expression Signature for Stage III Colorectal Cancer Patients. Clinical Cancer Research. ISSN 1078-0432. 18(21), s. 6001–6010. doi: 10.1158/1078-0432.CCR-11-3302. Fulltekst i vitenarkiv
• Lind, Guro Elisabeth; Raiborg, Camilla; Danielsen, Stine Aske; Rognum, Torleiv Ole; Thiis-Evensen, Espen & Hoff, Geir [Vis alle 9 forfattere av denne artikkelen] (2011). SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis. Oncogene. ISSN 0950-9232. 30(37), s. 3967–3978. doi: 10.1038/onc.2011.109. Fulltekst i vitenarkiv
• Sjo, Ole Helmer; Berg, Marianne; Merok, Marianne Aarstad; Kolberg, Matthias; Svindland, Aud & Lothe, Ragnhild A [Vis alle 7 forfattere av denne artikkelen] (2011). Peritoneal Carcinomatosis of Colon Cancer Origin: Highest Incidence in Women and in Patients With Right-Sided Tumors. Journal of Surgical Oncology. ISSN 0022-4790. 104(7), s. 792–797. doi: 10.1002/jso.21959. Fulltekst i vitenarkiv
• Larssen, Lene; Medhus, Asle Wilhelm; Hjermstad, Marianne Jensen; Kørner, Hartwig; Glomsaker, Tom & Søberg, Taran [Vis alle 12 forfattere av denne artikkelen] (2011). Patient-reported outcomes in palliative gastrointestinal stenting: a Norwegian multicenter study. Surgical Endoscopy. ISSN 0930-2794. 25(10), s. 3162–3169. doi: 10.1007/s00464-011-1680-7. Fulltekst i vitenarkiv Vis sammendrag

  Background The clinical effect of stent treatment has been evaluated by mainly physicians; only a limited number of prospective studies have used patient-reported outcomes for this purpose. The aim of this work was to study the clinical effect of self-expanding metal stents in treatment of malignant gastrointestinal obstructions, as evaluated by patient-reported outcomes, and compare the rating of the treatment effect by patients and physicians. Methods Between November 2006 and April 2008, 273 patients treated with SEMS for malignant GI and biliary obstructions were recruited from nine Norwegian hospitals. Patients and physicians assessed symptoms independently at the time of treatment and after 2 weeks using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire supplemented with specific questions related to obstruction. Results A total of 162 patients (99 males; median age = 72 years) completed both assessments and were included in the study. A significant improvement in the mean global health score was observed after 2 weeks (from 9 to 18 on a 0–100 scale, P\0.03) for all stent locations. Both patients and physicians reported a significant reduction in all obstruction-related symptoms ([20 on the 0–100 scale, P\0.006) after SEMS treatment. The physicians reported a larger mean improvement in symptoms than did the patients, mainly because they reported more severe symptoms before treatment. Conclusion SEMS treatment is effective in relieving symptoms of malignant GI and biliary obstruction, as reported by patients and physicians. The physicians, however, reported a larger reduction in obstructive symptoms than did the patients. A prospective assessment of patientreported outcomes is important in evaluating SEMS treatment.

• Hølmebakk, Søren Torben; Solbakken, Arne Mide; Mala, Tom & Nesbakken, Arild (2011). Clinical prediction of survival by surgeons for patients with incurable abdominal malignancy. European Journal of Surgical Oncology. ISSN 0748-7983. 37(7), s. 571–575. doi: 10.1016/j.ejso.2011.02.009. Fulltekst i vitenarkiv
• Lind, Guro Elisabeth; Danielsen, Stine Aske; Ahlquist, Terje Cruickshank; Merok, Marianne Aarstad; Andresen, Kim & Skotheim, Rolf Inge [Vis alle 14 forfattere av denne artikkelen] (2011). Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas. Molecular Cancer. 10. doi: 10.1186/1476-4598-10-85. Fulltekst i vitenarkiv Vis sammendrag

  Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.

• Danielsen, Stine Aske; Cekaite, Lina; Ågesen, Trude Holmeide; Sveen, Anita; Nesbakken, Arild & Thiis-Evensen, Espen [Vis alle 9 forfattere av denne artikkelen] (2011). Phospholipase C Isozymes Are Deregulated in Colorectal Cancer - Insights Gained from Gene Set Enrichment Analysis of the Transcriptome. PLOS ONE. 6(9). doi: 10.1371/journal.pone.0024419. Fulltekst i vitenarkiv
• Andersson, Thea; Lunde, Ole Christian; Johnson, Egil; Moum, Torbjørn & Nesbakken, Arild (2011). Long-term functional outcome and quality of life after restorative proctocolectomy with ileo-anal anastomosis for colitis. Colorectal Disease. ISSN 1462-8910. 13(4), s. 431–437. doi: 10.1111/j.1463-1318.2009.02163.x. Fulltekst i vitenarkiv
• Færden, Arne Engebret; Sjo, Ole Helmer; Bukholm, Ida Rashida Khan; Andersen, Solveig Norheim; Svindland, Aud & Nesbakken, Arild [Vis alle 7 forfattere av denne artikkelen] (2011). Lymph Node Micrometastases and Isolated Tumor Cells Influence Survival in Stage I and II Colon Cancer. Diseases of the Colon & Rectum. ISSN 0012-3706. 54(2), s. 200–206. doi: 10.1007/DCR.0b013e3181fd4c7c. Fulltekst i vitenarkiv
• Sveen, Anita; Ågesen, Trude Holmeide; Nesbakken, Arild; Rognum, Torleiv Ole; Lothe, Ragnhild A & Skotheim, Rolf Inge (2011). Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival. Genome Medicine. 3(5). doi: 10.1186/gm248. Fulltekst i vitenarkiv Vis sammendrag

  Background Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level. Methods Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores. Results There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03). Conclusions We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing factor expression levels and poor patient survival.

• Ågesen, Trude Holmeide; Berg, Marianne; Clancy, Trevor; Thiis-Evensen, Espen; Cekaite, Lina & Lind, Guro Elisabeth [Vis alle 16 forfattere av denne artikkelen] (2011). CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer. Genes and Immunity. ISSN 1466-4879. 12(8), s. 653–662. doi: 10.1038/gene.2011.43. Fulltekst i vitenarkiv
• Nesbakken, Arild; Kristinsson, Jon Adalsteinn; Svindland, Aud & Lunde, Ole Christian (2011). ENDOSCOPIC SNARE RESECTION FOLLOWED BY LASER ABLATION IN THE TREATMENT OF LARGE, SESSILE RECTAL ADENOMAS. Scandinavian Journal of Surgery. ISSN 1457-4969. 100(2), s. 99–104. Fulltekst i vitenarkiv
• Knævelsrud, Helene; Ahlquist, Terje Cruickshank; Merok, Marianne Aarstad; Nesbakken, Arild; Stenmark, Harald Alfred & Lothe, Ragnhild A [Vis alle 7 forfattere av denne artikkelen] (2010). UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy. Autophagy. ISSN 1554-8627. 6(7), s. 863–870. doi: 10.4161/auto.6.7.13033. Fulltekst i vitenarkiv

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• Glaire, Mark; Domingo, Enric; Sveen, Anita; Bruun, Jarle; Nesbakken, Arild & Nicholson, George [Vis alle 16 forfattere av denne artikkelen] (2019). Correction: Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage (British Journal of Cancer, (2019), 121, 6, (474-482), 10.1038/s41416-019-0540-4). British Journal of Cancer. ISSN 0007-0920. 121(9). doi: 10.1038/s41416-019-0590-7. Fulltekst i vitenarkiv
• Ommundsen, Nina; Wyller, Torgeir Bruun; Nesbakken, Arild; Bakka, Arne Olav; Jordhøy, Marit Slaaen & Skovlund, Eva [Vis alle 7 forfattere av denne artikkelen] (2018). Reply to Lawday et al. Colorectal Disease. ISSN 1462-8910. 20(4), s. 350–351. doi: 10.1111/codi.14059. Fulltekst i vitenarkiv
• Joranger, Pål; Nesbakken, Arild; Hoff, Geir; Sorbye, Halfdan; Oshaug, Arne & Aas, Eline (2015). Modell for å beregne overlevelse og kostnader av behandling for kolorektal cancer. Fulltekst i vitenarkiv Vis sammendrag

  Bakgrunn: Tykktarmskreft (CRC) er en viktig årsak til kreftdødsfall i Norge. Målet med denne studien var (i) å beskrive en kolorektal cancer (CRC) modell for å beregne behandlingskostnader og overlevelse og (ii) validere modellen. Materiale og metode: Vi brukte en semi-Markovmodell med 70 helsetilstander og tok hensyn til alder og tiden som har gått etter viktige inngrep/behandlinger. Modellparametrene var basert på data for 2049 CRC-pasienter ved Oslo universitetssykehus (OUS) (overlevelse), Norsk pasientregister (ressursbruk), publisert litteratur og ekspertvurderinger. Modellen fulgte pasienter diagnostisert for CRC ved en alder av 70 år og til død. Resultater: Modellen ble validert for ”face-”, intern-, ”cross”-, og ekstern validitet. Valideringene viste tilfredsstillende samsvar med andre modeller og empiriske estimater for både kostnader og overlevelse (ingen forutgående kalibrering av modellen). I en ”cross”-validering av ti års total overlevelse avvek modellens estimat med 11,5 dager (0,38 måned) sammenlignet med OUS data. Kostnadsestimatene fra vår modell var 0,3% lavere enn estimater fra en irsk modell (3,0, 1,3, -3,6 og 1,2% lavere i en irsk modell for henholdsvis TNM- stadium I, II, III og IV). I en ekstern validering sammenlignet vi relativ overlevelse estimert av modellen med pasientdata fra Kreftregisteret som inneholder et komplett sett med data for CRC pasienter i Norge. Modellen predikerte 3,9% høyere relativ overlevelse enn Kreftregisterets data viser i løpet av første året, og 0,9, 5,6 og 5,6% lavere relativ overlevelse fem, ti og femten år etter diagnose. I en annen ekstern validering ble modellen sammenliknet med empirisk estimerte ("model-free") totale kostnader basert på Norsk pasientregister. Justert for forskjeller i forutsetninger var modellens anslag 3,1% høyere enn de empirisk estimerte. Konklusjoner: CRC-modellen predikerte på en god måte overlevelse og kostnader for de ulike TNM-stadiene, og vil kunne være valid mht å estimere helsemessige og ressursmessige konsekvenser av CRC-behandling.

• Joranger, Pål; Nesbakken, Arild; Hoff, Geir; Sorbye, Halfdan; Oshaug, Arne & Aas, Eline (2014). Development and validation of a Norwegian model for colorectal cancer. Fulltekst i vitenarkiv
• Ahmed, Deeqa; Ågesen, Trude Holmeide; Danielsen, Stine Aske; Bretthauer, Michael; Thiis-Evensen, Espen & Hoff, Geir [Vis alle 10 forfattere av denne artikkelen] (2012). METHYLATION BASED BIOMARKERS FOR NON-INVASIVE EARLY DETECTION OF COLORECTAL CANCER. Annals of Oncology. ISSN 0923-7534. 23, s. 23–23. Fulltekst i vitenarkiv
• Holmebakk, T.; Solbakken, Arne Mide; Mala, Tom & Nesbakken, Arild (2011). Clinical Prediction of Survival by Surgeons for Patients With Incurable Malignant Disease. European Journal of Cancer. ISSN 0959-8049. 47, s. S221–S221. Fulltekst i vitenarkiv
• Ågesen, Trude Holmeide; Berg, Marianne; Cekaite, Lina; Thiis-Evensen, Espen; Merok, Marianne Aarstad & Nesbakken, Arild [Vis alle 8 forfattere av denne artikkelen] (2010). Transcriptional profiling of early onset colorectal cancer identifies CLC as a potential cancer susceptibility gene. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 205–205. Fulltekst i vitenarkiv

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