Anne Hansen Ree

• Ree, Anne Hansen; Meltzer, Sebastian; Flatmark, Kjersti & Dueland, Svein (2026). Low-intensity induction chemotherapy before chemoradiotherapy for rectal cancer: 10-year overall survival in the LARC-RRP trial. British Journal of Radiology (BJR). ISSN 0007-1285. 99(1186), p. 2129–2136. doi: 10.1093/bjr/tqag133. Full text in Research Archive
• Johnsen, Oddne Fjellstad; Riis, Rolf; Meltzer, Sebastian; Ree, Anne Hansen & Augestad, Knut Magne (2026). Long-term disease-free survival in young-onset rectal cancer patients surgically treated with curative intent: a retrospective cohort study. International Journal of Colorectal Disease. ISSN 0179-1958. 41(1). doi: 10.1007/s00384-026-05191-x. Full text in Research Archive
• Varende, Anne Laure Mallard de La; Tian, Ai Ling; Thomas, Simon; Lahmar, Imran; Messaoudene, Meriem & Li, Sijing [Show all 55 contributors for this article] (2026). Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy. Cancer Cell. ISSN 1535-6108. 44(8), p. 1653–1671.e16. doi: 10.1016/j.ccell.2026.06.022.
• Sanabria-Moreno, Adriana Maria; Bjørnetrø, Tonje; Fuglestad, Anniken Jørlo; Meltzer, Sebastian; Køstner, Anne Helene & Lüders, Torben [Show all 8 contributors for this article] (2026). Assessment of 16S rRNA sequencing for analysis of circulating microbial DNA in colorectal cancer patients–proof of concept and early changes during experimental chemoimmunotherapy. Frontiers in Microbiology. 17, p. 1–11. doi: 10.3389/fmicb.2026.1802448. Full text in Research Archive
• Lunder, Aida Kapic; Meltzer, Sebastian; Frøyen, Elin Agathe; Lyckander, Lars Gustav; Grandal, Ole Jacob & Ree, Anne Hansen [Show all 8 contributors for this article] (2026). MRI versus histopathology in EMVI detection for rectal cancer: prognostic relevance and survival outcomes. European Radiology. ISSN 0938-7994. doi: 10.1007/s00330-026-12658-6. Full text in Research Archive
• Meltzer, Sebastian; Landmark, Silje Sjåvik; Benth, Jurate Saltyte; Negård, Anne; Hamre, Hanne Mari & Kersten, Christian [Show all 11 contributors for this article] (2026). Carcinoembryonic Antigen Flare Under Oxaliplatin-Based Chemotherapy Predicts Benefit from Nivolumab in Metastatic Microsatellite-Stable Colorectal Cancer–A Post Hoc Analysis of METIMMOX Trial Data. ImmunoTargets and Therapy. 15. doi: 10.2147/ITT.S594176. Full text in Research Archive Show summary

  Background: The randomized METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with the immune checkpoint inhibitor nivolumab in patients with previously untreated, unresectable abdominal metastases from microsatellite-stable/mismatch repair-proficient colorectal cancer. A subgroup receiving this experimental treatment showed remarkably improved outcome compared to control arm patients who received chemotherapy alone and had median progression-free survival (PFS) of 9.3 months. We examined whether the kinetics of serum carcinoembryonic antigen (CEA) could provide insights into responsiveness to the METIMMOX regimen. Methods: Patients were randomly assigned to the control arm (oxaliplatin with bolus 5-fluorouracil/folinic acid, Q2W) or the experimental arm (alternating two cycles of chemotherapy Q2W and nivolumab Q2W). In this post hoc biomarker analysis, CEA levels were measured at baseline, at each treatment administration, and every two months during prespecified treatment breaks. Patients were categorized according to CEA kinetics—Flare (transient ≥ 20% increase above baseline), Non-responding (gradual increase), and Stable/Responding (values around baseline or gradually decreasing). Results: Flare comprised 16 out of 71 patients. According to Log rank test, experimental-arm Flare (n = 6) had significantly improved PFS (median 34.9 months) compared to Stable/Responding (n = 21; median PFS 9.9 months; p = 0.005) and Non-responding (n = 9; median PFS 2.1 months; p = 0.007). Flare was not associated with improved PFS for control-arm subjects. Adjusted Cox regression analysis indicated that experimental-arm Flare exhibited a lower progression risk than Non-responding for up to 6.2 months, creating an observation period for a potential decrease following the initial increase. Conclusion: CEA-Flare may indicate immune checkpoint inhibitor responsiveness following short-course oxaliplatin-based chemotherapy in this patient population; however, this is an exploratory finding that requires prospective validation.

• Ree, Anne Hansen; Bousquet, Paula; Visnovska, Martina; Lüders, Torben; Geisler, Benjamin Peter & Wang, Shixiong [Show all 16 contributors for this article] (2026). Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer. British Journal of Cancer. ISSN 0007-0920. 134, p. 1176–1182. doi: 10.1038/s41416-026-03357-6. Full text in Research Archive Show summary

  ABackground The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients’ systemic inflammation might provide insights into responsiveness to the METIMMOX regimen. Methods Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay. Results The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1–13). The experimental-arm patients with TMB ≥9 or BRAF -V600E mutation ( n  = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3–28.3), longer ( p  = 0.0090) than experimental-arm patients with TMB < 9 not BRAF -V600E ( n  = 19) and control-arm patients with either TMB and BRAF status combination ( n  = 31). With TMB ≥9 or BRAF -V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab ( n  = 11), median PFS was 35.0 months (95% confidence interval, 6.8–63.0; p  < 0.0001). Conclusions TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.

• Aken, Evert S.M. van; Gandhi, Ajeet Kumar; O’Cathail, Sean M.; Borst, Gerben; Barriuso, Jorge & Fokas, Emmanouil [Show all 32 contributors for this article] (2026). ESMO-ESTRO consensus statements on the safety of combining radiotherapy with CDK4/6, HER2, PARP, or mTOR inhibitors. Radiotherapy and Oncology. ISSN 0167-8140. 215. doi: 10.1016/j.radonc.2025.111330. Full text in Research Archive Show summary

  Background While combining radiotherapy (RT) with targeted agents or immunotherapy may improve outcomes, it may also increase toxicity. High-quality toxicity data and multidisciplinary, evidence-based guidelines on the combination of these treatment modalities are scarce. Design The European Society for Medical Oncology (ESMO) and the European SocieTy for Radiotherapy and Oncology (ESTRO) developed a series of systematic reviews with multidisciplinary, tumor-agnostic, evidence-based Delphi consensus statements regarding the safety of combining RT with targeted agents or immunotherapy. The current study addresses the safety of combining RT with CDK4/6 inhibitors, anti-HER2 monoclonal antibodies, PARP inhibitors, or mTOR-inhibitors. During the modified Delphi process, two digital voting rounds were organized with 18 international experts. By systematically evaluating the different drug classes and irradiated areas, 74 clinical scenarios were assessed. Safety statements were formulated for all scenarios, based on the evidence from the systematic literature reviews. Results A total of 1,341 records were screened during the systematic literature reviews, of which 107 studies were ultimately included in the final reviews and the literature database. After two Delphi voting rounds, agreement was reached on all 74 scenario-specific safety statements. Conclusions The expected combined toxicity is often low for anti-HER2 monoclonal antibodies. For most scenarios with CDK4/6, PARP, or mTOR inhibitors, exercising caution is recommended.

• Fuglestad, Anniken Jørlo; Bousquet, Paula; Køstner, Anne Helene; Meltzer, Sebastian; Kleist, Britta & Ree, Anne Hansen [Show all 10 contributors for this article] (2025). Circulating Levels of the Proinflammatory Monomeric Isoform of C-Reactive Protein (mCRP) Correlate with Intra-Tumoral mCRP Abundance in Stage II-III Colon Cancer Patients. Journal of Inflammation Research. 2025(18), p. 7115–7125. doi: 10.2147/jir.s485050. Full text in Research Archive Show summary

  Purpose: Colorectal cancer (CRC) is the third most common type of cancer worldwide. The link between inflammation and CRC is well established. Elevated levels of C-reactive protein (CRP) upon diagnosis is a known negative prognostic factor for CRC patients. Monomeric CRP (mCRP) has been demonstrated in tissues of several diseases associated with inflammation, including colon cancer (CC). mCRP possesses proinflammatory properties and is a possible mediator of tumor-promoting inflammation. This study aimed to detect and quantify circulating mCRP and assess potential correlations with clinical CRP and intra-tumoral mCRP in CC patients. Patients and methods: Forty patients treated for stage II-III CC between 2012 and 2015 at Sorlandet Hospital, Norway, were included in the study. Twenty patients had CRP level <10 mg/l and 20 patients had CRP ≥10 mg/l, measured routinely at diagnosis (clinical CRP). EDTA plasma was used for mCRP detection by enzyme-linked immunosorbent assay (ELISA; n = 40) and mass spectrometry (MS; n = 20) (MS data are available via ProteomeXchange with identifier PXD046746). Tumor mCRP abundance was classified into three categories by reference scoring, using an antigen-retrieval technique on formalin-fixed paraffin-embedded tissue samples (n = 29). Results: Circulating mCRP levels were detectable by both ELISA and MS. Median mCRP level measured by ELISA was 2.55 ng/mL, while the MS analysis detected 19.02 ng/mL. Both analyses exhibited significant correlations with clinical CRP (ELISA, p = 0.012; MS, p < 0.001). Intra-tumoral mCRP correlated with circulating mCRP measured by MS (p < 0.001) and with clinical CRP (p < 0.001). Conclusion: To the authors' knowledge, this is the first report of mCRP in the circulation of cancer patients. By employing two different analytical methods, mCRP was reliably detected in CC patients. Patients with elevated circulating mCRP measured by MS had higher intra-tumoral mCRP abundance. The interesting correlation of circulating and intra-tumoral mCRP levels may represent another facet of the interplay between local and systemic inflammation in CC patients.

• Hundvin, Johanna Austrheim; Bornstein, Marius; Negård, Anne; Holmedal, Stein Harald; Meltzer, Sebastian & Ree, Anne Hansen [Show all 8 contributors for this article] (2025). Low b-values in apparent diffusion coefficient calculations overestimate diffusion in rectal cancer. Acta Oncologica. ISSN 0284-186X. 64, p. 1430–1436. doi: 10.2340/1651-226x.2025.44028. Full text in Research Archive Show summary

  Background and purpose: The apparent diffusion coefficient (ADC), derived from diffusion-weighted MRI (DWI), is commonly calculated using a monoexponential model. However, there is no consensus on optimal b-value selection for ADC quantification in rectal cancer. This prospective observational study evaluated how varying b-value combinations influence ADC values. Patient/material and methods: DWI with seven b-values (b = 0, 25, 50, 100, 500, 1,000, and 1,300 s/mm2) was acquired from 23 rectal cancer patients in the OxyTarget study (NCT01816607) using a 1.5T Philips Achieva scanner. Two radiologists independently delineated whole-tumour volumes of interest. ADC values were calculated using 18 different b-value combinations and compared with a biexponential reference. Results: Tumour ADCs varied significantly across b-value combinations. Excluding low b-values (b ≤ 100 s/mm²) led to reduced ADCs. Although b = 0 s/mm² is commonly included in ADC calculations, this study demonstrates that its inclusion leads to substantial overestimation. The use of two or three b-values from b = 500, 1,000, and 1,300 s/mm² yielded the smallest deviations from the biexponential reference. Interpretation: In rectal cancer, tumour ADC calculated using the monoexponential model is strongly influenced by the choice of b-values. By eliminating the contribution from perfusion (b ≤ 100 s/mm2) the uncertainty in the calculations is significantly reduced. Our findings support the use of b-values exceeding 100 s/mm², ideally in combination with a high b-value of at least 1,000 s/mm², when assessing diffusion using the monoexponential model. Consistent b-value combinations across studies are recommended for reliable quantitative comparisons of ADC values.

• Bakke, Kine Mari; Bjørnetrø, Tonje; Bousquet, Paula; Sanabria-Moreno, Adriana Maria; Meltzer, Sebastian & Lüders, Torben [Show all 15 contributors for this article] (2025). Dissemination of Mitochondrial DNA Variants: Looking at the ‘Bigger’ Picture of the Tumour Microenvironment in Rectal Cancer Patients. Journal of Extracellular Biology (J Ex Bio). 4(11). doi: 10.1002/jex2.70097. Full text in Research Archive Show summary

  ABSTRACT The tumour microenvironment (TME) constitution is decisive for cancer outcome and is manifested in diffusion‐weighted (DW) magnetic resonance imaging (MRI). We hypothesized that the TME metabolic state is reflected by mitochondrial DNA (mtDNA) secreted in extracellular vesicles (EVs) and examined whether plasma EV‐mtDNA variants may divulge MRI‐assessed TME attributes of rectal cancer aggressiveness. On the diagnostic MRI scans from 60 rectal cancer patients, the apparent diffusion coefficient (ADC) was calculated on DW images ( n = 29), and tumour volume ( n = 57) and extramural vascular invasion (EMVI; all patients) were determined on anatomical images. Plasma EVs (all patients) were isolated by size exclusion chromatography and verified for EV features. The EV‐mtDNA was sequenced along with mtDNA in whole blood (WB; normal tissue) to calculate the EV/WB‐mtDNA total variant number (TVN) and heteroplasmic variant number (HVN)—as a proxy for TME intracellular mtDNA variants expelled in EVs. Low EV/WB‐mtDNA TVN and HVN, indicative of hampered clearance of mutated mtDNA via EVs, were associated with low ADC (high TME cell density; p = 0.018, p = 0.005) and a large tumour volume ( p = 0.002, p = 0.003). Likewise, low EV/WB‐mtDNA TVN and HVN were associated with positive EMVI (tumour infiltration in blood vessels; p = 0.002, p = 0.003) and histologic ypN stage 1–2 (lymph nodes with tumour cells surviving radiotherapy; p = 0.002, p = 0.005), both indicators of high tumour aggressiveness. High cellular density may hamper the clearance of pathogenic tumour mtDNA variants by EVs and thus promote rectal cancer aggressiveness. Trial Registration : ClinicalTrials.gov: NCT01816607. Registered 22 March 2013, https://clinicaltrials.gov/ct2/show/NCT01816607

• Bakke, Kine Mari; Bousquet, Paula; Meltzer, Sebastian; Bjørnetrø, Tonje; Rise, Frode & Wilkins, Alistair Lawrence [Show all 8 contributors for this article] (2025). Serum metabolite levels identify incipient metastatic progression of rectal cancer. Communications Medicine. 5. doi: 10.1038/s43856-025-00868-w. Full text in Research Archive Show summary

  Background The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression. Methods One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification. Results Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test). Conclusions We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.

• Svalastoga, Marte; Larsen, Trine-Lise; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Garresori, Herish [Show all 15 contributors for this article] (2025). Effect of drug interactions with apixaban on clinical outcomes in cancer patients with venous thromboembolism. Frontiers in Oncology. 15. doi: 10.3389/fonc.2025.1520725. Full text in Research Archive Show summary

  Introduction: It is unclear how drug-interaction with apixaban influences recurrent venous thromboembolism (VTE) and bleedings in cancer patients. Methods: A post-hoc analysis of a single-arm interventional clinical trial on apixaban treatment of cancer patients with VTE to investigate whether the occurrence of any of the endpoints could be associated with the concurrent use of an interacting drug. Drugs taken by the patients during the trial period were categorized as either increasing bleeding risk, increasing thrombosis risk, both or neither. Results: 298 patients were divided into groups based on whether they used no interacting drugs (controls, n=74), drugs increasing bleeding risk (n=55), drugs increasing thrombosis risk (n=8), or both (n=161). Odds ratios (OR) were calculated for recurrent VTE, clinically relevant non-major bleeding (CRNMB), and major bleeding during the 36-month follow-up period. Each patient took a median of 13 different drugs over the study period. 67% of the patients used drugs expected to both increase bleeding and thrombosis. The use of fluconazole appeared associated with CRNMB (OR 3.6, 95% confidence interval (CI) 0.99-13), but not with major bleeding (OR 0.56, 95% CI 0.06 - 4.8). Non-steroid anti-inflammatory drugs were not associated with CRNMB (OR 1.0, 95% CI 0.25-4.1) or major bleedings (OR 0.72, 95% CI 0.14 - 3.6). Use of antiplatelet therapy was not associated with CRNMB (OR 0.75, 95% CI, 0.22 - 2.58) or major bleeding (OR 0.2, 95% CI, 0.02-1.6). There were no major bleedings in 23 patients using aprepitant nor in the 10 patients taking macrolides. We found no association between drugs and recurrent VTE, except that there were no recurrent VTE in 19 patients using bevacizumab. Conclusions: Despite the high number of drugs taken that could potentially interact with apixaban, none were found to clearly influence clinical outcomes, except that fluconazole may increase the risk of CRNMB.

• Heras, Sara Cabrero-de las; Hernández-Yagüe, Xavier; González, Andrea; Losa, Ferran; Soler, Gemma & Bugés, Cristina [Show all 24 contributors for this article] (2024). Changes In Serum CXCL13 Levels Are Associated With Outcomes of Colorectal Cancer Patients Undergoing First-Line Oxaliplatin-Based Treatment. Biomedicine & Pharmacotherapy. ISSN 0753-3322. 176. doi: 10.1016/j.biopha.2024.116857. Full text in Research Archive Show summary

  Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment

• Ree, Anne Hansen; Benth, Jurate Saltyte; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva & Guren, Marianne [Show all 14 contributors for this article] (2024). First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer—the randomised METIMMOX trial. British Journal of Cancer. ISSN 0007-0920. 130(12), p. 1921–1928. doi: 10.1038/s41416-024-02696-6. Full text in Research Archive Show summary

  Background We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Methods Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Results Eighty patients were randomised and 38 in each group received treatment. PFS was comparable—control group: median 9.2 months (95% confidence interval (CI), 6.3–12.7); experimental group: median 9.2 months (95% CI, 4.5–15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04–0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8–23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. Conclusions The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. Trial registration ClinicalTrials.gov number, NCT03388190 (02/01/2018).

• Knuth, Franziska; Tohidinezhad, Fariba; Winter, Rene Mario; Bakke, Kine Mari; Negård, Anne & Holmedal, Stein Harald [Show all 10 contributors for this article] (2024). Quantitative MRI-based radiomics analysis identifies blood flow feature associated to overall survival for rectal cancer patients. Scientific Reports. 14(1). doi: 10.1038/s41598-023-50966-9. Full text in Research Archive Show summary

  Radiomics objectively quantifies image information through numerical metrics known as features. In this study, we investigated the stability of magnetic resonance imaging (MRI)-based radiomics features in rectal cancer using both anatomical MRI and quantitative MRI (qMRI), when different methods to define the tumor volume were used. Second, we evaluated the prognostic value of stable features associated to 5-year progression-free survival (PFS) and overall survival (OS). On a 1.5 T MRI scanner, 81 patients underwent diagnostic MRI, an extended diffusion-weighted sequence with calculation of the apparent diffusion coefficient (ADC) and a multiecho dynamic contrast sequence generating both dynamic contrast-enhanced and dynamic susceptibility contrast (DSC) MR, allowing quantification of Ktrans, blood flow (BF) and area under the DSC curve (AUC). Radiomic features were extracted from T2w images and from ADC, Ktrans, BF and AUC maps. Tumor volumes were defined with three methods; machine learning, deep learning and manual delineations. The interclass correlation coefficient (ICC) assessed the stability of features. Internal validation was performed on 1000 bootstrap resamples in terms of discrimination, calibration and decisional benefit. For each combination of image and volume definition, 94 features were extracted. Features from qMRI contained higher prognostic potential than features from anatomical MRI. When stable features (> 90% ICC) were compared with clinical parameters, qMRI features demonstrated the best prognostic potential. A feature extracted from the DSC MRI parameter BF was associated with both PFS (p = 0.004) and OS (p = 0.004). In summary, stable qMRI-based radiomics features was identified, in particular, a feature based on BF from DSC MRI was associated with both PFS and OS.

• O'Brien, Rebecca M.; Meltzer, Sebastian; Buckley, Croí E.; Heeran, Aisling B.; Nugent, Timothy S. & Donlon, Noel E. [Show all 22 contributors for this article] (2024). Complement is increased in treatment resistant rectal cancer and modulates radioresistance. Cancer Letters. ISSN 0304-3835. 604. doi: 10.1016/j.canlet.2024.217253. Full text in Research Archive Show summary

  Resistance to neoadjuvant chemoradiation therapy (neo-CRT) is a significant clinical problem in the treatment of locally advanced rectal cancer. Identification of novel therapeutic targets and biomarkers predicting therapeutic response is required to improve patient outcomes. Increasing evidence supports a role for the complement system in resistance to anti-cancer therapy. In this study, increased expression of complement effectors C3 and C5 and increased production of anaphylatoxins, C3a and C5a, was observed in radioresistant rectal cancer cells. Modulation of the central complement effector, C3, was demonstrated to functionally alter the radioresponse, with C3 overexpression significantly enhancing radioresistance, whilst C3 inhibition significantly increased sensitivity to a clinically-relevant dose of radiation. Inhibition of C3 was demonstrated to increase DNA damage and alter cell cycle distribution, mediating a shift towards a radiosensitive cell cycle phenotype suggesting a role for C3 in reprogramming of the tumoural radioresponse. Expression of the complement effectors C3 and C5 was significantly increased in human rectal tumour tissue, as was expression of CFB, a component of the alternative pathway of activation. Elevated levels of C3a and C5b-9 in pre-treatment sera from rectal cancer patients was associated with subsequent poor responses to neo-CRT and poorer survival. Together these data demonstrate a role for complement in the radioresistance of rectal cancer and identify key complement components as potential biomarkers predicting response to neo-CRT and outcome in rectal cancer.

• Mecinaj, Albulena; Gulati, Geeta; Ree, Anne Hansen; Gravdehaug, Berit; Røsjø, Helge Rørvik & Steine, Kjetil [Show all 10 contributors for this article] (2024). Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction. JACC: CardioOncology. 6(1), p. 83–95. doi: 10.1016/j.jaccao.2023.10.008. Full text in Research Archive Show summary

  Background The impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)

• Ree, Anne Hansen; Høye, Eirik; Esbensen, Qin Ying; Beitnes, Ann-Christin Røberg; Negård, Anne & Bernklev, Linn [Show all 16 contributors for this article] (2024). Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. ISSN 2162-4011. 13(1). doi: 10.1080/2162402X.2024.2372886. Full text in Research Archive Show summary

  The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2–11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20–35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

• Bjørnetrø, Tonje; Bousquet, Paula; Redalen, Kathrine Røe; Siebke, Anne-Marie; Lüders, Torben & Stang, Espen [Show all 12 contributors for this article] (2023). Next-generation sequencing reveals mitogenome diversity in plasma extracellular vesicles from colorectal cancer patients. BMC Cancer. 23(1). doi: 10.1186/s12885-023-11092-x. Full text in Research Archive Show summary

  Background Recent reports have demonstrated that the entire mitochondrial genome can be secreted in extracellular vesicles (EVs), but the biological attributes of this cell-free mitochondrial DNA (mtDNA) remain insufficiently understood. We used next-generation sequencing to compare plasma EV-derived mtDNA to that of whole blood (WB), peripheral blood mononuclear cells (PBMCs), and formalin-fixed paraffin-embedded (FFPE) tumor tissue from eight rectal cancer patients and WB and fresh-frozen (FF) tumor tissue from eight colon cancer patients. Methods Total DNA was isolated before the mtDNA was enriched by PCR with either two primer sets generating two long products or multiple primer sets (for the FFPE tumors), prior to the sequencing. mtDNA diversity was assessed as the total variant number, level of heteroplasmy (mutant mtDNA copies mixed with wild-type copies), variant distribution within the protein-coding genes, and the predicted functional effect of the variants in the different sample types. Differences between groups were compared by paired Student’s t-test or ANOVA with Dunnett’s multiple comparison tests when comparing matched samples from patients. Mann–Whitney U test was used when comparing differences between the cancer types and patient groups. Pearson correlation analysis was performed. Results In both cancer types, EV mtDNA presented twice as many variants and had significantly more low-level heteroplasmy than WB mtDNA. The EV mtDNA variants were clustered in the coding regions, and the proportion of EV mtDNA variants that were missense mutations (i.e., estimated to moderately affect the mitochondrial protein function) was significantly higher than in WB and tumor tissues. Nonsense mutations (i.e., estimated to highly affect the mitochondrial protein function) were only observed in the tumor tissues and EVs. Conclusion Taken together, plasma EV mtDNA in CRC patients exhibits a high degree of diversity.

• Larsen, Trine-Lise; Svalastoga, Marte; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Garresori, Herish [Show all 16 contributors for this article] (2023). Arterial events in cancer patients treated with apixaban for venous thrombosis. Thrombosis Research. ISSN 0049-3848. 228, p. 128–133. doi: 10.1016/j.thromres.2023.05.017. Full text in Research Archive
• Bakke, Kine Mari; Meltzer, Sebastian; Grøvik, Endre; Negård, Anne; Holmedal, Stein Harald & Mikalsen, Lars Tore Gyland [Show all 13 contributors for this article] (2023). Imaging the tumour microenvironment in rectal cancer: Decline in tumour blood flow during radiotherapy predicts good outcome. Physics and imaging in radiation oncology (PIRO). 25, p. 1–7. doi: 10.1016/j.phro.2023.100417. Full text in Research Archive Show summary

  Background and purpose Measuring rectal tumour response to radiation is pivotal to restaging patients and for possibly stratification to a watch-and-wait strategy. Recognizing the importance of the tumour microenvironment, we investigated a less explored quantitative imaging marker assessing tumour blood flow (BF) for its potential to predict overall survival (OS). Materials and methods 24 rectal cancer patients given curative-intent neoadjuvant radiotherapy underwent a multi-echo dynamic magnetic resonance imaging (MRI) sequence with gadolinium contrast for quantification of tumour BF before either 25x2 Gy (n = 18) with concomitant chemotherapy or 5x5 Gy (n = 6). CD34 staining of excised tumour tissue was performed and baseline blood samples were analysed for lactate dehydrogenase (LDH) and angiopoietin-2 (ANGPT-2). Tumour volumes were measured before and after treatment. After subsequent surgery, ypTN scoring assessed tumour response. Cox regression for 5-year OS analysis and t-test for group comparisons were performed. Results The change in tumour BF (ΔBF) during neoadjuvant radiotherapy was a significant marker of OS, whereas tumour stage and volume were not related to OS. All patients with >20 % decline in BF were long-term survivors. Separating cases in two groups based on ΔBF revealed that patients with increase or a low decrease had higher baseline LDH (p = 0.032) and ANGPT-2 (p = 0.028) levels. Conclusion MRI-assessed tumour ΔBF during neoadjuvant treatment is a significant predictor of OS in rectal cancer patients, making ΔBF a potential quantitative imaging biomarker for treatment stratification. Blood LDH and ANGPT-2 indicate that non-responding tumours may have a hypoxic microenvironment resistant to radiotherapy.

• Nygaard, Vigdis; Ree, Anne Hansen; Dagenborg, Vegar Johansen; Børresen-Dale, Anne-Lise; Edwin, Bjørn von Gohren & Fretland, Åsmund Avdem [Show all 10 contributors for this article] (2023). A PRRX1 Signature Identifies TIM-3 and VISTA as Potential Immune Checkpoint Targets in a Subgroup of Microsatellite Stable Colorectal Cancer Liver Metastases. Cancer Research Communications. 3(2), p. 235–244. doi: 10.1158/2767-9764.CRC-22-0295. Full text in Research Archive Show summary

  Disease recurrence and drug resistance are major challenges in the clinical management of patients with colorectal cancer liver metastases (CLM), and because tumors are generally microsatellite stable (MSS), responses to immune therapies are poor. The mesenchymal phenotype is overrepresented in treatment-resistant cancers and is associated with an immunosuppressed microenvironment. The aim of this work was to molecularly identify and characterize a mesenchymal subgroup of MSS CLM to identify novel therapeutic approaches. We here generated a mesenchymal gene expression signature by analysis of resection specimens from 38 patients with CLM using ranked expression level of the epithelial-to-mesenchymal transition–related transcription factor PRRX1. Downstream pathway analysis based on the resulting gene signature was performed and independent, publicly available datasets were used to validate the findings. A subgroup comprising 16% of the analyzed CLM samples were classified as mesenchymal, or belonging to the PRRX1high group. Analysis of the PRRX1 signature genes revealed a distinct immunosuppressive phenotype with high expression of immune checkpoints HAVCR2/TIM-3 and VISTA, in addition to the M2 macrophage marker CD163. The findings were convincingly validated in datasets from three external CLM cohorts. Upregulation of immune checkpoints HAVCR2/TIM-3 and VISTA in the PRRX1high subgroup is a novel finding, and suggests immune evasion beyond the PD-1/PD-L1 axis, which may contribute to poor response to PD-1/PD-L1–directed immune therapy in MSS colorectal cancer. Importantly, these checkpoints represent potential novel opportunities for immune-based therapy approaches in a subset of MSS CLM. Significance: CLM is an important cause of colorectal cancer mortality where the majority of patients have yet to benefit from immunotherapies. In this study of gene expression profiling analyses, we uncovered novel immune checkpoint targets in a subgroup of patients with MSS CLMs harboring a mesenchymal phenotype.

• Høye, Eirik; Dagenborg, Vegar Johansen; Kristensen, Annette Torgunrud; Lund-Andersen, Christin; Fretland, Åsmund Avdem & Lorenz, Susanne [Show all 13 contributors for this article] (2023). T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases. GigaScience. 12. doi: 10.1093/gigascience/giad032. Full text in Research Archive Show summary

  Background - Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T-cell infiltration in CLM using T-cell receptor (TCR) repertoire sequencing. Eighty-five resected CLMs from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T-cell fractions were calculated, repertoire clonality was analyzed based on Hill evenness curves, and TCR sequence convergence was assessed using network analysis.<p> <p>Results - Increased T-cell fractions (10.6% vs. 6.3%) were detected in CLMs exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT-exposed tumors independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence.<p> <p>Conclusions - TCR repertoire sequencing can be used to quantify T-cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T-cell clonal expansion in CLM in a clinical context.

• Buckley, Croí E.; Yin, Xiaofei; Meltzer, Sebastian; Ree, Anne Hansen; Redalen, Kathrine Røe & Brennan, Lorraine [Show all 8 contributors for this article] (2023). Energy Metabolism Is Altered in Radioresistant Rectal Cancer. International Journal of Molecular Sciences. ISSN 1661-6596. 24(8). doi: 10.3390/ijms24087082. Full text in Research Archive Show summary

  Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients.

• Meltzer, Sebastian; Negård, Anne; Bakke, Kine Mari; Hamre, Hanne Mari; Kersten, Christian & Hofsli, Eva [Show all 10 contributors for this article] (2022). Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer. British Journal of Cancer. ISSN 0007-0920. 127, p. 2227–2233. doi: 10.1038/s41416-022-02004-0. Full text in Research Archive Show summary

  Background: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. Methods: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. Results: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3–19.7) and 3.9 months (95% CI, 2.3–5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9–14.7) for control arm patients (N = 31). Conclusions: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.

• Ree, Anne Hansen; Mælandsmo, Gunhild Mari; Flatmark, Kjersti; Russnes, Hege Elisabeth Giercksky; Casteneda, Monica Gomez & Aas, Eline (2022). Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer – the MetAction precision medicine study. Acta Oncologica. ISSN 0284-186X. 61(8), p. 955–962. doi: 10.1080/0284186X.2022.2098053. Full text in Research Archive Show summary

  Background: Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials.<p> <p>Methods: We designed three partitioned survival models to evaluate the healthcare costs and qualityadjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty. <p>Results: We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy. <p>Conclusions: The models suggested that the high ICERs of PCM were driven by costs of the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold. This can be an incentive for a public-private partnership for sharing drug costs in PCM, exemplified by ongoing European initiatives.

• Larsen, Trine-Lise; Garresori, Herish; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Jacobsen, Eva-Marie [Show all 15 contributors for this article] (2022). Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients – 30 months follow-up. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 20(5), p. 1166–1181. doi: 10.1111/jth.15666. Full text in Research Archive Show summary

  Background There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. Methods We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. Results During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%–11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%–6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%–12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41–1.6) at 2–6 months with full-dose apixaban, and 1.0% (95% CI 0.5–1.9) at 7–12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6–2.0) at 2–6 months, and 0.3% (95% CI 0.1–1.0) at 7–12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. Conclusion Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

• Ambrosini, Margherita; Re, Marzia Del; Manca, Paolo; Hendifar, Andrew; Drilon, Alexander & Harada, Guilherme [Show all 21 contributors for this article] (2022). ALK Inhibitors in Patients with ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series. JCO Precision Oncology (JCO PO). 6(1). doi: 10.1200/PO.22.00015. Full text in Research Archive Show summary

  PURPOSE In GI cancers, anaplastic lymphoma kinase (ALK) rearrangements are extremely less frequent than in non–small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis. RESULTS Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response). CONCLUSION Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion–positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.

• Malenge, Marion Masitsa; Maaland, Astri Fjelde; Repetto-Llamazares, Ada H.V.; Middleton, Brian; Nijland, Marcel & Visser, Lydia [Show all 12 contributors for this article] (2022). Anti-CD37 radioimmunotherapy with 177Lu-NNV003 synergizes with the PARP inhibitor olaparib in treatment of non-Hodgkin's lymphoma in vitro. PLOS ONE. 17(4). doi: 10.1371/journal.pone.0267543. Full text in Research Archive Show summary

  Background and purpose: PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 β-emitting 177Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines. Materials and methods: The combined effect of 177Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes. Results: The combination of olaparib and 177Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment. Conclusion: The cytotoxic effect of the combination of the PARP inhibitor olaparib and the β-emitting radioimmunoconjugate 177Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines.

• Fuglestad, Anniken Jørlo; Meltzer, Sebastian; Ree, Anne Hansen; McMillan, Donald C.; Park, James H. & Kersten, Christian (2022). The clinical value of C-reactive protein and its association with tumour location in patients undergoing curative surgery for colorectal cancer–a ScotScan collaborative study. Acta Oncologica. ISSN 0284-186X. 61(10), p. 1248–1255. doi: 10.1080/0284186X.2022.2117572. Full text in Research Archive Show summary

  Introduction The presence of preoperative systemic inflammatory response (SIR) is an established negative prognostic factor for patients diagnosed with colorectal cancer (CRC). C-reactive protein (CRP) is known to be implicated in detrimental immune responses. The biological differences between right-sided and left-sided CRC are gaining increasing attention. Our aim was to analyse the prognostic value of CRP and explore the association between tumour location and SIR. Material and methods A total of 2059 patients treated for stage I–III CRC, identified from the prospectively sampled ScotScan Collaborative dataset, were included. The clinical and prognostic value of five CRP levels (<10/11–30/31–60/61–100/>100 mg/l) were examined. Additionally, the relationship between SIR and tumour location was explored. Results Increasing levels of CRP were associated with impaired overall and cancer-specific outcome. Presence of SIR was independently associated with right-sided tumour location (p<0.001). However, the impact of SIR on cancer-specific survival (CSS) was greater for left-sided tumour location, even when adjusted for other clinicopathological factors. Conclusions This study confirms CRP as a routinely available, valid, and clinically relevant strong prognostic marker of SIR in CRC patients. Right-sided tumours were more often associated with SIR, but the prognostic impact was stronger in left-sided tumours.

• Meltzer, Sebastian; Kristensen, Annette Torgunrud; Abrahamsson, Hanna Josefine; Solbakken, Arne Mide; Flatmark, Kjersti & Dueland, Svein [Show all 15 contributors for this article] (2021). The circulating soluble form of the CD40 costimulatory immune checkpoint receptor and liver metastasis risk in rectal cancer. British Journal of Cancer. ISSN 0007-0920. 125, p. 240–246. doi: 10.1038/s41416-021-01377-y. Full text in Research Archive Show summary

  Background In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk. Methods We measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I–III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II–III rectal cancer patients in three independent cohorts. Results We identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts—the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis. Conclusions Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.

• Dagenborg, Vegar Johansen; Marshall, Serena; Grzyb, Krzysztof; Fretland, Åsmund Avdem; Lund-Iversen, Marius & Mælandsmo, Gunhild Mari [Show all 10 contributors for this article] (2021). Low Concordance Between T-Cell Densities in Matched Primary Tumors and Liver Metastases in Microsatellite Stable Colorectal Cancer. Frontiers in Oncology. 11, p. 1–9. doi: 10.3389/fonc.2021.671629. Full text in Research Archive Show summary

  Background: The subtype, density and location of tumor infiltrating T-cells are being explored as prognostic and predictive biomarkers in primary colorectal cancer (pCRC) and colorectal liver metastases (CLM). Very limited data exist comparing findings in pCRC and matched CLM.<p> <p>Patients and methods: Fifty-eight patients with available pCRC and matched CLM (57/58 microsatellite stable) were included in this OSLO-COMET substudy. In immunohistochemically stained sections, total (Ttot), helper (TH), cytotoxic (CTL), and regulatory (Treg) T-cells were manually counted in hotspots from the invasive margin (IM), intratumor (IT), and tumor adjacent regions to determine T-cell densities.<p> <p>Results: A striking accumulation of T-cells was found in IM of both pCRC and CLM with much lower densities in the IT region, exemplified by Ttot of 2838 versus 340 cells/mm2, respectively, in CLM. The correlation at the individual level between T-cell densities in pCRC and corresponding CLM was poor for all regions and T-cell subtypes; for instance, the correlation coefficient (R2) for IM Ttot was 0.07. The IT TH : CTL and Treg : TH ratios were 2.94 and 0.44, respectively, in pCRC, and 1.84 and 0.24, respectively, in CLM.<p> <p>Conclusion: The observed accumulation of T-cells in the IM regions of pCRC and CLM with low penetration to the IT regions, combined with high TH : CTL and Treg : TH ratios, point to the presence of an immune suppressive microenvironment. T-cell densities of CLM differed markedly from the matched pCRC, indicating that to evaluate T-cell biomarkers in metastasis, the commonly available pCRC cannot serve as a surrogate for the metastatic tumor.

• Heck, Siri Lagethon; Mecinaj, Albulena; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette & Fagerland, Morten [Show all 12 contributors for this article] (2021). Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): Extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Circulation. ISSN 0009-7322. 143(25), p. 2431–2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Full text in Research Archive Show summary

  Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

• Bjørnetrø, Tonje; Steffensen, Lilly Alice; Vestad, Beate; Brusletto, Berit Sletbakk; Olstad, Ole Kristoffer & Siebke, Anne-Marie [Show all 15 contributors for this article] (2021). Uptake of circulating extracellular vesicles from rectal cancer patients and differential responses by human monocyte cultures. FEBS Open Bio. 11(3), p. 724–740. doi: 10.1002/2211-5463.13098. Full text in Research Archive Show summary

  Extracellular vesicles (EVs) released by tumor cells can directly or indirectly modulate the phenotype and function of the immune cells of the microenvironment locally or at distant sites. The uptake of circulating EVs and the responses by human monocytes in vitro may provide new insights into the underlying biology of the invasive and metastatic processes in cancer. Although a mixed population of vesicles is obtained with most isolation techniques, we predominantly isolated exosomes (small EVs) and microvesicles (medium EVs) from the SW480 colorectal cancer cell line (established from a primary adenocarcinoma of the colon) by sequential centrifugation and ultrafiltration, and plasma EVs were prepared from 22 patients with rectal adenoma polyps or invasive adenocarcinoma by size-exclusion chromatography. The EVs were thoroughly characterized. The uptake of SW480 EVs was analyzed, and small SW480 EVs were observed to be more potent than medium SW480 EVs in inducing monocyte secretion of cytokines. The plasma EVs were also internalized by monocytes; however, their cytokine-releasing potency was lower than that of the cell line-derived vesicles. The transcriptional changes in the monocytes highlighted differences between adenoma and adenocarcinoma patient EVs in their ability to regulate biological functions, whereas the most intriguing changes were found in monocytes receiving EVs from patients with metastatic compared with localized cancer.

• Knuth, Franziska Hanna; Adde, Ingvild Askim; Huynh, Bao Ngoc; Grøndahl, Aurora Rosvoll; Winter, René & Negård, Anne [Show all 15 contributors for this article] (2021). MRI-based automatic segmentation of rectal cancer using 2D U-Net on two independent cohorts. Acta Oncologica. ISSN 0284-186X. 61(2), p. 255–263. doi: 10.1080/0284186X.2021.2013530. Full text in Research Archive Show summary

  Background Tumor delineation is time- and labor-intensive and prone to inter- and intraobserver variations. Magnetic resonance imaging (MRI) provides good soft tissue contrast, and functional MRI captures tissue properties that may be valuable for tumor delineation. We explored MRI-based automatic segmentation of rectal cancer using a deep learning (DL) approach. We first investigated potential improvements when including both anatomical T2-weighted (T2w) MRI and diffusion-weighted MR images (DWI). Secondly, we investigated generalizability by including a second, independent cohort. Material and methods Two cohorts of rectal cancer patients (C1 and C2) from different hospitals with 109 and 83 patients, respectively, were subject to 1.5 T MRI at baseline. T2w images were acquired for both cohorts and DWI (b-value of 500 s/mm2) for patients in C1. Tumors were manually delineated by three radiologists (two in C1, one in C2). A 2D U-Net was trained on T2w and T2w + DWI. Optimal parameters for image pre-processing and training were identified on C1 using five-fold cross-validation and patient Dice similarity coefficient (DSCp) as performance measure. The optimized models were evaluated on a C1 hold-out test set and the generalizability was investigated using C2. Results For cohort C1, the T2w model resulted in a median DSCp of 0.77 on the test set. Inclusion of DWI did not further improve the performance (DSCp 0.76). The T2w-based model trained on C1 and applied to C2 achieved a DSCp of 0.59. Conclusion T2w MR-based DL models demonstrated high performance for automatic tumor segmentation, at the same level as published data on interobserver variation. DWI did not improve results further. Using DL models on unseen cohorts requires caution, and one cannot expect the same performance.

• Abrahamsson, Hanna Josefine; Meltzer, Sebastian; Hagen, Vidar Nyløkken; Johansen, Christin; Bousquet, Paula & Redalen, Kathrine [Show all 7 contributors for this article] (2021). Sex disparities in vitamin D status and the impact on systemic inflammation and survival in rectal cancer. BMC Cancer. 21. doi: 10.1186/s12885-021-08260-2. Full text in Research Archive Show summary

  Background We reported previously that rectal cancer patients given curative-intent chemotherapy, radiation, and surgery for non-metastatic disease had enhanced risk of metastatic progression and death if circulating levels of 25-hydroxyvitamin D [25(OH) D] were low. Here we investigated whether the association between the vitamin D status and prognosis pertains to the general, unselected population of rectal cancer patients. Methods Serum 25(OH) D at the time of diagnosis was assessed in 129 patients, enrolled 2013–2017 and representing the entire range of rectal cancer stages, and analyzed with respect to season, sex, systemic inflammation, and survival. Results In the population-based cohort residing at latitude 60°N, 25(OH) D varied according to season in men only, who were overrepresented among the vitamin D-deficient (< 50 nmol/L) patients. Consistent with our previous findings, the individuals presenting with T4 disease had significantly reduced 25(OH) D levels. Low vitamin D was associated with systemic inflammation, albeit with distinct modes of presentation. While men with low vitamin D showed circulating markers typical for the systemic inflammatory response (e.g., elevated erythrocyte sedimentation rate), the corresponding female patients had elevated serum levels of interleukin-6 and the chemokine (C-X-C motif) ligand 7. Despite disparities in vitamin D status and the potential effects on disease attributes, significantly shortened cancer-specific survival was observed in vitamin D-deficient patients irrespective of sex. Conclusion This unselected rectal cancer cohort confirmed the interconnection of low vitamin D, more advanced disease presentation, and poor survival, and further suggested it may be conditional on disparate modes of adverse systemic inflammation in men and women.

• Bousquet, Paula; Meltzer, Sebastian; Fuglestad, Anniken Jørlo; Lüders, Torben; Esbensen, Qin Ying & Juul, Hedvig Vidarsdotter [Show all 13 contributors for this article] (2021). The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression. Clinical and Translational Oncology. ISSN 1699-048X. doi: 10.1007/s12094-021-02756-w. Full text in Research Archive Show summary

  Abstract Purpose A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. Patients and methods We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. Results Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3 + ) helper T-cell population, with the proportion of LAG-3 + cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation. Conclusion Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility. Trial registration ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

• Bakke, Kine Mari; Meltzer, Sebastian; Grøvik, Endre; Negård, Anne; Holmedal, Stein Harald & Gjesdal, Kjell-Inge [Show all 9 contributors for this article] (2020). Sex differences and tumor blood flow from dynamic susceptibility contrast MRI are associated with treatment response after chemoradiation and long-term survival in rectal cancer. Radiology. ISSN 0033-8419. 297(2), p. 352–360. doi: 10.1148/RADIOL.2020200287. Full text in Research Archive Show summary

  Sex differences, tumor vascularity, and blood flow seen on multiecho dynamic contrast–based MRI scans enabled prediction of treatment response and overall survival in patients with rectal cancer. Background: MRI is the standard tool for rectal cancer staging. However, more precise diagnostic tests that can assess biologic tumor features decisive for treatment outcome are necessary. Tumor perfusion and hypoxia are two important features; however, no reference methods that measure these exist in clinical use. Purpose: To assess the potential predictive and prognostic value of MRI-assessed rectal cancer perfusion, as a surrogate measure of hypoxia, for local treatment response and survival. Materials and Methods: In this prospective observational cohort study, 94 study participants were enrolled from October 2013 to December 2017 (ClinicalTrials.gov: NCT01816607). Participants had histologically confirmed rectal cancer and underwent routine diagnostic MRI, an extended diffusion-weighted sequence, and a multiecho dynamic contrast agent–based sequence. Predictive and prognostic values of dynamic contrast-enhanced, dynamic susceptibility contrast (DSC), and intravoxel incoherent motion MRI were investigated with response to neoadjuvant treatment, progression-free survival, and overall survival as end points. Secondary objectives investigated potential sex differences in MRI parameters and relationship with lymph node stage. Statistical methods used were Cox regression, Student t test, and Mann-Whitney U test.Results: A total of 94 study participants (mean age, 64 years ± 11 [standard deviation]; 61 men) were evaluated. Baseline tumor blood flow from DSC MRI was lower in patients who had poor local tumor response to neoadjuvant treatment (96 mL/min/100 g ± 33 for ypT2–4, 120 mL/min/100 g ± 21 for ypT0–1; P = .01), shorter progression-free survival (hazard ratio = 0.97; 95% confidence interval: 0.96, 0.98; P < .001), and shorter overall survival (hazard ratio = 0.98; 95% confidence interval: 0.98, 0.99; P < .001). Women had higher blood flow (125 mL/min/100 g ± 27) than men (74 mL/min/100 g ± 26, P < .001) at stage 4. Volume transfer constant and plasma volume from dynamic contrast-enhanced MRI as well as ΔR2* peak and area under the curve for 30 and 60 seconds from DSC MRI were associated with local malignant lymph nodes (pN status). Median area under the curve for 30 seconds was 0.09 arbitrary units (au) ± 0.03 for pN1–2 and 0.19 au ± 0.12 for pN0 (P = .001). Conclusion:Low tumor blood flow from dynamic susceptibility contrast MRI was associated with poor treatment response in study participants with rectal cancer.

• Kalanxhi, Ert; Meltzer, Sebastian & Ree, Anne Hansen (2020). Immune-modulating effects of conventional therapies in colorectal cancer. Cancers. 12:2193(8), p. 1–22. doi: 10.3390/cancers12082193. Full text in Research Archive Show summary

  Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments.

• Dagenborg, Vegar Johansen; Marshall, Serena; Yaqub, Sheraz; Grzyb, Krzysztof; Pedersen, Kjetil Boye & Lund-Iversen, Marius [Show all 12 contributors for this article] (2020). Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biology & Therapy. ISSN 1538-4047. 21(5), p. 432–440. doi: 10.1080/15384047.2020.1721252. Full text in Research Archive Show summary

  Patients with colorectal liver metastases (CLM) commonly receive neoadjuvant chemotherapy (NACT) prior to surgical resection. NACT may induce immunogenic cell death with subsequent recruitment of T-cells to the tumor microenvironment, which could be exploited by immune checkpoint inhibition (ICI). In theory, this could expand the use of ICI to obtain responses also in microsatellite stable colorectal cancer, but evidence to suggest optimal treatment schedules are lacking. In this study, densities of total-, cytotoxic-, helper- and regulatory T-cells were quantified by immunohistochemistry in resected CLM from 92 patients included in the OSLO-COMET trial (NCT01516710). All but one patient had microsatellite stable tumors (91/92). Associations between T-cell densities and clinicopathological parameters were analyzed. Fluoropyrimidine-based NACT (in most cases with addition of oxaliplatin or irinotecan) was administered to 45 patients completed median 8 weeks prior to surgical resection. No overall association was found between NACT administration and intratumoral T-cell densities. However, within the NACT group, a short time interval (<9.5 weeks) between NACT completion and CLM resection was strongly associated with high intratumoral T-cell densities compared to the long-interval and no NACT groups (medians 491, 236, and 292 cells/mm2, respectively; P < .0001). The results from this study suggest that the observed increase in intratumoral T-cells after NACT administration may be transient. The significance of this finding should be further explored to ensure that optimal treatment schedules are chosen for studies combining cytotoxic chemotherapy and ICI.

• Meltzer, Sebastian; Bjørnetrø, Tonje; Lyckander, Lars Gustav; Flatmark, Kjersti; Dueland, Svein & Samiappan, Rampradeep [Show all 10 contributors for this article] (2020). Corrigendum to “Circulating exosomal miR-141-3p and miR-375 in metastatic progression of rectal cancer” [Transl Oncol 12 (8) (2019) 1038-1044]. Translational Oncology. ISSN 1944-7124. 133(1), p. 122–124. doi: 10.1016/j.tranon.2019.09.005. Full text in Research Archive Show summary

  The authors regret to inform that we recently discovered an error in this article. One of the exosomal miRNAs that was detected in all patient samples, miR-29a-3p, was in the article erroneously labeled and described as being significantly differently expressed between two patient groups (TRG 1 versus TRG 2-3) within the investigation and validation cohorts. Fortunately, miR-29a-3p had not been selected for down-stream analyses, averting consequential errors within the study. Below follows a list of edits pertaining to the correct labeling of miR-29a-3p as not being differently expressed between the patient groups TRG 1 and TRG 2-3 in the investigation and validation cohorts. The edits are in bold and underlined. We sincerely regret if our inadvertent mistake has caused confusions. The conclusions drawn from the experiments are not affected.

• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein & Bergheim, Inger Riise [Show all 25 contributors for this article] (2020). Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer?the MetAction study. Acta Oncologica. ISSN 0284-186X. p. 1–10. doi: 10.1080/0284186X.2020.1742377. Full text in Research Archive Show summary

  <i>Background</i>: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014–2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016–2019).<p><p> <i>Material and methods</i>: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints.<p><p> <i>Results</i>: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2–3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment.<p><p> <i>Conclusions</i>: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity <i>versus</i> resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies.

• Malenge, Marion Masitsa; Patzke, Sebastian; Ree, Anne Hansen; Stokke, Trond; Ceuppens, Peter & Middleton, Brian [Show all 8 contributors for this article] (2020). 177Lu-lilotomab satetraxetan has the potential to counteract resistance to rituximab in non-Hodgkin lymphoma. Journal of Nuclear Medicine. ISSN 0161-5505. 61(10), p. 1468–1475. doi: 10.2967/jnumed.119.237230. Full text in Research Archive Show summary

  Patients with non-Hodgkin lymphoma (NHL) who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next-generation β-particle–emitting radioimmunoconjugate 177Lu-lilotomab-satetraxetan (Betalutin) was shown to up-regulate CD20 expression in different rituximab-sensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that 177Lu-lilotomab-satetraxetan may be used to reverse rituximab resistance in NHL. Methods: The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was measured by a bioluminescence reporter assay. The efficacies of combined treatments with 177Lu-lilotomab-satetraxetan (150 or 350 MBq/kg) and rituximab (4 × 10 mg/kg) were compared with those of single agents or phosphate-buffered saline in a Raji2R-xenograft model. Cox regression and the Bliss independence model were used to assess synergism. Results: Rituximab binding in Raji2R cells was 36% ± 5% of that in the rituximab-sensitive Raji cells. 177Lu-lilotomab-satetraxetan treatment of Raji2R cells increased the binding to 53% ± 3% of the parental cell line. Rituximab ADCC induction in Raji2R cells was 20% ± 2% of that induced in Raji cells, whereas treatment with 177Lu-lilotomab-satetraxetan increased the ADCC induction to 30% ± 3% of that in Raji cells, representing a 50% increase (P < 0.05). The combination of rituximab with 350 MBq/kg 177Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1nu mice. Conclusion: 177Lu-lilotomab-satetraxetan has the potential to reverse rituximab resistance; it can increase rituximab binding and ADCC activity in vitro and can synergistically improve antitumor efficacy in vivo.

• Hannevik, Trine-Lise; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege; Ahmed, Herish & Jacobsen, Eva-Marie [Show all 15 contributors for this article] (2020). Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thrombosis Research. ISSN 0049-3848. 196, p. 238–244. doi: 10.1016/j.thromres.2020.08.042. Full text in Research Archive Show summary

  Introduction: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. Materials and methods: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. Results: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1–6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8–7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3–11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5–12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1–6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3–16%). Conclusion: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

• Dagenborg, Vegar Johansen; Marshall, Serena Elizabeth; Grzyb, Krzysztof; Fretland, Åsmund Avdem; Lund-Iversen, Marius & Mælandsmo, Gunhild Mari [Show all 10 contributors for this article] (2020). Low concordance between T-cell densities in matched primary tumors and liver metastases in microsatellite stable colorectal cancer. Frontiers in Oncology. 11. Full text in Research Archive
• Bains, Simer Jit; Abrahamsson, Hanna Josefine; Flatmark, Kjersti; Dueland, Svein; Hole, Knut Håkon & Seierstad, Therese [Show all 9 contributors for this article] (2019). Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer. Cancer Immunology and Immunotherapy. ISSN 0340-7004. doi: 10.1007/s00262-019-02458-x. Full text in Research Archive Show summary

  Objective High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity. Methods We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome. Results Patients who met the main study end point—freedom from distant recurrence—showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11–0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity. Conclusion The findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.

• Bjørnetrø, Tonje; Redalen, Kathrine; Meltzer, Sebastian; Thusyanthan, Nirujah Sivarajah; Samiappan, Rampradeep & Jegershöld, Caroline [Show all 8 contributors for this article] (2019). An experimental strategy unveiling exosomal microRNAs 486-5p, 181a-5p and 30d-5p from hypoxic tumour cells as circulating indicators of high-risk rectal cancer. Journal of Extracellular Vesicles. 8(1). doi: 10.1080/20013078.2019.1567219. Full text in Research Archive Show summary

  Tumour hypoxia contributes to poor treatment outcome in locally advanced rectal cancer (LARC) and circulating extracellular vesicles (EVs) as potential biomarkers of tumour hypoxia and adverse prognosis have not been fully explored. We examined EV miRNAs from hypoxic colorectal cancer cell lines as template for relevant miRNAs in LARC patients participating in a prospective biomarker study (NCT01816607). Five cell lines were cultured under normoxia (21% O2) or hypoxia (0.2% O2) for 24 h, and exosomes were isolated by differential ultracentrifugation. Using a commercial kit, exosomes were precipitated from 24 patient plasma samples collected at the time of diagnosis. Exosome size distribution and protein cargo were determined by cryo-electron microscopy, nanoparticle tracking analysis, immunoblotting and flow cytometry. The vesicles harboured strong cell line-specific miRNA profiles with 35 unique miRNAs differentially expressed between hypoxic and normoxic cells. Six of these miRNAs were considered candidate-circulating markers of tumour hypoxia in the patients based on the frequency or magnitude of variance in hypoxic versus normoxic cell line experiments and prevalence in patient plasma. Of these, low plasma levels of exosomal miR-486-5p and miR-181a-5p were associated with organ-invasive primary tumour (p = 0.029) and lymph node metastases (p = 0.024), respectively, both attributes of adverse LARC prognosis. In line with this, the plasma level of exosomal miR-30d-5p was elevated in patients who experienced metastatic progression (p = 0.036). Our strategy confirmed that EVs from colorectal cancer cell lines were exosomes containing the oxygen-sensitive miRNAs 486-5p, 181a-5p and 30d-5p, which were retrieved as circulating markers of high-risk LARC.

• Abrahamsson, Hanna Josefine; Jensen, Benny Vittrup; Berven, Lise; Nielsen, Dorte Lisbet; Saltyte-Benth, Jurate & Johansen, Jakob Sidenius [Show all 9 contributors for this article] (2019). Antitumour immunity invoked by hepatic arterial infusion of first-line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8-12 years of follow-up. International Journal of Cancer. ISSN 0020-7136. doi: 10.1002/ijc.32847. Full text in Research Archive Show summary

  In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first‐line oxaliplatin‐HAI for long‐term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms‐related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1–3 sequences of oxaliplatin‐HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow‐up 8–12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour‐directed immunity invoked by oxaliplatin‐containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the ‘classic’ tumour response to the cytotoxic treatment.

• Flørenes, Vivi Ann; Flem-Karlsen, Karine; McFadden, Erin; Bergheim, Inger Riise; Nygaard, Vigdis & Nygård, Vegard Mokleiv [Show all 17 contributors for this article] (2019). A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases. Translational Oncology. ISSN 1944-7124. 12(7), p. 951–958. doi: 10.1016/j.tranon.2019.04.001. Full text in Research Archive Show summary

  Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) <i>ex vivo</i> drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (<i>P</i> < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the <i>ex vivo</i> results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between <i>ex vivo</i> drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow <i>ex vivo</i> evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost <i>ex vivo</i> drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients.

• Meltzer, Sebastian; Bakke, Kine Mari; Rød, Karina Lund; Negård, Anne; Flatmark, Kjersti & Solbakken, Arne Mide [Show all 19 contributors for this article] (2019). Sex-related differences in primary metastatic site in rectal cancer; associated with hemodynamic factors? Clinical and Translational Radiation Oncology. 21, p. 5–10. doi: 10.1016/j.ctro.2019.11.006. Full text in Research Archive Show summary

  Background and purpose We investigated how features relating to pelvic cavity anatomy and tumor hemodynamic factors may influence systemic failure in rectal cancer. Materials and methods Rectal cancer patients (207 women, 343 men), who had been prospectively enrolled onto six cohorts and given curative-intent therapy, were analyzed for the first metastatic event. In one of the cohorts, the diameter of the inferior mesenteric vein (IMV) was assessed on diagnostic abdominal computed tomography images (n = 113). Tumor volume (n = 193) and histologic response to neoadjuvant therapy (n = 445) were recorded from diagnostic magnetic resonance images and surgical specimens, respectively. Results More women than men developed lung metastasis (p = 0.037), while the opposite was the case for liver metastasis (p = 0.040). Wider IMV diameter correlated with larger tumor volume (r = 0.481, p < 0.001) and male sex (p < 0.001). Female sex was the only adverse prognostic factor for lung metastasis. When sex, tumor volume, and histologic response were taken into consideration, poor tumor response remained the only determinant for liver metastasis (p = 0.002). Conclusions In a diverse rectal cancer population given curative-intent treatment, women and men had different outcome with regard to the primary metastatic site. Tumor hemodynamic factors should be considered in rectal cancer risk stratification.

• Meltzer, Sebastian; Bjørnetrø, Tonje; Lyckander, Lars Gustav; Flatmark, Kjersti; Dueland, Svein & Samiappan, Rampradeep [Show all 10 contributors for this article] (2019). Circulating Exosomal miR-141-3p and miR-375 in Metastatic Progression of Rectal Cancer. Translational Oncology. ISSN 1944-7124. 12(8), p. 1038–1044. doi: 10.1016/j.tranon.2019.04.014. Full text in Research Archive Show summary

  As many as 30% to 40% of locally advanced rectal cancer (LARC) patients experience metastatic progression of the disease. Recognizing the potential of the genetic cargo in tumor-derived exosomes, we hypothesized that plasma exosomal microRNA (miRNA) may reflect biological aggressiveness in LARC and provide new markers for rectal cancer aggressiveness and risk stratification. In a prospective LARC cohort (NCT01816607), plasma samples were collected from 29 patients at the time of diagnosis, before neoadjuvant therapy and surgery. Exosomes, precipitated from plasma using a commercial kit, were verified by cryo-electron microscopy, nanoparticle tracking analysis, and western blotting. Expression of exosomal miRNAs was profiled using a miRCURY LNA miRNA microarray and validation of six miRNAs associated with pathological and clinical end-points was undertaken in plasma collected at the time of diagnosis from 64 patients in an independent prospective LARC cohort (NCT00278694). In both cohorts, exosomal miR-141-3p and miR-375 were higher in patients with synchronous liver metastasis than in those without (P = .010 and P = .017 respectively in the investigative cohort, and P < .001 for both in the validation cohort). Further, high exosomal miR-141-3p was associated with post-operative metastatic liver progression in the investigative cohort (P = .034). Because both miRNAs are associated with tumor angiogenesis and immune modulation, we propose that these miRNAs in circulating exosomes may reflect rectal cancer aggressiveness and accordingly be candidate biomarkers for further investigations.

• Bakke, Kine Mari; Grøvik, Endre; Meltzer, Sebastian; Negård, Anne; Holmedal, Stein Harald & Mikalsen, Lars Tore G [Show all 11 contributors for this article] (2019). Comparison of Intravoxel incoherent motion imaging and multiecho dynamic contrast-based MRI in rectal cancer. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. 50(4), p. 1114–1124. doi: 10.1002/jmri.26740. Full text in Research Archive Show summary

  Background Dynamic contrast‐based MRI and intravoxel incoherent motion imaging (IVIM) MRI are both methods showing promise as diagnostic and prognostic tools in rectal cancer. Both methods aim at measuring perfusion‐related parameters, but the relationship between them is unclear. Purpose To investigate the relationship between perfusion‐ and permeability‐related parameters obtained by IVIM‐MRI, T1‐weighted dynamic contrast‐enhanced (DCE)‐MRI and T2*‐weighted dynamic susceptibility contrast (DSC)‐MRI. Study Type Prospective. Subjects In all, 94 patients with histologically confirmed rectal cancer. Field Strength/Sequence Subjects underwent pretreatment 1.5T clinical procedure MRI, and in addition a study‐specific diffusion‐weighted sequence (b = 0, 25, 50, 100, 500, 1000, 1300 s/mm2) and a multiecho dynamic contrast‐based echo‐planer imaging sequence. Assessment Median tumor values were obtained from IVIM (perfusion fraction [f], pseudodiffusion [D*], diffusion [D]), from the extended Tofts model applied to DCE data (Ktrans, kep, vp, ve) and from model free deconvolution of DSC (blood flow [BF] and area under curve). A subgroup of the excised tumors underwent immunohistochemistry with quantification of microvessel density and vessel size. Statistical Test Spearman's rank correlation test. Results D* was correlated with BF (rs = 0.47, P < 0.001), and f was negatively correlated with kep (rs = –0.31, P = 0.002). BF was correlated with Ktrans (rs = 0.29, P = 0.004), but this correlation varied extensively when separating tumors into groups of low (rs = 0.62, P < 0.001) and high (rs = –0.06, P = 0.68) BF. Ktrans was negatively correlated with vessel size (rs = –0.82, P = 0.004) in the subgroup of tumors with high BF. Data Conclusion We found an association between D* from IVIM and BF estimated from DSC‐MRI. The relationship between IVIM and DCE‐MRI was less clear. Comparing parameters from DSC‐MRI and DCE‐MRI highlights the importance of the underlying biology for the interpretation of these parameters. Level of Evidence: 2 Technical Efficacy: Stage 1

• Abrahamsson, Hanna Josefine; Porojnicu, Alina Carmen; Lindstrøm, Jonas Christoffer; Dueland, Svein; Flatmark, Kjersti & Hole, Knut Håkon [Show all 11 contributors for this article] (2019). High level of circulating vitamin D during neoadjuvant therapy may lower risk of metastatic progression in high-risk rectal cancer. BMC Cancer. 19(1). doi: 10.1186/s12885-019-5724-z. Full text in Research Archive Show summary

  Background:Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastaticprogression is still dominant. We investigated if patients’circulating 25-hydroxyvitamin D [25(OH)D] levels wereassociated with outcome.Methods:Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samplescollected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation beforesurgery, and analyzed with respect to season, disease presentation, and treatment effects.Results:In the cohort of patients residing at latitude 58–62°N, baseline 25(OH)D differed significantly over theseasons, with highest measures (mean of 71.2 ± 5.6 nmol/L) in summer and lowest (48.7 ± 4.5 nmol/L) in spring, andchanged over the three-month neoadjuvant period till response evaluation solely owing to season. The patientsubgroup with slightly reduced performance status, anemia, and T4 disease that did not respond to theneoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D (below 50 nmol/L) than T4 cases withresponse (ypT0–3) and T2–3 cases (above 60 nmol/L). Compared to the T4 patients with levels above 50 nmol/L,regarded as sufficient for a healthy bone status, those presenting levels below had significantly heightened risk ofdisease progression (mainly metastasis) and death, with hazard ratio of 3 and 17, respectively, on adjustment forage, sex, body mass index, and season.Conclusion:Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levelswere insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse thanpatients with T2–3 disease when 25(OH)D was sufficient.

• Ree, Anne Hansen; Nygaard, Vigdis; Russnes, Hege Elisabeth Giercksky; Heinrich, Daniel; Nygaard, Vegard & Johansen, Christin [Show all 13 contributors for this article] (2019). Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain. Cancer immunology research. ISSN 2326-6066. 7(5), p. 701–706. doi: 10.1158/2326-6066.CIR-18-0777. Full text in Research Archive Show summary

  Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain (CNG), in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis biopsy from a patient who had disease refractory to standard therapies. Following immune checkpoint blockade (ICB) with pembrolizumab (anti–PD-1), the patient experienced conversion of the tumor phenotype from one with epithelial features to that of an inflamed microenvironment, detected by high-resolution RNA sequencing. Circulating tumor DNA disappeared over the first weeks of therapy. As assessed by standard radiographic measurement, the patient had a partial response that was durable. This patient's response may support the use of histology-agnostic ICB in solid tumors that carry the rare 9p24.1 CNG.

• Gopinathan, Unni; Redalen, Kathrine; Siebke, Anne-Marie; Kierulf, Peter; Brandtzæg, Petter & Ree, Anne Hansen [Show all 8 contributors for this article] (2018). Large-scale reduction of tyrosine kinase activities in human monocytes stimulated in vitro with N. meningitidis. PLOS ONE. 13(1). doi: 10.1371/journal.pone.0181912. Full text in Research Archive Show summary

  N. meningitidis induces extensive gene expression changes in human monocytes, suggesting that complex networks of signaling pathways are activated during meningococcal sepsis. These effects are modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). To further study changes in signal transduction suggested by mRNA data, we used kinase substrate arrays to identify composite kinase activities induced by lysates from a primary human monocyte model system. Cell lysates were prepared from monocytes treated with the following experimental conditions: 106 N. meningitidis/mL, 25 ng/mL IL-10, 106 N. meningitidis/mL in combination with 25 ng/mL IL-10, and vehicle. Lysates were subjected to kinase activity profiling with Tyrosine Kinase PamChip® arrays containing 144 kinase peptide substrates. In our experimental model, we were not able to detect a statistically significant large-scale change in ex vivo array peptide phosphorylation by lysates from monocytes treated for 15 minutes. Targets of the IL-10 anti-inflammatory response were not identified. A profound inhibition of array peptide phosphorylation by monocytes treated for 60 minutes was identified, suggesting low activity of a large number of kinases associated with different signaling pathways and immune cell functions, including STAT3 activity, Nf-κB and VEGF signaling, and PTEN signaling activity. The peptide representing ZBTB16, which was reduced in phosphorylation by lysates from all three experimental conditions, was in Ingenuity Pathway Analysis identified to be linked to reduced cytokine release and mRNA levels of tumor necrosis factor (TNF), IL-6, and CXCL10. Further studies should investigate changes in tyrosine kinase-mediated signal transduction in human immune cells, in order to evaluate the potential clinical application of kinome profiling in the study of systemic inflammatory responses to pathogens.

• Boysen, Anders Kindberg; Sørensen, Boe Sandahl; Lefevre, Anna C.; Abrantes, Rafaela; Johansen, Julia Sidenius & Jensen, Benny Vittrup [Show all 17 contributors for this article] (2018). Methodological development and biological observations of cell free DNA with a simple direct fluorescent assay in colorectal cancer. Clinica Chimica Acta. ISSN 0009-8981. 487, p. 107–111. doi: 10.1016/j.cca.2018.09.029. Full text in Research Archive
• Kalanxhi, Ert; Meltzer, Sebastian; Schou, Jakob Vasehus; Larsen, Finn Ole; Dueland, Svein & Flatmark, Kjersti [Show all 12 contributors for this article] (2018). Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer. British Journal of Cancer. ISSN 0007-0920. 118(10), p. 1322–1328. doi: 10.1038/s41416-018-0085-y. Full text in Research Archive Show summary

  Background Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. Methods In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). Results In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). Conclusion In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression.

• Bousquet, Paula; Meltzer, Sebastian; Sønstevold, Linda; Esbensen, Qin Ying; Dueland, Svein & Flatmark, Kjersti [Show all 12 contributors for this article] (2018). Markers of mitochondrial metabolism in tumor hypoxia, systemic inflammation, and adverse outcome of rectal cancer. Translational Oncology. ISSN 1944-7124. 12(1), p. 76–83. doi: 10.1016/j.tranon.2018.09.010. Full text in Research Archive Show summary

  Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to cancer-induced systemic inflammation and poor outcome. Levels of ROS and mtDNA damage were analyzed in three colorectal cancer (CRC) cell lines cultured for 24 hours under normoxia (21% O2) or hypoxia (0.2% O2) and serum sampled at the time of diagnosis from 35 LARC patients participating in a prospective therapy study. Compared with normoxia, ROS were significantly repressed and mtDNA damage was significantly enhanced in the hypoxic CRC cell lines; hence, a low ratio of ROS to mtDNA damage was an indicator of hypoxic conditions. In the LARC patients, low serum ROS were associated with elevated levels of circulating carcinoembryonic antigen and tumor choline concentration, both indicative of unfavorable biology, as well as adverse progression-free and overall survival. A low ratio of ROS to mtDNA damage in serum was associated with poor local tumor response to the neoadjuvant treatment and, of note, elevated systemic inflammation factors (C-reactive protein, the interleukin-1 receptor antagonist, and factors involved in tumor necrosis factor signaling), indicating that deficient treatment response locally and detrimental inflammation systemically link to a hypoxic mitochondrial metabolism. In conclusion, serum ROS and damaged mtDNA may be markers of the mitochondrial metabolism driven by the state of oxygenation of the primary tumor and possibly implicated in systemic inflammation and adverse outcome of LARC.

• Gulati, Geeta; Heck, Siri Lagethon; Røsjø, Helge; Ree, Anne Hansen; HOFFMANN, PAVEL & Hagve, Tor-Arne [Show all 11 contributors for this article] (2017). Neurohormonal blockade and circulating cardiovascular biomarkers during anthracycline therapy in breast cancer patients: Results from the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) study. Journal of the American Heart Association (JAHA). 6(11). doi: 10.1161/JAHA.117.006513. Full text in Research Archive Show summary

  Background Anthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on‐treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines. Methods and Results This report encompasses 121 women included in the 2×2 factorial, placebo‐controlled, double‐blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240–400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B‐type natriuretic peptide, N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, and galectin‐3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy. Conclusions Treatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta‐blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.

• Østrup, Olga; Dagenborg, Vegar Johansen; Rødland, Einar Andreas; Skarpeteig, Veronica; Silwal-Pandit, Laxmi & Grzyb, Krzysztof [Show all 14 contributors for this article] (2017). Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. OncoTarget. 8(44), p. 76290–76304. doi: 10.18632/oncotarget.19350. Full text in Research Archive Show summary

  Background: Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. <p> Methods: In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. <p> Results: Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). <p> Conclusions: The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.

• Bakke, Kine Mari; Hole, Knut Håkon; Dueland, Svein; Kotanska-Grøholt, Krystyna; Flatmark, Kjersti & Ree, Anne Hansen [Show all 8 contributors for this article] (2017). Diffusion-weighted magnetic resonance imaging of rectal cancer: tumour volume and perfusion fraction predict chemoradiotherapy response and survival. Acta Oncologica. ISSN 0284-186X. 56(6), p. 813–818. doi: 10.1080/0284186X.2017.1287951. Full text in Research Archive Show summary

  Background: In locally advanced rectal cancer (LARC), responses to preoperative treatment are highly heterogeneous and more accurate diagnostics are likely to enable more individualised treatment approaches with improved responses. We investigated the potential of diffusion-weighted magnetic resonance imaging (DW MRI), with quantification of the apparent diffusion coefficient (ADC) and perfusion fraction (F), as well as volumetry from T2-weighted (T2W) MRI, for prediction of therapeutic outcome. Material and methods: In 27 LARC patients receiving neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT), T2W- and DW MRI were obtained before and after NACT. Tumour volumes were delineated in T2W MRI and ADCs and Fs were estimated from DW MRI using a simplified approach to the intravoxel incoherent motion (IVIM) model. Mean tumour values and histogram analysis of whole-tumour heterogeneity were correlated with histopathologic tumour regression grade (TRG) and 5-year progression-free survival (PFS). Results: At baseline, high tumour F predicted good tumour response (TRG1-2) (AUC = 0.79, p = 0.01), with a sensitivity of 69% and a specificity of 100%. The combination of F and tumour volume (Fpre/Vpre) gave the highest prediction of poor tumour response (AUC = 0.93, p < 0.001) with a sensitivity of 88% and a specificity of 91%, and also predicted PFS (p < 0.01). Baseline tumour ADC was not significantly related to therapeutic outcome, whereas a positive change in ADC from baseline to after NACT, ΔADC, significantly predicted good tumour response (AUC = 0.83, p < 0.01, 83% sensitivity, 73% specificity), but not PFS. Conclusions: The MRI parameter F/V at baseline was a remarkably strong predictor of both histopathologic tumour response and 5-year PFS in patients with LARC.

• Ree, Anne Hansen; Russnes, Hege Elisabeth Giercksky; Heinrich, Daniel; Dueland, Svein; Pedersen, Kjetil Boye & Nygaard, Vigdis [Show all 34 contributors for this article] (2017). Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate. ESMO Open. 2(2), p. 1–10. doi: 10.1136/esmoopen-2017-000158. Full text in Research Archive Show summary

  Objective Through the conduct of an individual-based intervention study, the main purpose of this project was to build and evaluate the required infrastructure that may enable routine practice of precision cancer medicine in the public health services of Norway, including modelling of costs. Methods An eligible patient had end-stage metastatic disease from a solid tumour. Metastatic tissue was analysed by DNA sequencing, using a 50-gene panel and a study-generated pipeline for analysis of sequence data, supplemented with fluorescence in situ hybridisation to cover relevant biomarkers. Cost estimations compared best supportive care, biomarker-agnostic treatment with a molecularly targeted agent and biomarker-based treatment with such a drug. These included costs for medication, outpatient clinic visits, admission from adverse events and the biomarker-based procedures. Results The diagnostic procedures, which comprised sampling of metastatic tissue, mutation analysis and data interpretation at the Molecular Tumor Board before integration with clinical data at the Clinical Tumor Board, were completed in median 18 (8-39) days for the 22 study patients. The 23 invasive procedures (12 from liver, 6 from lung, 5 from other sites) caused a single adverse event (pneumothorax). Per patient, 0–5 mutations were detected in metastatic tumours; however, no actionable target case was identified for the current single-agent therapy approach. Based on the cost modelling, the biomarker-based approach was 2.5-fold more costly than best supportive care and 2.5-fold less costly than the biomarker-agnostic option. Conclusions The first project phase established a comprehensive diagnostic infrastructure for precision cancer medicine, which enabled expedite and safe mutation profiling of metastatic tumours and data interpretation at multidisciplinary tumour boards for patients with end-stage cancer. Furthermore, it prepared for protocol amendments, recently approved by the designated authorities for the second study phase, allowing more comprehensive mutation analysis and opportunities to define therapy targets.

• Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen [Show all 12 contributors for this article] (2017). Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: The PRADA trial. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 19(5), p. 544–552. doi: 10.1093/ehjci/jex159. Full text in Research Archive Show summary

  Aims: Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade. Methods and results: PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003). Conclusions: Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume.

• Grøvik, Endre; Redalen, Kathrine Røe; Storås, Tryggve; Negard, Anne; Holmedal, Stein Harald & Ree, Anne Hansen [Show all 9 contributors for this article] (2017). Dynamic multi-echo DCE- and DSC-MRI in rectal cancer: Low primary tumor Ktrans and ΔR2* peak are significantly associated with lymph node metastasis. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. 46(1), p. 194–206. doi: 10.1002/jmri.25566. Full text in Research Archive Show summary

  Purpose: To implement a dynamic contrast-based multi-echo MRI sequence in assessment of rectal cancer and evaluate associations between histopathologic data and the acquired dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) -MRI parameters. Materials and Methods: This pilot study reports results from 17 patients with resectable rectal cancer. Dynamic contrast-based multi-echo MRI (1.5T) was acquired using a three-dimensional multi-shot EPI sequence, yielding both DCE- and DSC-data following a single injection of contrast agent. The Institutional Review Board approved the study and all patients provided written informed consent. Quantitative analysis was performed by pharmacokinetic modeling on DCE data and tracer kinetic modeling on DSC data. Mann-Whitney U-test and receiver operating characteristics curve statistics was used to evaluate associations between histopathologic data and the acquired DCE- and DSC-MRI parameters. Results: For patients with histologically confirmed nodal metastasis, the primary tumor demonstrated a significantly lower Ktrans and peak change in R 2, R 2-peakenh, than patients without nodal metastasis, showing a P-value of 0.010 and 0.005 for reader 1, and 0.043 and 0.019 for reader 2, respectively. Conclusion: This study shows the feasibility of acquiring DCE- and DSC-MRI in rectal cancer by dynamic multi-echo MRI. A significant association was found between both Ktrans and R 2-peakenh in the primary tumor and histological nodal status of the surgical specimen, which may improve stratification of patients to intensified multimodal treatment.

• Kalanxhi, Ert; Risberg, Karianne; Barua, Imon Shoumitra; Dueland, Svein; Waagene, Stein & Andersen, Solveig Norheim [Show all 11 contributors for this article] (2017). Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy. Cancer research and treatment : official journal of Korean Cancer Association. ISSN 1598-2998. 49(2), p. 374–386. doi: 10.4143/crt.2016.080. Full text in Research Archive Show summary

  Purpose When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. Materials and Methods This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. Results PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. Conclusion The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

• Meltzer, Sebastian; Kalanxhi, Ert; Hektoen, Helga; Dueland, Svein; Flatmark, Kjersti & Redalen, Kathrine Røe [Show all 7 contributors for this article] (2016). Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer. OncoTarget. 7(23), p. 34907–34917. doi: 10.18632/oncotarget.8995. Full text in Research Archive Show summary

  In colorectal cancer, immune effectors may be determinative for disease outcome. Following curatively intended combined-modality therapy in locally advanced rectal cancer metastatic disease still remains a dominant cause of failure. Here, we investigated whether circulating immune factors might correlate with outcome. An antibody array was applied to assay changes of approximately 500 proteins in serial serum samples collected from patients during oxaliplatin-containing induction chemotherapy and sequential chemoradiotherapy before final pelvic surgery. Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay. Patients experiencing increase in circulating osteoprotegerin during the chemotherapy had significantly better 5-year progression-free survival than those without increase (78% versus 48%; P = 0.009 by log-rank test). Hence, systemic release of this soluble tumor necrosis factor decoy receptor following the induction phase of neoadjuvant therapy was associated with favorable long-term outcome in patients given curatively intended chemoradiotherapy and surgery but with metastatic disease as the main adverse event. This finding suggests that osteoprotegerin may mediate or reflect systemic anti-tumor immunity invoked by combined-modality therapy in locally advanced rectal cancer.

• Kalanxhi, Ert; Hektoen, Helga; Meltzer, Sebastian; Dueland, Svein; Flatmark, Kjersti & Ree, Anne Hansen (2016). Circulating proteins in response to combined-modality therapy in rectal cancer identified by antibody array screening. BMC Cancer. 16:536. doi: 10.1186/s12885-016-2601-x. Full text in Research Archive Show summary

  Background The increasingly complex programs of contemporary cancer therapy emphasize the need for biological indicators of both therapeutic response and adverse effects. One example is combined-modality treatment aimed at improving long-term outcome in patients with locally advanced rectal cancer, which commonly comes at the price of extended limits of patient tolerance. Methods In a prospective study with intensified neoadjuvant treatment of rectal cancer patients, using an antibody array, the profiling of approximately 500 proteins was performed in serial serum samples collected at different stages of the treatment course. Results The small number of proteins whose levels significantly changed after induction neoadjuvant chemotherapy (NACT) expanded substantially following the sequential chemoradiotherapy (CRT) and persisted four weeks later at treatment evaluation before pelvic surgery. Serum levels of proteins selected for validation of the experimental design, lipocalin-2 and matrix metalloproteinase-9, declined after NACT and gradually reverted to baseline values during the remaining neoadjuvant course. Of note, the greater the decline in post-NACT and post-CRT matrix metalloproteinase-9 levels, the more favorable progression-free survival. No correlation was found, however, with diarrhea scores, the clinical correlate of adverse therapeutic effects. Conclusions Even though the findings were indicative of only tumor and not normal tissue effects, multiplex immunoassay analysis of circulating proteins in patients undergoing combined-modality therapy may in principle dissect the contribution of the individual modalities to overall systemic responses in patient outcome and tolerance. Trial registration ClinicalTrials.gov NCT00278694 ; registration date: January 16, 2006, retrospective to enrollment of the first 10 patients of the current report.

• Gulati, Geeta; Heck, Siri Lagethon; Ree, Anne Hansen; HOFFMANN, PAVEL; Schulz-Menger, Jeanette & Fagerland, Morten [Show all 15 contributors for this article] (2016). Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. European Heart Journal. ISSN 0195-668X. 37(21), p. 1671–1680. doi: 10.1093/eurheartj/ehw022. Full text in Research Archive
• Redalen, Kathrine Røe; Sitter, Beathe; Bathen, Tone Frost; Kotanska-Grøholt, Krystyna; Hole, Knut Håkon & Dueland, Svein [Show all 9 contributors for this article] (2016). High tumor glycine concentration is an adverse prognostic factor in locally advanced rectal cancer. Radiotherapy and Oncology. ISSN 0167-8140. 118(2), p. 393–398. doi: 10.1016/j.radonc.2015.11.031. Full text in Research Archive

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• Bakke, Kine Mari; Meltzer, Sebastian; Grøvik, Endre; Negård, Anne; Holmedal, Stein Harald & Lyckander, Lars Gustav [Show all 11 contributors for this article] (2022). Imaging the tumor microenvironment in rectal cancer: Decline in tumor blood flow (BF) during neoadjuvant treatment predicts excellent outcome. Cancer Research. ISSN 0008-5472. 82. doi: 10.1158/1538-7445.AM2022-5269. Full text in Research Archive
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Show all 116 contributors for this article] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), p. 885–887. doi: 10.1038/s41591-022-01777-4. Full text in Research Archive
• Larsen, Trine-Lise; Garresori, Herish; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Jacobsen, Eva-Marie [Show all 15 contributors for this article] (2022). “Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up”: Reply. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 20(8), p. 1937–1939. doi: 10.1111/jth.15774. Full text in Research Archive
• Meltzer, Sebastian; Negård, Anne; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva & Guren, Marianne Grønlie [Show all 9 contributors for this article] (2022). Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5). Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03518-0. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. Journal of Translational Medicine. 20(1), p. 1–11. doi: 10.1186/s12967-022-03432-5. Full text in Research Archive Show summary

  Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

• Kalveland, Julie; Tasken, Kjetil; Ree, Anne Hansen & Opdalshei, Ole Alexander (2022). Studie: Presisjonsmedisin dobbelt så dyr som annen behandling av kreftpasienter i siste fase. [Journal]. Dagens Medisin. Full text in Research Archive
• Knuth, Franziska Hanna; Adde, Ingvild Askim; Huynh, Bao Ngoc; Grøndahl, Aurora Rosvoll; Winter, René & Negård, Anne [Show all 15 contributors for this article] (2021). MRI-based automatic segmentation of rectal cancer using 2D U-Net on two independent cohorts. Full text in Research Archive
• Ree, Anne Hansen; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva; Guren, Marianne Grønlie & Sørbye, Halfdan [Show all 10 contributors for this article] (2021). Repeat sequential oxaliplatin-based chemotherapy (FLOX) and nivolumab versus FLOX alone as first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Initial results from the randomized METIMMOX study. Full text in Research Archive
• Ree, Anne Hansen (2021). Precision cancer medicine – still expedient for the few. doi: 10.4045/tidsskr.20.0980. Full text in Research Archive
• Ree, Anne Hansen (2021). Presisjonsmedisin ved kreft – førebels føremålstenleg for dei få. 141(5), p. 1–5. doi: 10.4045/tidsskr.20.0980. Full text in Research Archive
• Ree, Anne Hansen; Bousquet, Anna Paula; Bjørnetrø, Tonje; Fuglestad, Anniken Jørlo; Lüders, Torben & Esbensen, Qin Ying [Show all 12 contributors for this article] (2020). Circulating mitochondrial DNA (mtDNA) variants to predict metastatic progression of rectal cancer. Full text in Research Archive
• Frøyen, Elin Agathe; Lyckander, Lars Gustav; Grandal, Ole Jacob; Lunder, Aida Kapic; Meltzer, Sebastian & Redalen, Kathrine [Show all 8 contributors for this article] (2019). MRI of Extramural Venous Invasion in rectal cancer: assessment of the interobserver agreement and comparison with histopathology stained with hematoxylin/eosin and elastin. Full text in Research Archive
• Meltzer, Sebastian; Redalen, Kathrine; Dueland, Svein; Kristensen, Annette Torgunrud; Solbakken, Arne Mide & Flatmark, Kjersti [Show all 7 contributors for this article] (2019). Circulating angiogenic factors predict metastatic liver progression in rectal cancer patients given curative-intent oxaliplatin-containing neoadjuvant therapy. Full text in Research Archive
• Bakke, Kine Mari; Meltzer, Sebastian; Grøvik, Endre; Negård, Anne; Holmedal, Stein Harald & Ree, Anne Hansen [Show all 8 contributors for this article] (2019). Tumour blood perfusion from baseline contrast-based MRI predicts radiation outcome in rectal cancer. Full text in Research Archive
• Meltzer, Sebastian; Bakke, Kine Mari; Rød, Karina Lund; Dueland, Svein; Flatmark, Kjersti & Kristensen, Annette Torgunrud [Show all 12 contributors for this article] (2019). Gender disparities in outcome after neoadjuvant chemoradiotherapy for locally advanced rectal cancer are associated with hemodynamic differences. Full text in Research Archive
• Grøvik, Endre; Redalen, Kathrine Røe; Storås, Tryggve; Holmedal, Stein Harald; Negard, Anne & Ree, Anne Hansen [Show all 9 contributors for this article] (2017). Improved sensitivity for rectal cancer differentiation by T2*-correction in DCE-MRI. Full text in Research Archive
• Bakke, Kine Mari; Hole, Knut Håkon; Dueland, Svein; Grøholt, Krystyna Kotanska; Ree, Anne Hansen & Flatmark, Kjersti [Show all 8 contributors for this article] (2017). Diffusion-weighted MRI of rectal cancer: baseline tumour perfusion fraction predicts chemoradiotherapy response and survival. Full text in Research Archive
• Barua, Imon Shoumitra; Ree, Anne Hansen; Sønstevold, Linda; Redalen, Kathrine Røe & Kalanxhi, Ert (2017). Mechanisms of normal tissue toxicity from SAHA - an HDAC inhibitor and radiosensitizer. Full text in Research Archive
• Bousquet, Paula; Meltzer, Sebastian; Sønstevold, Linda; Esbensen, Qin Ying; Lyckander, Lars Gustav & Dueland, Svein [Show all 10 contributors for this article] (2017). Reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage in tumor hypoxia, poor radiotherapy response, and metastatic progression of rectal cancer. Cancer Research. ISSN 0008-5472. 77, p. 1782–1782. doi: 10.1158/1538-7445.AM2017-1782. Full text in Research Archive
• Bjørnetrø, Tonje; Risberg, Karianne; Meltzer, Sebastian; Samiappan, Rampradeep; Lyckander, Lars Gustav & Jegerschöld, Caroline [Show all 10 contributors for this article] (2017). Low release of exosomal miR-663a from hypoxic tumor cells and poor tumor response to neoadjuvant radiotherapy in rectal cancer patients. Cancer Research. ISSN 0008-5472. 77, p. 4514–4514. doi: 10.1158/1538-7445.AM2017-4514. Full text in Research Archive
• Meltzer, Sebastian; Lyckander, Lars Gustav; Ree, Anne Hansen & Redalen, Kathrine Røe (2017). Circulating angiogenesis factors predicting poor chemoradiotherapy outcome in rectal cancer. Full text in Research Archive
• Meltzer, Sebastian; Ree, Anne Hansen; Lyckander, Lars Gustav & Redalen, Kathrine Røe (2017). Circulating exosomal miRNA related to chemoradiotherapy outcome in locally advanced rectal cancer. Full text in Research Archive
• Bjørnetrø, Tonje; Ree, Anne Hansen; Redalen, Kathrine Røe & Risberg, Karianne (2016). Exosomes from hypoxic colorectal cancer cells – miRNA cargo as indicator of adverse CRC biology? Full text in Research Archive
• Heck, Siri Lagethon; Gulati, Geeta; HOFFMANN, PAVEL; Knobelsdorff-Brenkenhoff, Florian von; Storås, Tryggve & Ree, Anne Hansen [Show all 11 contributors for this article] (2016). Effects of Candesartan and Metoprolol on Myocardial Mass, Edema, and Fibrosis During Anthracycline Treatment in Early Breast Cancer: APRADA-CMR substudy. Full text in Research Archive
• Gulati, Geeta; Heck, Siri Lagethon; HOFFMANN, PAVEL; Ree, Anne Hansen; Schulz-Menger, Jeanette & Knobelsdorff-Brenkenhoff, Florian von [Show all 12 contributors for this article] (2016). Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial. Circulation. ISSN 0009-7322. Full text in Research Archive
• Gulati, Geeta; Heck, Siri Lagethon; Geisler, Jürgen; Gravdehaug, Berit; HOFFMANN, PAVEL & Steine, Kjetil [Show all 9 contributors for this article] (2016). Troponin I and Cardiac Function During Breast Cancer Therapy in Human Epidermal Growth Factor Receptor 2 Positive and Negative Patients: Results from the PRADA Study. Full text in Research Archive
• Gulati, Geeta; Heck, Siri Lagethon; Geisler, Jürgen; Gravdehaug, Berit; Ree, Anne Hansen & HOFFMANN, PAVEL [Show all 9 contributors for this article] (2016). Atrio-ventricular plane excursion is impaired after ten weeks of anthracycline treatment in breast cancer patients; Data from the PRADA-study. Full text in Research Archive
• Ree, Anne Hansen (2016). Kreftbehandling - tilbake til framtida : er stråle- og kjemoterapi effektiv immunterapi ved kreft? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(19), p. 1605–1605. doi: 10.4045/tidsskr.16.0630. Full text in Research Archive
• Gulati, Geeta; Heck, Siri Lagethon; Geisler, Jürgen; Fagerland, Morten; HOFFMANN, PAVEL & Gravdehaug, Berit [Show all 10 contributors for this article] (2016). Effect of candesartan and metoprolol on subclinical myocardial injury during anthracycline therapy: data from the prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) study. Full text in Research Archive

View all works in NVA