Kjersti Flatmark

• 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), s. 2129–2136. doi: 10.1093/bjr/tqag133. Fulltekst i vitenarkiv
• Meltzer, Sebastian; Landmark, Silje Sjåvik; Benth, Jurate Saltyte; Negård, Anne; Hamre, Hanne Mari & Kersten, Christian [Vis alle 11 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Torgunrud, Annette; Davidson, Ben; Nilsen, Thale Andrea; Marcussen, Ina Katrine Nitschke; Dagenborg, Vegar Johansen & Lund-Andersen, Christin [Vis alle 7 forfattere av denne artikkelen] (2026). Limited clinical utility of mutation-based circulating tumor DNA detection in pseudomyxoma peritonei. European Journal of Surgical Oncology. ISSN 0748-7983. 52(7). doi: 10.1016/j.ejso.2026.111873. Fulltekst i vitenarkiv
• Ree, Anne Hansen; Bousquet, Paula; Visnovska, Martina; Lüders, Torben; Geisler, Benjamin Peter & Wang, Shixiong [Vis alle 16 forfattere av denne artikkelen] (2026). Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer. British Journal of Cancer. ISSN 0007-0920. 134, s. 1176–1182. doi: 10.1038/s41416-026-03357-6. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Andersson, Yvonne Gerd; Løvstakken, Emil; Herud, Theodor Malmer; Waagene, Stein; Flatmark, Kjersti & Fleten, Karianne Giller (2025). Intraperitoneal Perfusion with Cisplatin or Mitomycin C Improves Survival in Mice Bearing Peritoneal Metastases from Ovarian Cancer. Annals of Surgical Oncology. ISSN 1068-9265. 32(12), s. 9333–9340. doi: 10.1245/s10434-025-18025-x. Fulltekst i vitenarkiv
• Torgunrud, Annette; Lund-Andersen, Christin; Davidson, Ben; Pettersen, Ina Katrine Nitschke; Larsen, Stein Gunnar & Dagenborg, Vegar Johansen [Vis alle 7 forfattere av denne artikkelen] (2025). High prevalence of KRAS and GNAS mutations in pseudomyxoma peritonei underscores opportunities for targeted therapeutic strategies. Pleura and Peritoneum. ISSN 2364-7671. s. 1–8. doi: 10.1515/pp-2025-0034. Fulltekst i vitenarkiv Vis sammendrag

  Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer with few efficacious treatment options in unresectable cases. Mutations in the KRAS and GNAS oncogenes are common, but the reported frequencies vary greatly, most likely because of low tumor cellularity in peritoneal tumor samples. With treatments targeting these mutations becoming increasingly available, reliable detection of mutations is essential

• Abrantes, Rafaela; Forcados, Christopher; Warren, David; Santos-Ferreira, Liliana; Fleten, Karianne Giller & Senra, Emanuel [Vis alle 23 forfattere av denne artikkelen] (2025). Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors. Cell Reports Medicine. 6(9). doi: 10.1016/j.xcrm.2025.102350. Fulltekst i vitenarkiv Vis sammendrag

  Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.

• Rau, Beate; Bhatt, Aditi; Bijelic, Lana; Sgarbura, Olivia; Goere, Diane & Bakrin, Naoual [Vis alle 10 forfattere av denne artikkelen] (2025). Peritoneal Surface Oncology surgery: Reflections on key determinants of success for female surgeons in this challenging discipline. European Journal of Surgical Oncology. ISSN 0748-7983. doi: 10.1016/j.ejso.2025.110434. Fulltekst i vitenarkiv Vis sammendrag

  Abstract This article explores the career pathways of women in the field of surgical oncology, specifically their growth and development as surgical oncologists. Nine global female surgical oncologists and experts in Peritoneal Surface Oncology (PSO) share personal reflections of the challenges and facilitators of career success in this challenging and highly specialized field of surgery. Methods Nine high profile female surgeons with expertise in PSO were recruited by direct contact with the lead author and asked to provide a detailed reflection of their career pathways, with a focus on barriers and facilitators to success. Results Most participants were highly driven, motivated by the poor prognosis of the disease early in their careers and the new opportunities PSO offered. Many moved between units or countries in search of training, often sacrificing work–life balance. Strong role models—usually male—were cited as mentors, and many participants now lead the units they helped establish. None expressed regrets, and all took pride in the advances achieved during their careers. While some women mentioned gender bias, most felt that within PSO, surgical skills and commitment outweighed such barriers. Conclusions These reflections should provide encouragement to the next generation of aspiring surgical oncologists to pursue their desire to enter this challenging area of surgery in the future.

• Høye, Eirik; Kanduri, Chakravarthi; Kristensen, Annette Torgunrud; Lorenz, Susanne; Edwin, Bjørn von Gohren & Larsen, Stein Gunnar [Vis alle 10 forfattere av denne artikkelen] (2025). Enrichment of Cancer-Associated Fibroblasts, Macrophages, and Up-Regulated TNF-α Signaling in the Tumor Microenvironment of CMS4 Colorectal Peritoneal Metastasis. Cancer Medicine. 14(1). doi: 10.1002/cam4.70521. Fulltekst i vitenarkiv Vis sammendrag

  Background Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic tumor microenvironment (TME) by comparing cell populations in colorectal liver (CLM), lung (mLu), and peritoneal (PM) metastases. Methods RNA isolated from 20 CLM, 15 mLu, and 35 PM samples was subjected to mRNA sequencing and explored through TME deconvolution tools, consensus molecular subtyping (CMS), and differential gene expression and gene set enrichment analysis, with respect to the metastatic sites. Clinical data and KRAS/BRAF hotspot mutation status were also obtained for all the cases. Results The cell type fractions in the TME were relatively similar between the metastatic sites, except for cancer-associated fibroblasts (CAFs), B cells, endothelial cells, and CD4+ T cells. Notably, PM showed enrichment for CAFs and endothelial cells, consistent with distinct pathways associated with metastatic growth and progression in the peritoneal cavity. PM with the mesenchymal subtype, CMS4, had increased CAFs, endothelial cells, and macrophages, along with up-regulated genes related to TNF-α signaling via NF-κB, EMT, and angiogenesis. Conclusions Tumor samples from different metastatic sites exhibited a broadly similar TME in terms of immune cell composition, with some intriguing differences. Targeting CAF-associated pathways, macrophages, and TNF-α signaling through NR4A could represent potential novel therapeutic approaches in CMS4 PM.

• Asvall, Jørund; Haugaa, Håkon; Larsen, Stein Gunnar; Skarholt, Trine Faye Rode; Botnen, Birgitte Maria & Flatmark, Kjersti [Vis alle 8 forfattere av denne artikkelen] (2025). Early detection of deep pelvic surgical site infection by microdialysis after abdominoperineal resection for locally advanced rectal cancer. Techniques in Coloproctology. ISSN 1123-6337. 29(1). doi: 10.1007/s10151-025-03156-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Patients with locally advanced rectal cancer (LARC) treated with (chemo)-radiotherapy before abdominoperineal resection (APR) are at high risk of developing pelvic organ/space surgical site infection (O/S-SSI). This increases morbidity and prolongs length of stay. Vague symptoms delay diagnosis. In microdialysis, thin catheters are placed in tissue enabling monitoring of metabolism. We hypothesize that local metabolic changes related to O/S-SSI might be detected by microdialysis. Methods In a prospective observational study, 38 patients who underwent open APR for LARC were analysed. At the end of surgery microdialysis catheters were placed in remnant tissue of the pelvic floor. Postoperatively, metabolic parameters including lactate, pyruvate, glucose and glycerol were measured, and the lactate-to-pyruvate (L/P) ratio was calculated. Out of 38 patients, 12 (32%) developed O/S-SSI. Results O/S-SSI was diagnosed median 9 (range 6–17) days after surgery. On the day of surgery, mean lactate in the O/S-SSI group was 6.0 mmol/L, whereas it was 3.6 mmol/L in the no-O/S-SSI group. ROC analysis (AUC = 0.73), with cut-point lactate 5.7, detected O/S-SSI with 92% sensitivity and 65% specificity. Overall mean lactate was 1.9 mmol/L higher in the O/S-SSI group than in the no-O/S-SSI group (P = 0.002). Overall mean L/P ratio was 34 units higher in the O/S-SSI group (P = 0.001). Conclusions In patients developing pelvic O/S-SSI, tissue lactate and L/P ratio measured by microdialysis were significantly higher and evident already from the day of surgery, 9 days prior to diagnosis, with high negative predictive value and moderate positive predictive value. Local monitoring using microdialysis may aid detection of O/S-SSI.

• Ree, Anne Hansen; Benth, Jurate Saltyte; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva & Guren, Marianne [Vis alle 14 forfattere av denne artikkelen] (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), s. 1921–1928. doi: 10.1038/s41416-024-02696-6. Fulltekst i vitenarkiv Vis sammendrag

  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).

• Davidson, Ben; Holth, Arild; Hummel, Charlotte; Flatmark, Kjersti & Torgunrud, Annette (2024). Different Frequency and Clinical Role for MTAP Loss in Pleural and Peritoneal Mesothelioma. Applied immunohistochemistry & molecular morphology (Print). ISSN 1541-2016. 32(6), s. 280–284. doi: 10.1097/PAI.0000000000001206. Fulltekst i vitenarkiv
• Foote, Jeremy B.; Mattox, Tyler E.; Keeton, Adam B.; Chen, Xi; Smith, Forrest T. & Berry, Kristy [Vis alle 35 forfattere av denne artikkelen] (2024). A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer. Cancer Research. ISSN 0008-5472. 85(5), s. 956–972. doi: 10.1158/0008-5472.CAN-24-0323. Fulltekst i vitenarkiv
• Ree, Anne Hansen; Høye, Eirik; Esbensen, Qin Ying; Beitnes, Ann-Christin Røberg; Negård, Anne & Bernklev, Linn [Vis alle 16 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Dagenborg, Vegar Johansen; Brudvik, Kristoffer Watten; Lund-Andersen, Christin; Kristensen, Annette Torgunrud; Lund-Iversen, Marius & Flatmark, Kjersti [Vis alle 8 forfattere av denne artikkelen] (2024). Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Liver Resection is a Treatment Option for Patients with Peritoneal and Liver Metastases from Colorectal Cancer. Annals of Surgery. ISSN 0003-4932. 280(5), s. 745–752. doi: 10.1097/SLA.0000000000006492. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To study outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients also treated for colorectal liver metastases (CLM). Background: Colorectal cancer (CRC) frequently metastasizes to the liver and peritoneum and is associated with a poor prognosis. In selected patients, a benefit in overall survival (OS) was shown for both peritoneal metastases (PM-CRC) offered CRS-HIPEC, and CLM treated with surgical resection. However, the presence of CLM was considered a relative contraindication to CRS-HIPEC, causing a paucity of outcome data in this patient group. Methods: Patients with PM-CRC having CRS-HIPEC at a single national center between 2007 and 2023, with additional intervention for CLM, were included (previous curative treatment for extraperitoneal and extrahepatic metastases was allowed). Three groups were defined: CLM before CRS-HIPEC (pre-CRS-HIPEC), CLM resected simultaneously with CRS-HIPEC (sim-CRS-HIPEC), and CLM after CRS-HIPEC (post-CRS-HIPEC), aiming to retrospectively analyze outcomes. Results: Fifty-seven patients were included and classified as: pre-CRS-HIPEC (n = 11), sim-CRS-HIPEC (n = 29), and post-CRS-HIPEC (n = 17). Median Peritoneal Cancer Index (PCI) was 8; 13 patients had severe complications (Clavien-Dindo ≥3), and no 90-day mortality. Median OS was 48 months after CRS-HIPEC. PCI was a predictor of OS (hazard ratio: 1.11, P < 0.001). We observed no difference in short or long-term outcomes between intervention groups. Discussion: This study demonstrated that patients with CLM having CRS-HIPEC had comparable OS to reports on CRS-HIPEC only, likely explained by a low PCI. Simultaneous CLM resection did not increase the risk of severe complications. Conclusions: In this national cohort, CRS-HIPEC and CLM intervention offers long-term survival, suggesting that this treatment may be offered to selected patients with PM-CRC and CLM.

• Lund-Andersen, Christin; Kristensen, Annette Torgunrud; Kanduri, Chakravarthi; Dagenborg, Vegar Johansen; Frøysnes, Ida Storhaug & Larsen, Mette Mellbye [Vis alle 9 forfattere av denne artikkelen] (2024). Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer. Journal of Translational Medicine. 22:646(1), s. 1–15. doi: 10.1186/s12967-024-05467-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Methods Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors. Results BRAF mutations were detected in 27% of the patients, and the BRAF-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36 months, respectively, p < 0.001). BRAF mutations were associated with RNF43/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, BRAF mutations were associated with gene expression changes in transport solute carrier proteins (specifically SLC7A6) and drug metabolism enzymes (CES1 and CYP3A4) that could influence the efficacy of MMC and irinotecan, respectively. BRAF-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (BTN1A1 and BTNL9). Conclusions BRAF mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches.

• Thorgersen, Ebbe Billmann; Solbakken, Arne Mide; Strøm, Tuva Kristine; Goscinski, Mariusz Adam; Spasojevic, Milan & Larsen, Stein Gunnar [Vis alle 7 forfattere av denne artikkelen] (2023). Short-term results after robot-assisted surgery for primary rectal cancers requiring beyond total mesorectal excision in multiple compartments. Scandinavian Journal of Surgery. ISSN 1457-4969. doi: 10.1177/14574969231200654. Fulltekst i vitenarkiv Vis sammendrag

  Aim: Rectal cancers requiring beyond total mesorectal excision (bTME) are traditionally operated using an open approach, but the use of minimally invasive robot-assisted procedures is increasing. Introduction of minimal invasive surgery for complex cancer cases could be associated with compromised surgical margins or increased complication rates. Therefore, reporting results both clinical and oncological in large series is important. Since bTME procedure reports are heterogeneous, comparing results is often difficult. In this study, a magnetic resonance imaging (MRI) classification system was used to describe the bTME surgery according to pelvic compartments. Methods: Consecutive patients with primary rectal cancer operated with laparoscopic robot-assisted bTME were prospectively included for 2 years. All patients had tumors that threatened the mesorectal fascia, invaded adjacent organs, and/or involved metastatic pelvic lateral lymph nodes. Short-term clinical outcomes and oncological specimen quality were registered. Surgery was classified according to pelvic compartments resected. Results: Clear resection margins (R0 resection) were achieved in 95 out of 105 patients (90.5%). About 26% had Accordion Severity Grading System of Surgical Complications grade 3–4 complications and 15% required re-operations. About 7% were converted to open surgery. The number of compartments resected ranged from one to the maximum seven, with 83% having two or three compartments resected. All 10 R1 resections occurred in the lateral and posterior compartments. Conclusions: The short-term clinical outcomes and oncological specimen quality after robot-assisted bTME surgery were comparable to previously published open bTME surgery. The description of surgical procedures using the Royal Marsden MRI compartment classification was feasible.

• Patrick-Brown, Dawn Judith; Mohamed, Faheez; Thrower, Andrew; Kristensen, Annette Torgunrud; Cosyns, Sarah & Canbay, Emel [Vis alle 9 forfattere av denne artikkelen] (2023). Determining a minimum data set for reporting clinical and radiologic data for pseudomyxoma peritonei. Pleura and Peritoneum. ISSN 2364-7671. 8(1), s. 1–9. doi: 10.1515/pp-2022-0200. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Pseudomyxoma peritonei (PMP) is a rare cancer currently affecting over 11,736 patients across Europe. Since PMP is so uncommon, collaboration between scientific centers is key to discovering the mechanisms behind the disease, efficient treatments, and targets pointing to a cure. To date, no consensus has been reached on the minimum data that should be collected during PMP research studies. This issue has become more important as biobanking becomes the norm. This paper begins the discussion around a minimum data set that should be collected by researchers through a review of available clinical trial reports in order to facilitate collaborative efforts within the PMP research community. Content A review of articles from PubMed, CenterWatch, ClinicalTrials.gov and MedRxiv was undertaken, and clinical trials reporting PMP results selected. Summary There is a core set of data that researchers report, including age and sex, overall survival, peritoneal cancer index (PCI) score, and completeness of cytoreduction, but after this, reports become variable. Outlook Since PMP is a rare disease, it is important that reports include as large of a number of standardised data points as possible. Our research indicates that there is still much ground to cover before this becomes a reality.

• Ito, Ichiaki; M.G.Yousef, Abdelrahman M.G. Abdelrahman; Chowdhury, Saikat; Dickson, Princess N.; Naini, Zahra A. & White, Michael G. [Vis alle 11 forfattere av denne artikkelen] (2023). Intraperitoneal Paclitaxel Is a Safe and Effective Therapeutic Strategy for Treating Mucinous Appendiceal Adenocarcinoma. Cancer Research. ISSN 0008-5472. 83(19), s. 3184–3191. doi: 10.1158/0008-5472.CAN-23-0013. Fulltekst i vitenarkiv
• Arjona-Sanchez, A.; Martinez-López, A.; Moreno-Montilla, M.T.; Mulsow, J.; Lozano-Lominchar, P. & Martínez-Torres, B. [Vis alle 50 forfattere av denne artikkelen] (2023). External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification. European Journal of Surgical Oncology. ISSN 0748-7983. 49(8), s. 1481–1488. doi: 10.1016/j.ejso.2023.03.206. Fulltekst i vitenarkiv
• Nygaard, Vigdis; Ree, Anne Hansen; Dagenborg, Vegar Johansen; Børresen-Dale, Anne-Lise; Edwin, Bjørn von Gohren & Fretland, Åsmund Avdem [Vis alle 10 forfattere av denne artikkelen] (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), s. 235–244. doi: 10.1158/2767-9764.CRC-22-0295. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Solbakken, Arne Mide; Sellevold, Simen; Spasojevic, Milan; Julsrud, Lars; Emblemsvåg, Hanne-Line & Reims, Henrik Mikael [Vis alle 14 forfattere av denne artikkelen] (2023). Navigation-Assisted Surgery for Locally Advanced Primary and Recurrent Rectal Cancer. Annals of Surgical Oncology. ISSN 1068-9265. 30, s. 7602–7602. doi: 10.1245/s10434-023-13964-9. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background In some surgical disciplines, navigation-assisted surgery has become standard of care, but in rectal cancer, indications for navigation and the utility of different technologies remain undetermined. Methods The NAVI-LARRC prospective study (NCT 04512937; IDEAL Stage 2a) evaluated feasibility of navigation in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC). Included patients had advanced tumours with high risk of incomplete (R1/R2) resection, and navigation was considered likely to improve the probability of complete resection (R0). Tumours were classified according to pelvic compartmental involvement, as suggested by the Royal Marsden group. The Brainlab TM navigation platform was used for preoperative segmentation of tumour and pelvic anatomy, and for intraoperative navigation with optical tracking. R0 resection rates, surgeons’ experiences, and adherence to the preoperative resection plan were assessed. Results Seventeen patients with tumours involving the posterior/lateral compartments underwent navigation-assisted procedures. Fifteen patients required abdominosacral resection, and 3 had resection of the sciatic nerve. R0 resection was obtained in 6/8 (75%) LARC and 6/9 (69%) LRRC cases. Preoperative segmentation was time-consuming (median 3.5 h), but intraoperative navigation was accurate. Surgeons reported navigation to be feasible, and adherence to the resection plan was satisfactory. Conclusions Navigation-assisted surgery using optical tracking was feasible. The preoperative planning was time-consuming, but intraoperative navigation was accurate and resulted in acceptable R0 resection rates. Selected patients are likely to benefit from navigation-assisted surgery.

• Høye, Eirik; Dagenborg, Vegar Johansen; Kristensen, Annette Torgunrud; Lund-Andersen, Christin; Fretland, Åsmund Avdem & Lorenz, Susanne [Vis alle 13 forfattere av denne artikkelen] (2023). T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases. GigaScience. 12. doi: 10.1093/gigascience/giad032. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Hyldbakk, Astrid; Fleten, Karianne Giller; Snipstad, Sofie; Åslund, Andreas; Davies, Catharina de Lange & Flatmark, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2023). Intraperitoneal administration of cabazitaxel-loaded nanoparticles in peritoneal metastasis models. Nanomedicine: Nanotechnology, Biology and Medicine. ISSN 1549-9634. 48, s. 1–11. doi: 10.1016/j.nano.2023.102656. Fulltekst i vitenarkiv Vis sammendrag

  Colorectal and ovarian cancers frequently develop peritoneal metastases with few treatment options. Intraperitoneal chemotherapy has shown promising therapeutic effects, but is limited by rapid drug clearance and systemic toxicity. We therefore encapsulated the cabazitaxel taxane in poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs), designed to improve intraperitoneal delivery. Toxicity of free and encapsulated cabazitaxel was investigated in rats by monitoring clinical signs, organ weight and blood hematological and biochemical parameters. Pharmacokinetics, biodistribution and treatment response were evaluated in mice. Biodistribution was investigated by measuring both cabazitaxel and the 2-ethylbutanol NP degradation product. Drug encapsulation was shown to increase intraperitoneal drug retention, leading to prolonged intraperitoneal drug residence time and higher drug concentrations in peritoneal tumors. As a result, encapsulation of cabazitaxel improved the treatment response in two in vivo models bearing intraperitoneal tumors. Together, these observations indicate a strong therapeutic potential of NP-based cabazitaxel encapsulation as a novel treatment for peritoneal metastases.

• Larsen, Stein Gunnar; Goscinski, Mariusz Adam; Dueland, Svein; Steigen, Sonja Eriksson; Hofsli, Eva & Kristensen, Annette Torgunrud [Vis alle 10 forfattere av denne artikkelen] (2022). Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients. British Journal of Cancer. ISSN 0007-0920. s. 726–735. doi: 10.1938/s41416-021-01620-6. Fulltekst i vitenarkiv
• Meltzer, Sebastian; Negård, Anne; Bakke, Kine Mari; Hamre, Hanne Mari; Kersten, Christian & Hofsli, Eva [Vis alle 10 forfattere av denne artikkelen] (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, s. 2227–2233. doi: 10.1038/s41416-022-02004-0. Fulltekst i vitenarkiv Vis sammendrag

  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), s. 955–962. doi: 10.1080/0284186X.2022.2098053. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Ambrosini, Margherita; Re, Marzia Del; Manca, Paolo; Hendifar, Andrew; Drilon, Alexander & Harada, Guilherme [Vis alle 21 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Fleten, Karianne Giller; Hyldbakk, Astrid; Einen, Caroline; Benjakul, Sopisa; Strand, Berit Løkensgard & Davies, Catharina de Lange [Vis alle 8 forfattere av denne artikkelen] (2022). Alginate Microsphere Encapsulation of Drug-Loaded Nanoparticles: A Novel Strategy for Intraperitoneal Drug Delivery. Marine Drugs. 20(12). doi: 10.3390/md20120744. Fulltekst i vitenarkiv Vis sammendrag

  Alginate hydrogels have been broadly investigated for use in medical applications due to their biocompatibility and the possibility to encapsulate cells, proteins, and drugs. In the treatment of peritoneal metastasis, rapid drug clearance from the peritoneal cavity is a major challenge. Aiming to delay drug absorption and reduce toxic side effects, cabazitaxel (CAB)-loaded poly(alkyl cyanoacrylate) (PACA) nanoparticles were encapsulated in alginate microspheres. The PACAlg alginate microspheres were synthesized by electrostatic droplet generation and the physicochemical properties, stability, drug release kinetics, and mesothelial cytotoxicity were analyzed before biodistribution and therapeutic efficacy were studied in mice. The 450 µm microspheres were stable at in vivo conditions for at least 21 days after intraperitoneal implantation in mice, and distributed evenly throughout the peritoneal cavity without aggregation or adhesion. The nanoparticles were stably retained in the alginate microspheres, and nanoparticle toxicity to mesothelial cells was reduced, while the therapeutic efficacy of free CAB was maintained or improved in vivo. Altogether, this work presents the alginate encapsulation of drug-loaded nanoparticles as a promising novel strategy for the treatment of peritoneal metastasis that can improve the therapeutic ratio between toxicity and therapeutic efficacy.

• Høye, Eirik; Fromm, Bastian; Böttger, Paul H.M.; Domanska, Diana; Kristensen, Annette Torgunrud & Lund-Andersen, Christin [Vis alle 13 forfattere av denne artikkelen] (2022). A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer. NAR Cancer. 4(1), s. 1–13. doi: 10.1093/narcan/zcab051. Fulltekst i vitenarkiv Vis sammendrag

  Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published nextgeneration sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as upregulated at multiple metastatic sites Mir-210 3p, Mir191 5p, Mir-8-P1b 3p [mir-141–3p], Mir-1307 5p and Mir-155 5p. Several have previously been implicated in metastasis through involvement in epithelial-tomesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

• Flatmark, Kjersti; Torgunrud, Annette; Fleten, Karianne G; Davidson, Ben; Juul, Hedvig Vidarsdotter & Mensali, Nadia [Vis alle 8 forfattere av denne artikkelen] (2021). Peptide vaccine targeting mutated GNAS: A potential novel treatment for pseudomyxoma peritonei. Journal for ImmunoTherapy of Cancer (JITC). 9:e003109(10), s. 1–10. doi: 10.1136/jitc-2021-003109. Fulltekst i vitenarkiv Vis sammendrag

  Background Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the GNAS oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor neoantigen, presenting an opportunity for targeting by a therapeutic cancer vaccine. Methods Tumor and blood samples were collected from 25 patients undergoing surgery for PMP (NCT02073500). GNAS mutation analysis was performed by next-generation targeted sequencing or digital droplet PCR. Responses to stimulation with Gsα mutated (point mutations R201H and R201C) 30 mer peptides were analyzed in peripheral blood T cells derived from patients with PMP and healthy donors. Fresh PMP tumor samples were analyzed by mass cytometry using a panel of 35 extracellular markers, and cellular subpopulations were clustered and visualized using the visual stochastic network embedding analysis tool. Results GNAS mutations were detected in 22/25 tumor samples (88%; R201H and R201C mutations detected in 16 and 6 cases, respectively). Strong T cell proliferation against Gsα mutated peptides was observed in 18/24 patients with PMP. Mass cytometry analysis of tumor revealed infiltration of CD3 +T cells in most samples, with variable CD4+:CD8 + ratios. A large proportion of T cells expressed immune checkpoint molecules, in particular programmed death receptor-1 and T cell immunoreceptor with Ig and ITIM, indicating that these T cells were antigen experienced. Conclusion These findings point to the existence of a pre-existing immunity in patients with PMP towards mutated Gsα, which has been insufficient to control tumor growth, possibly because of inhibition of antitumor T cells by upregulation of immune checkpoint molecules. The results form a rationale for exploring peptide vaccination with Gsα peptides in combination with immune checkpoint inhibiton as a possible curative treatment for PMP and other GNAS mutated cancers.

• Lund-Andersen, Christin; Kristensen, Annette Torgunrud; Fleten, Karianne Giller & Flatmark, Kjersti (2021). Omics analyses in peritoneal metastasis-utility in the management of peritoneal metastases from colorectal cancer and pseudomyxoma peritonei: a narrative review. Journal of Gastrointestinal Oncology (JGO). ISSN 2078-6891. 12(Supplement 1). doi: 10.21037/JGO-20-136. Fulltekst i vitenarkiv Vis sammendrag

  High-throughput “-omics” analysis may provide a broader and deeper understanding of cancer biology to define prognostic and predictive biomarkers and identify novel therapy targets. In this review we provide an overview of studies where the peritoneal tumor component of peritoneal metastases from colorectal cancer (PM-CRC) and pseudomyxoma peritonei (PMP) were analyzed. Most of the available data was derived from DNA mutation analysis, but a brief review of findings from transcriptomic and protein expression analysis was also performed. Studies reporting genomic analysis of peritoneal tumor samples from 1,779 PM-CRC and 623 PMP cases were identified. The most frequently mutated genes in PM-CRC were KRAS, APC, SMAD4, BRAF, and PIK3CA, while in PMP KRAS, GNAS, FAT4, TGFBR1, TP53 and SMAD3/4 mutations were most commonly identified. Analyses were performed by single-gene analyses and to some extent targeted next-generation sequencing, and a very limited amount of broad explorative data exists. The investigated cohorts were typically small and heterogeneous with respect to the methods used and to the reporting of clinical data. This was even more apparent regarding transcriptomic and protein data, as the low number of cases examined and quality of clinical data would not support firm conclusions. Even for the most frequently mutated genes, the results varied greatly; for instance, KRAS mutations were reported at frequencies between 20–57% in PM-CRC and 38–100% in PMP. Such variation could be caused by random effects in small cohorts, heterogeneity in patient selection, or sensitivity of applied technology. Although a large number of samples have been subjected to analysis, cross-study comparisons are difficult to perform, and combined with small cohorts and varying quality and detail of clinical information, the observed variation precludes useful interpretation in a clinical context. Although omics data in theory could answer questions to aid management decisions in PM-CRC and PMP, the existing data does not presently support clinical implementation. With the necessary technologies being generally available, the main challenge will be to obtain sufficiently large, representative cohorts with adequate clinical data and standardized reporting of results. Importantly, studies where the focus is specifically on peritoneal disease are needed, where the study designs are aligned with clearly defined research questions to allow robust conclusions. Such studies are highly warranted if patients with PM-CRC and PMP are to derive benefit from recent advances in precision cancer medicine.

• Andersson, Yvonne; Fleten, Karianne Giller; Abrahamsen, Torveig Weum; Reed, Wenche; Davidson, Ben & Flatmark, Kjersti (2021). Anti-Angiogenic Treatment in Pseudomyxoma Peritonei - Still a Strong Preclinical Rationale. Cancers. 13:2819(11), s. 1–11. doi: 10.3390/cancers13112819. Fulltekst i vitenarkiv Vis sammendrag

  Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.

• Chok, Aik Yong; Oliver, A; Rasheed, S; Tan, E J; Kelly, M E & Aalbers, A G J [Vis alle 53 forfattere av denne artikkelen] (2021). Perioperative management and anaesthetic considerations in pelvic exenterations using Delphi methodology: results from the PelvEx Collaborative. BJS Open. 5(1). doi: 10.1093/bjsopen/zraa055. Fulltekst i vitenarkiv Vis sammendrag

  Background The multidisciplinary perioperative and anaesthetic management of patients undergoing pelvic exenteration is essential for good surgical outcomes. No clear guidelines have been established, and there is wide variation in clinical practice internationally. This consensus statement consolidates clinical experience and best practice collectively, and systematically addresses key domains in the perioperative and anaesthetic management. Methods The modified Delphi methodology was used to achieve consensus from the PelvEx Collaborative. The process included one round of online questionnaire involving controlled feedback and structured participant response, two rounds of editing, and one round of web-based voting. It was held from December 2019 to February 2020. Consensus was defined as more than 80 per cent agreement, whereas less than 80 per cent agreement indicated low consensus. Results The final consensus document contained 47 voted statements, across six key domains of perioperative and anaesthetic management in pelvic exenteration, comprising preoperative assessment and preparation, anaesthetic considerations, perioperative management, anticipating possible massive haemorrhage, stress response and postoperative critical care, and pain management. Consensus recommendations were developed, based on consensus agreement achieved on 34 statements. Conclusion The perioperative and anaesthetic management of patients undergoing pelvic exenteration is best accomplished by a dedicated multidisciplinary team with relevant domain expertise in the setting of a specialized tertiary unit. This consensus statement has addressed key domains within the framework of current perioperative and anaesthetic management among patients undergoing pelvic exenteration, with an international perspective, to guide clinical practice, and has outlined areas for future clinical research.

• Fleten, Karianne Giller; Eksteen, Jacobus Johannes; Mauseth, Brynjar; Camilio, Ketil André; Vasskog, Terje & Sveinbjørnsson, Baldur [Vis alle 9 forfattere av denne artikkelen] (2021). Oncolytic peptides DTT-205 and DTT-304 induce complete regression and protective immune response in experimental murine colorectal cancer. Scientific Reports. 11. doi: 10.1038/s41598-021-86239-6. Fulltekst i vitenarkiv Vis sammendrag

  Oncolytic peptides represent a novel, promising cancer treatment strategy with activity in a broad spectrum of cancer entities, including colorectal cancer (CRC). Cancer cells are killed by immunogenic cell death, causing long-lasting anticancer immune responses, a feature of particular interest in non-immunogenic CRC. Oncolytic peptides DTT-205 and DTT-304 were administered by intratumoral injection in subcutaneous tumors established from murine CRC cell lines CT26 and MC38, and complete regression was obtained in the majority of animals. When cured animals were rechallenged by splenic injection of tumor cells, 1/23 animals developed liver metastases, compared to 19/22 naïve animals. Treatment with both peptides was well tolerated, but monitoring post-injection hemodynamic parameters in rats, less extensive changes were observed with DTT-205 than DTT-304, favoring DTT-205 for future drug development. DTT-205 was subsequently shown to have strong in vitro activity in a panel of 33 cancer cell lines. In conclusion, both peptides exerted a strong inhibitory effect in two immunocompetent CRC models and induced a systemic effect preventing development of liver metastases upon splenic rechallenge. If a similar effect could be obtained in humans, these drugs would be of particular interest for combinatory treatment with immune checkpoint inhibitors in metastatic CRC.

• Meltzer, Sebastian; Kristensen, Annette Torgunrud; Abrahamsson, Hanna Josefine; Solbakken, Arne Mide; Flatmark, Kjersti & Dueland, Svein [Vis alle 15 forfattere av denne artikkelen] (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, s. 240–246. doi: 10.1038/s41416-021-01377-y. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Thorgersen, Ebbe Billmann & Flatmark, Kjersti (2021). ASO Author Reflections: The Peritoneum is an Active Immunological Compartment. Annals of Surgical Oncology. ISSN 1068-9265. s. 1–2. doi: 10.1245/s10434-021-10036-8. Fulltekst i vitenarkiv
• Dagenborg, Vegar Johansen; Marshall, Serena; Grzyb, Krzysztof; Fretland, Åsmund Avdem; Lund-Iversen, Marius & Mælandsmo, Gunhild Mari [Vis alle 10 forfattere av denne artikkelen] (2021). Low Concordance Between T-Cell Densities in Matched Primary Tumors and Liver Metastases in Microsatellite Stable Colorectal Cancer. Frontiers in Oncology. 11, s. 1–9. doi: 10.3389/fonc.2021.671629. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Larsen, Stein Gunnar; Goscinski, Mariusz Adam; Dueland, Svein; Steigen, Sonja Eriksson; Hofsli, Eva & Torgunrud, Annette [Vis alle 10 forfattere av denne artikkelen] (2021). Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients. British Journal of Cancer. ISSN 0007-0920. doi: 10.1038/s41416-021-01620-6. Fulltekst i vitenarkiv Vis sammendrag

  Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. Methods In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. Results In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. Conclusions PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.

• Thorgersen, Ebbe Billmann; Asvall, Jørund; Frøysnes, Ida Storhaug; Schjalm, Camilla; Larsen, Stein Gunnar & Dueland, Svein [Vis alle 10 forfattere av denne artikkelen] (2021). Increased Local Inflammatory Response to MOC31PE Immunotoxin After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Annals of Surgical Oncology. ISSN 1068-9265. doi: 10.1245/s10434-021-10022-0. Fulltekst i vitenarkiv Vis sammendrag

  Background - Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial cell adhesion molecule, and kills cancer cells by distinct mechanisms, simultaneously causing immune activation by induction of immunogenic cell death (ICD). Methods - Systemic and local cytokine responses were analyzed in serum and intraperitoneal fluid samples collected the first three postoperative days from clinically comparable patients undergoing CRS-HIPEC with (n = 12) or without (n = 26) intraperitoneal instillation of MOC31PE. A broad panel of 27 pro- and antiinflammatory interleukins, chemokines, interferons, and growth factors was analyzed using multiplex technology. Results - The time course and magnitude of the systemic and local postoperative cytokine response after CRS-HIPEC were highly compartmentalized, with modest systemic responses contrasting substantial intraperitoneal responses. Administration of MOC31PE resulted in changes that were broader and of higher magnitude compared with CRS-HIPEC alone. Significantly increased levels of innate proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF) as well as an interesting time response curve for the strong T-cell stimulator interferon (IFN)-γ and its associated chemokine interferon gamma-induced protein/chemokine (C-X-C motif) ligand 10 (IP-10) were detected, all associated with ICD. Conclusions - Our study revealed a predominately local rather than systemic inflammatory response to CRS-HIPEC, which was strongly enhanced by MOC31PE treatment. The MOC31PE-induced intraperitoneal inflammatory reaction could contribute to improve remnant cancer cell killing, but the mechanisms remain to be elucidated in future studies.

• Knuth, Franziska Hanna; Adde, Ingvild Askim; Huynh, Bao Ngoc; Grøndahl, Aurora Rosvoll; Winter, René & Negård, Anne [Vis alle 15 forfattere av denne artikkelen] (2021). MRI-based automatic segmentation of rectal cancer using 2D U-Net on two independent cohorts. Acta Oncologica. ISSN 0284-186X. 61(2), s. 255–263. doi: 10.1080/0284186X.2021.2013530. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Mariathasan, Anthony Burton; Boye, Kjetil; Dueland, Svein; Flatmark, Kjersti & Larsen, Stein Gunnar (2021). Metastases in locally advanced rectal cancer undergoing curatively intended treatment. European Journal of Surgical Oncology. ISSN 0748-7983. doi: 10.1016/j.ejso.2021.04.023. Fulltekst i vitenarkiv
• Aghayan, Davit; Kazaryan, Airazat; Dagenborg, Vegar Johansen; Røsok, Bård Ingvald; Fagerland, Morten Wang & Bjørnelv, Gudrun Maria Waaler [Vis alle 10 forfattere av denne artikkelen] (2020). Long-term oncologic outcomes after laparoscopic versus open resection for colorectal liver metastasis. Annals of Internal Medicine. ISSN 0003-4819. 174(2), s. 175–182. doi: 10.7326/M20-4011. Fulltekst i vitenarkiv Vis sammendrag

  Background: Despite the recent worldwide dissemination of laparoscopic liver surgery, no high-level evidence supports the oncologic safety of this approach. Objective: To evaluate long-term oncologic outcomes after laparoscopic versus open liver resection in patients with colorectal metastases. Design: A single-center, assessor-blinded, randomized controlled trial (OSLO-COMET [Oslo Randomized Laparoscopic Versus Open Liver Resection for Colorectal Metastases Trial]). (ClinicalTrials.gov: NCT01516710) Setting: Oslo University Hospital, the only provider of liver surgery for the 3 million inhabitants of southeastern Norway. Participants: Patients with resectable colorectal liver metastases were randomly assigned to have open or laparoscopic liver resection. Intervention: From February 2012 to January 2016, a total of 280 patients were included in the trial (laparoscopic surgery: n = 133; open surgery: n = 147). Measurements: The primary outcome was postoperative morbidity within 30 days. Five-year rates of overall and recurrence-free survival were predefined secondary end points. Results: At a median follow-up of 70 months, rates of 5-year overall survival were 54% in the laparoscopic group and 55% in the open group (between-group difference, 0.5 percentage point [95% CI, −11.3 to 12.3 percentage points]; hazard ratio, 0.93 [CI, 0.67 to 1.30]; P = 0.67). Rates of 5-year recurrence-free survival were 30% in the laparoscopic group and 36% in the open group (between-group difference, 6.0 percentage points [CI, −6.7 to 18.7 percentage points]; hazard ratio, 1.09 [CI, 0.80 to 1.49]; P = 0.57). Limitation: The trial was not powered to detect differences in secondary end points and was not designed to address a noninferiority hypothesis for survival outcomes. Conclusion: In this randomized trial of laparoscopic and open liver surgery, no difference in survival outcomes was found between the treatment groups. However, differences in 5-year overall survival up to about 10 percentage points in either direction cannot be excluded. This trial should be followed by pragmatic multicenter trials and international registries. Primary Funding Source: The South-Eastern Norway Regional Health Authority.

• Fleten, Karianne Giller; Lund-Andersen, Christin; Waagene, Stein; Abrahamsen, Torveig Weum; Mørch, Ýrr Asbjørg & Pedersen, Kjetil Boye [Vis alle 8 forfattere av denne artikkelen] (2020). Experimental Treatment of Mucinous Peritoneal Metastases Using Patient-Derived Xenograft Models. Translational Oncology. ISSN 1944-7124. 13(8). doi: 10.1016/j.tranon.2020.100793. Fulltekst i vitenarkiv Vis sammendrag

  Mucinous peritoneal metastases (PM) generally respond poorly to systemic treatment, and there is a clear unmet need for new treatment strategies to improve survival and quality of life for patients with PM. In this work, the growth inhibitory effect of five drugs (oxaliplatin (OXA; 5 mg/kg), irinotecan (IRI; 60 mg/kg), cabazitaxel (CBZ; 15 or 30 mg/kg), regorafenib (REG; 10, 30 or 60 mg/kg), and capecitabine (CAP; 359 or 755 mg/kg) was investigated in three orthotopic patient-derived xenograft models that mimic mucinous PM. Drugs were administered intraperitoneally (i.p.) as monotherapy weekly for 4 weeks (OXA, IRI), as one single i.p. injection (CBZ), or orally (REG, CAP) daily 5 of 7 days per week for four weeks, and i.p. tumor growth and survival were monitored and compared between treatment groups. The i.p. administered drugs (OXA, IRI, CBZ) had the strongest growth inhibitory effect, with OXA being most efficacious, completely inhibiting tumor growth in the majority of the animals. CBZ and IRI also strongly inhibited tumor growth, but with more variation in efficacy between the models. A moderate reduction in tumor growth was observed in all models treated with REG, while CAP had little to no growth inhibitory effect. Targeted next-generation-sequencing has identified mutational profiles typically associated with PM (mutations in KRAS, GNAS, and BRAF oncogenes), supporting the representativeness of the models. The results presented in this work support the continued exploration of i.p. treatment protocols for PM, with OXA remaining and CBZ emerging as particularly interesting candidates for further studies.

• Patrick-Brown, Thale Dawn J.H.; Carr, Norman John; Swanson, David; Larsen, Stein Gunnar; Mohamed, Faheez & Flatmark, Kjersti (2020). Estimating the Prevalence of Pseudomyxoma Peritonei in Europe Using a Novel Statistical Method. Annals of Surgical Oncology. ISSN 1068-9265. 28(1), s. 252–257. doi: 10.1245/s10434-020-08655-8. Fulltekst i vitenarkiv Vis sammendrag

  Background: The determination of the incidence and prevalence of rare diseases is important for economists and health-care providers. Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer that represents a substantial burden on both patients and health-care systems. The incidence rate was previously approximated at 1-2 people per million per year; this incidence has never been challenged, and the prevalence has not been estimated. Methods: Epidemiological data from Norway and England were obtained and analysed to calculate a minimum incidence rate based on the number of patients having a first surgical intervention for PMP. A novel method was then used to determine a prevalence rate for PMP, incorporating incidence, death, and cure rates in a multi-year analysis that accounted for the increasing population of Europe over a 10-year period. Results: An incidence rate of 3.2 people per million per year was calculated, with a corresponding estimated prevalence rate of 22 people per million per year. By this calculation, 11,736 people in Europe were estimated to be living with PMP in 2018. Conclusion: Incidence and prevalence are essential tools for assessment of the financial and human cost of a disease. For rare diseases, such as PMP, the lack of accurate registries presents a particular challenge in determining such health-related statistical parameters. Based on our calculations, a significant number of people are living with PMP in Europe, underlining the need for appropriate resource allocation to ensure that adequate health-care measures are provided.

• Dagenborg, Vegar Johansen; Marshall, Serena; Yaqub, Sheraz; Grzyb, Krzysztof; Pedersen, Kjetil Boye & Lund-Iversen, Marius [Vis alle 12 forfattere av denne artikkelen] (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), s. 432–440. doi: 10.1080/15384047.2020.1721252. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 10 forfattere av denne artikkelen] (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), s. 122–124. doi: 10.1016/j.tranon.2019.09.005. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Flatmark, Kjersti & Mohamed, Faheez (2020). ASO Author Reflections: Estimating the Prevalence of Pseudomyxoma Peritonei in Europe Using a Novel Statistical Method. Annals of Surgical Oncology. ISSN 1068-9265. 27, s. 771–772. doi: 10.1245/s10434-020-08691-4. Fulltekst i vitenarkiv
• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein & Bergheim, Inger Riise [Vis alle 25 forfattere av denne artikkelen] (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. s. 1–10. doi: 10.1080/0284186X.2020.1742377. Fulltekst i vitenarkiv Vis sammendrag

  <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.

• Dagenborg, Vegar Johansen; Marshall, Serena Elizabeth; Grzyb, Krzysztof; Fretland, Åsmund Avdem; Lund-Iversen, Marius & Mælandsmo, Gunhild Mari [Vis alle 10 forfattere av denne artikkelen] (2020). Low concordance between T-cell densities in matched primary tumors and liver metastases in microsatellite stable colorectal cancer. Frontiers in Oncology. 11. Fulltekst i vitenarkiv
• Andersson, Yvonne; Inderberg, Else Marit; Kvalheim, Gunnar; Herud, Morten Theodor Malmer; Engebråten, Olav & Flatmark, Kjersti [Vis alle 8 forfattere av denne artikkelen] (2019). Immune stimulatory effect of anti-EpCAM immunotoxin - improved overall survival of metastatic colorectal cancer patients. Acta Oncologica. ISSN 0284-186X. s. 1–7. doi: 10.1080/0284186X.2019.1704864. Fulltekst i vitenarkiv
• Fromm, Bastian; Domanska, Diana Ewa; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing & Aparicio-Puerta, Ernesto [Vis alle 13 forfattere av denne artikkelen] (2019). MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Research (NAR). ISSN 0305-1048. 48(D1), s. D132–D141. doi: 10.1093/nar/gkz885. Fulltekst i vitenarkiv Vis sammendrag

  Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are special because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad other small RNAs generated by cells. However, making this distinction is not a common practice and, thus, not surprisingly, the heterogeneous quality of available miRNA complements has become a major concern in microRNA research. We addressed this by extensively expanding our curated microRNA gene database - MirGeneDB - to 45 organisms, encompassing a wide phylogenetic swath of animal evolution. By consistently annotating and naming 10,899 microRNA genes in these organisms, we show that previous microRNA annotations contained not only many false positives, but surprisingly lacked &amp;gt;2000 bona fide microRNAs. Indeed, curated microRNA complements of closely related organisms are very similar and can be used to reconstruct ancestral miRNA repertoires. MirGeneDB represents a robust platform for microRNA-based research, providing deeper and more significant insights into the biology and evolution of miRNAs as well as biomedical and biomarker research. MirGeneDB is publicly and freely available at http://mirgenedb.org/.

• Bains, Simer Jit; Abrahamsson, Hanna Josefine; Flatmark, Kjersti; Dueland, Svein; Hole, Knut Håkon & Seierstad, Therese [Vis alle 9 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Flørenes, Vivi Ann; Flem-Karlsen, Karine; McFadden, Erin; Bergheim, Inger Riise; Nygaard, Vigdis & Nygård, Vegard Mokleiv [Vis alle 17 forfattere av denne artikkelen] (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), s. 951–958. doi: 10.1016/j.tranon.2019.04.001. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Sørensen, Olaf; Andersen, Anders Mikal; Larsen, Stein Gunnar; Giercksky, Karl-Erik & Flatmark, Kjersti (2019). Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of high-grade pseudomyxoma peritonei. Clinical and Experimental Metastasis. ISSN 0262-0898. 36(6), s. 511–518. doi: 10.1007/s10585-019-09991-0. Fulltekst i vitenarkiv Vis sammendrag

  Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven in randomized trials, and the objective of this study was to investigate the efficacy of intraperitoneal mitomycin C (MMC) and regional hyperthermia as components of this complex treatment. Xenograft tissue established from a patient with histologically high-grade PMP with signet ring cell differentiation was implanted intraperitoneally in 65 athymic nude male rats and the animals were stratified into three treatment groups; the cytoreductive surgery group (CRSG, CRS only), the normothermic group (NG, CRS and intraperitoneal chemotherapy perfusion (IPEC) with MMC at 35 ºC), and the hyperthermic group (HG, CRS and IPEC at 41 ºC). The main endpoints were survival and tumor weight at autopsy. Adequate imitation of the clinical setting and treatment approach was achieved. The median survival was 31 days in the CRSG, 60 days in NG and 67 days in HG. The median tumor weights at autopsy were 34 g in CRSG, 23 g NG and 20 g in HG. In conclusion, the addition of IPEC with MMC after CRS doubled the survival time and reduced tumor growth compared to CRS alone. Adding regional hyperthermia resulted in a modest improvement of treatment outcome.

• Meltzer, Sebastian; Bakke, Kine Mari; Rød, Karina Lund; Negård, Anne; Flatmark, Kjersti & Solbakken, Arne Mide [Vis alle 19 forfattere av denne artikkelen] (2019). Sex-related differences in primary metastatic site in rectal cancer; associated with hemodynamic factors? Clinical and Translational Radiation Oncology. 21, s. 5–10. doi: 10.1016/j.ctro.2019.11.006. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Aghayan, Davit; Fretland, Åsmund Avdem; Kazaryan, Airazat M.; Sahakyan, Mushegh; Dagenborg, Vegar Johansen & Bjørnbeth, Bjørn Atle [Vis alle 9 forfattere av denne artikkelen] (2019). Laparoscopic versus open liver resection in the posterosuperior segments: a sub-group analysis from the OSLO-COMET randomized controlled trial. HPB. ISSN 1365-182X. 21(11), s. 1485–1490. doi: 10.1016/j.hpb.2019.03.358. Fulltekst i vitenarkiv Vis sammendrag

  Background Laparoscopic liver resection in the posterosuperior segments is technically challenging. This study aimed to compare the perioperative outcomes for laparoscopic and open resection of colorectal liver metastases located in the posterosuperior segments. Methods This was a subgroup analysis of the OSLO-COMET randomized controlled trial, where 280 patients were randomly assigned to open or laparoscopic parenchyma-sparing liver resections of colorectal metastases. Patients with tumors in the posterosuperior segments were identified, and perioperative outcomes and health related quality of life (HRQoL) were compared. Results We identified a total of 136 patients, 62 in the laparoscopic and 74 in the open group. The postoperative complication rate was 26% in the laparoscopic and 31% in the open group. The blood loss was less in the open group (500 vs. 250 ml, P = 0.006), but the perioperative transfusion rate was similar. The operative time was similar, while postoperative hospital stay was shorter in the laparoscopic group (2 vs. 4 days, P < 0.001). HRQoL was significantly better after laparoscopy at 1 month. Conclusion In patients undergoing laparoscopic or open liver resection of colorectal liver metastases in the posterosuperior segments, laparoscopic surgery was associated with shorter hospital stay and comparable perioperative outcomes.

• Meltzer, Sebastian; Bjørnetrø, Tonje; Lyckander, Lars Gustav; Flatmark, Kjersti; Dueland, Svein & Samiappan, Rampradeep [Vis alle 10 forfattere av denne artikkelen] (2019). Circulating Exosomal miR-141-3p and miR-375 in Metastatic Progression of Rectal Cancer. Translational Oncology. ISSN 1944-7124. 12(8), s. 1038–1044. doi: 10.1016/j.tranon.2019.04.014. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Abrahamsson, Hanna Josefine; Porojnicu, Alina Carmen; Lindstrøm, Jonas Christoffer; Dueland, Svein; Flatmark, Kjersti & Hole, Knut Håkon [Vis alle 11 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Frøysnes, Ida Storhaug; Andersson, Yvonne; Larsen, Stein Gunnar; Davidson, Ben; Øien, Janne-Merete & Julsrud, Lars [Vis alle 9 forfattere av denne artikkelen] (2019). ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis. European Journal of Surgical Oncology. ISSN 0748-7983. s. 1–5. doi: 10.1016/j.ejso.2019.04.014. Fulltekst i vitenarkiv Vis sammendrag

  Background The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial. Methods This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with mitomycin C. Overall survival (OS) and disease-free survival (DFS) were secondary endpoints. Twenty-one patients received the study drug at four dose levels on the first postoperative day, including six patients constituting an expansion cohort. Results With a 34-month follow-up, the median OS was not reached and the estimated 3-year OS was 78%. Median DFS for all patients was 21 months and the 3-year DFS was 33%, with a median follow-up of 31 months. When excluding patients with potential favorable characteristics from the analysis (n = 4), the median DFS was 13 months and the 3-year OS 72%. Conclusions The promising long-term outcome combined with low systemic absorbance, high drug concentration and cytotoxic activity in peritoneal fluid support further investigations of clinical efficacy.

• Lund-Andersen, Christin; Nakken, Sigve; Nygård, Ståle; Fromm, Bastian; Aasheim, Lars Birger & Davidson, Ben [Vis alle 13 forfattere av denne artikkelen] (2019). Integrative genomic analysis of peritoneal malignant mesothelioma: Understanding a case with extraordinary chemotherapy response. Cold Spring Harbor Molecular Case Studies. 5:a003566(2), s. 1–15. doi: 10.1101/mcs.a003566. Fulltekst i vitenarkiv Vis sammendrag

  Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.

• Ree, Anne Hansen; Nygaard, Vigdis; Russnes, Hege Elisabeth Giercksky; Heinrich, Daniel; Nygaard, Vegard & Johansen, Christin [Vis alle 13 forfattere av denne artikkelen] (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), s. 701–706. doi: 10.1158/2326-6066.CIR-18-0777. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Mikalsen, Stine Gyland; Mikalsen, Lars Tore G; Sandvik, Joe Alexander; Aarnes, Eva-Katrine; Fenne, Siri & Flatmark, Kjersti [Vis alle 9 forfattere av denne artikkelen] (2018). Low dose-rate irradiation with [3H]-labelled valine to selectively target hypoxic cells in a human colorectal cancer xenograft model. Acta Oncologica. ISSN 0284-186X. 57(9), s. 1216–1224. doi: 10.1080/0284186X.2018.1457223. Fulltekst i vitenarkiv
• Fusser, Markus; Øverbye, Anders; Pandya, Abhilash D.; Mørch, Ýrr Asbjørg; Borgos, Sven Even F. & Kildal, Wanja [Vis alle 16 forfattere av denne artikkelen] (2018). Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft. Journal of Controlled Release. ISSN 0168-3659. 293, s. 183–192. doi: 10.1016/j.jconrel.2018.11.029. Fulltekst i vitenarkiv Vis sammendrag

  The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of free drug in the basal-like patient-derived xenograft and resulted in complete remission of 6 out of 8 tumors, whereas free drug gave complete remission only with 2 out of 9 tumors. To investigate the different efficacies obtained with nanoparticle-encapsulated versus free cabazitaxel, mass spectrometry quantification of cabazitaxel was performed in mice plasma and selected tissue samples. Nanoparticle-encapsulated drug had a longer circulation time in blood. There was approximately a three times higher drug concentration in tumor tissue 24 h after injection, and two times higher 96 h after injection of nanoparticles with drug compared to the free drug. The tissue biodistribution obtained after 24 h using mass spectrometry analyses correlates well with biodistribution data obtained using IVIS® Spectrum in vivo imaging of nanoparticles labeled with the fluorescent substance NR668, indicating that these data also are representative for the nanoparticle distribution. Furthermore, immunohistochemistry was used to estimate infiltration of macrophages into the tumor tissue following injection of nanoparticle-encapsulated and free cabazitaxel. The higher infiltration of anti-tumorigenic versus pro-tumorigenic macrophages in tumors treated with the nanoparticles might also contribute to the improved effect obtained with the nanoparticle-encapsulated drug. Tumor infiltration of pro-tumorigenic macrophages was four times lower when using nanoparticles containing cabazitaxel than when using particles without drug, and we speculate that the very good therapeutic efficacy obtained with our cabazitaxel-containing particles may be due to their ability to reduce the level of pro-tumorigenic macrophages in the tumor. In summary, encapsulation of cabazitaxel in poly(2-ethyl-butyl cyanoacrylate) nanoparticles seems promising for treatment of breast cancer.

• Mariathasan, Anthony Burton; Pedersen, Kjetil Boye; Giercksky, Karl-Erik; Brennhovd, Bjørn; Gullestad, Hans Petter & Emblemsvåg, Hanne-Line [Vis alle 10 forfattere av denne artikkelen] (2018). Beyond total mesorectal excision in locally advanced rectal cancer with organ or pelvic side-wall involvement. European Journal of Surgical Oncology. ISSN 0748-7983. 44(8), s. 1226–1232. doi: 10.1016/j.ejso.2018.03.029. Fulltekst i vitenarkiv
• Kalanxhi, Ert; Meltzer, Sebastian; Schou, Jakob Vasehus; Larsen, Finn Ole; Dueland, Svein & Flatmark, Kjersti [Vis alle 12 forfattere av denne artikkelen] (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), s. 1322–1328. doi: 10.1038/s41416-018-0085-y. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 12 forfattere av denne artikkelen] (2018). Markers of mitochondrial metabolism in tumor hypoxia, systemic inflammation, and adverse outcome of rectal cancer. Translational Oncology. ISSN 1944-7124. 12(1), s. 76–83. doi: 10.1016/j.tranon.2018.09.010. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Spasojevic, Milan; Mariathasan, Anthony Burton; Goscinski, Mariusz Adam; Thorgersen, Ebbe Billmann; Solbakken, Arne Mide & Gullestad, Hans Petter [Vis alle 9 forfattere av denne artikkelen] (2018). Vertical Rectus Abdominis Musculocutaneous Flap Repair Improves Perineal Wound Healing after Abdominoperineal Resection for Irradiated Locally Advanced Rectal Cancer. Annals of Surgical Oncology. ISSN 1068-9265. 25(5), s. 1357–1365. doi: 10.1245/s10434-018-6363-3. Fulltekst i vitenarkiv
• Fretland, Åsmund Avdem; Dagenborg, Vegar Johansen; Bjørnelv, Gudrun Maria Waaler; Kazaryan, Airazat M.; Kristiansen, Ronny & Fagerland, Morten [Vis alle 17 forfattere av denne artikkelen] (2018). Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO-COMET Randomized Controlled Trial. Annals of Surgery. ISSN 0003-4932. 267(2), s. 199–207. doi: 10.1097/SLA.0000000000002353. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To perform the first randomized controlled trial to compare laparoscopic and open liver resection. Summary Background Data: Laparoscopic liver resection is increasingly used for the surgical treatment of liver tumors.However, high-level evidence to conclude that laparoscopic liver resection is superior to open liver resection is lacking. Methods: Explanatory, assessor-blinded, single center, randomized superiority trial recruiting patients from Oslo University Hospital, Oslo, Norway from February 2012 to January 2016. A total of 280 patients with resectable liver metastases from colorectal cancer were randomly assigned to undergo laparoscopic (n ¼ 133) or open (n ¼ 147) parenchyma-sparing liver resection. The primary outcome was postoperative complications within 30 days (Accordion grade 2 or higher). Secondary outcomes included cost-effectiveness, postoperative hospital stay, blood loss, operation time, and resection margins. Results: The postoperative complication rate was 19% in the laparoscopicsurgery group and 31% in the open-surgery group (12 percentage points difference [95% confidence interval 1.67–21.8; P ¼ 0.021]). The postoperative hospital stay was shorter for laparoscopic surgery (53 vs 96 hours, P < 0.001), whereas there were no differences in blood loss, operation time, and resection margins. Mortality at 90 days did not differ significantly from the laparoscopic group (0 patients) to the open group (1 patient). In a 4-month perspective, the costs were equal, whereas patients in the laparoscopicsurgery group gained 0.011 quality-adjusted life years compared to patients in the open-surgery group (P ¼ 0.001). Conclusions: In patients undergoing parenchyma-sparing liver resection for colorectal metastases, laparoscopic surgery was associated with significantly less postoperative complications compared to open surgery. Laparoscopic resection was cost-effective compared to open resection with a 67% probability. The rate of free resection margins was the same in both groups. Our results support the continued implementation of laparoscopic liver resection. Keywords: colorectal liver metastases, cost and cost analysis, hepatectomy, laparoscopic, laparoscopy, liver resection, minimally invasive surgery, parenchyma-sparing liver surgery, randomized clinical trial, randomized controlled trial

• Graudenzi, Alex; Cava, Claudia; Bertoli, Gloria; Fromm, Bastian; Flatmark, Kjersti & Mauri, Giancarlo [Vis alle 7 forfattere av denne artikkelen] (2017). Pathway-based classification of breast cancer subtypes. Frontiers in Bioscience. ISSN 1093-9946. 22(10), s. 1697–1712. Fulltekst i vitenarkiv
• Fleten, Karianne Giller; Bakke, Kine Mari; Mælandsmo, Gunhild; Abildgaard, Andreas; Redalen, Kathrine Røe & Flatmark, Kjersti (2017). Use of non-invasive imaging to monitor response to aflibercept treatment in murine models of colorectal cancer liver metastases. Clinical and Experimental Metastasis. ISSN 0262-0898. 34(1), s. 51–62. doi: 10.1007/s10585-016-9829-3. Fulltekst i vitenarkiv
• Østrup, Olga; Dagenborg, Vegar Johansen; Rødland, Einar Andreas; Skarpeteig, Veronica; Silwal-Pandit, Laxmi & Grzyb, Krzysztof [Vis alle 14 forfattere av denne artikkelen] (2017). Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. OncoTarget. 8(44), s. 76290–76304. doi: 10.18632/oncotarget.19350. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Thorgersen, Ebbe Billmann; Goscinski, Mariusz Adam; Spasojevic, Milan; Solbakken, Arne Mide; Mariathasan, Anthony Burton & Pedersen, Kjetil Boye [Vis alle 8 forfattere av denne artikkelen] (2017). Deep Pelvic Surgical Site Infection After Radiotherapy and Surgery for Locally Advanced Rectal Cancer. Annals of Surgical Oncology. ISSN 1068-9265. 24(3), s. 721–728. doi: 10.1245/s10434-016-5621-5. Fulltekst i vitenarkiv
• Karlsen, Karine Flem; Tekle, Christina; Andersson, Yvonne; Flatmark, Kjersti; Fodstad, Øystein & Nunes-Xavier, Caroline Elisabeth (2017). Immunoregulatory protein B7-H3 promotes growth and decreases sensitivity to therapy in metastatic melanoma cells. Pigment Cell & Melanoma Research. ISSN 1755-1471. 30(5), s. 467–476. doi: 10.1111/pcmr.12599. Fulltekst i vitenarkiv Vis sammendrag

  B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor). Similar effects were observed in melanoma cells in the presence of an inhibitory B7-H3 monoclonal antibody, while the opposite was seen in B7-H3-overexpressing cells. Further, combining B7-H3 inhibition with small-molecule inhibitors resulted in significantly increased antiproliferative effect in melanoma cells, as well as in BRAFV600E mutated cell lines derived from patient biopsies. Our findings indicate that targeting B7-H3 may be a novel alternative to improve current therapy of metastatic melanoma.

• Bakke, Kine Mari; Hole, Knut Håkon; Dueland, Svein; Kotanska-Grøholt, Krystyna; Flatmark, Kjersti & Ree, Anne Hansen [Vis alle 8 forfattere av denne artikkelen] (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), s. 813–818. doi: 10.1080/0284186X.2017.1287951. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 34 forfattere av denne artikkelen] (2017). Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate. ESMO Open. 2(2), s. 1–10. doi: 10.1136/esmoopen-2017-000158. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Frøysnes, Ida Storhaug; Andersson, Yvonne; Larsen, Stein Gunnar; Davidson, Ben; Øien, Janne-Merete & Olsen, Kari Hauge [Vis alle 11 forfattere av denne artikkelen] (2017). Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: results from the ImmunoPeCa Phase 1 Trial. Annals of Surgical Oncology. ISSN 1068-9265. 24(7), s. 1916–1922. doi: 10.1245/s10434-017-5814-6. Fulltekst i vitenarkiv
• Øverbye, Anders; Holsæter, Ann Mari; Fusser, Markus; Skalko-Basnet, Natasa; Iversen, Tore Geir & Torgersen, Maria Lyngaas [Vis alle 12 forfattere av denne artikkelen] (2017). Ceramide-containing liposomes with doxorubicin: time and cell-dependent effect of C6 and C12 ceramide. OncoTarget. 8(44), s. 76921–76934. doi: 10.18632/oncotarget.20217. Fulltekst i vitenarkiv Vis sammendrag

  Doxorubicin, a widely used chemotherapeutic drug, has several potential high- risk side effects including cardiomyopathy. Furthermore, cellular resistance to this drug develops with time. By using liposomes as carrier vesicles both the side effects and drug resistance might be avoided. In this study we have investigated the cytotoxic effect of doxorubicin encapsulated in liposomes with and without ceramides containing 6 or 12 carbon atoms in the N-amidated fatty acyl chains. The short-chain ceramide species were included in the liposomal compositions due to their pro-apoptotic properties, which might cause a synergistic anticancer effect. We demonstrate that the ceramide species enhance the liposomal doxorubicin toxicity in a cell-specific manner. The C6-ceramide effect is most pronounced in cervical cancer cells (HeLa) and colon cancer cells (HCT116), whereas the C12-ceramide effect is strongest in breast cancer cells (MDA-MB-231). Moreover, the study reveals the importance of investigating cell toxicity at several time points and in different cell-lines, to assess drug-and formulation-induced cytotoxic effects in vitro . Furthermore, our data show that the cytotoxicity obtained with the nanocarriers in vitro , does not necessarily reflect their ability to inhibit tumor growth in vivo . We speculate that the larger effect of Caelyx® than our liposomes in vivo is due to a greater in vivo stability of Caelyx®.

• Kalanxhi, Ert; Risberg, Karianne; Barua, Imon Shoumitra; Dueland, Svein; Waagene, Stein & Andersen, Solveig Norheim [Vis alle 11 forfattere av denne artikkelen] (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), s. 374–386. doi: 10.4143/crt.2016.080. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Andersson, Yvonne; Ihler, Synne; Davidson, Ben; Dørum, Anne; Fleten, Karianne Giller & Fodstad, Øystein [Vis alle 7 forfattere av denne artikkelen] (2017). MOC31PE immunotoxin - targeting peritoneal metastasis from epithelial ovarian cancer. OncoTarget. 8(37), s. 61800–61809. doi: 10.18632/oncotarget.18694. Fulltekst i vitenarkiv
• Pedersen, Kjetil Boye; Jacob, Havjin; Frikstad, Kari-Anne; Nesland, Jahn M; Mælandsmo, Gunhild & Dahl, Olav [Vis alle 8 forfattere av denne artikkelen] (2016). Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy. Cancer Medicine. 5(8), s. 1840–1849. doi: 10.1002/cam4.766. Fulltekst i vitenarkiv Vis sammendrag

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

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• Andersson, Yvonne Gerd; Løvstakken, Emil; Herud, Theodor Malmer; Waagene, Stein; Flatmark, Kjersti & Fleten, Karianne Giller (2025). ASO Visual Abstract: Intraperitoneal Perfusion with Cisplatin or Mitomycin C Improves Survival in Mice Bearing Peritoneal Metastases from Ovarian Cancer. Annals of Surgical Oncology. ISSN 1068-9265. doi: 10.1245/s10434-025-18467-3. Fulltekst i vitenarkiv
• Mørch, Yrr Asbjörg; Åslund, Andreas K. O.; Hyldbakk, Astrid; Snipstad, Sofie; Fleten, Karianne Giller & Flatmark, Kjersti [Vis alle 8 forfattere av denne artikkelen] (2023). NaDeNo – Unleashing the potential of hard-to-deliver drugs. Fulltekst i vitenarkiv
• Fusser, Markus; Øverbye, Anders; Pandya, Abhilash D.; Mørch, Ýrr Asbjørg; Borgos, Sven Even F. & Kildal, Wanja [Vis alle 16 forfattere av denne artikkelen] (2022). Corrigendum to “Cabazitaxel-loaded Poly(2-ethylbutyl cyanoacrylate) nanoparticles improve treatment efficacy in a patient derived breast cancer xenograft”, [Journal of Control Release, 293 (2019) 183–192, (Journal of Control Release, (2019) 293(183-192) (S0168365918306928), (10.1016/j.jconrel.2018.11.029)). Journal of Controlled Release. ISSN 0168-3659. 349, s. 1–1. doi: 10.1016/j.jconrel.2022.06.040. Fulltekst i vitenarkiv
• Mørch, Yrr Asbjörg; Åslund, Andreas; Hyldbakk, Astrid; Snipstad, Sofie; Fleten, Karianne Giller & Flatmark, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2022). NaDeNo – Unleashing the potential of hard-to-deliver drugs. Fulltekst i vitenarkiv
• Hyldbakk, Astrid; Fleten, Karianne Giller; Flatmark, Kjersti; Åslund, Andreas; Snipstad, Sofie & Borgos, Sven Even F. [Vis alle 7 forfattere av denne artikkelen] (2022). The in vivo fate of poly(alkyl cyanoacrylate) (PACA) nanoparticles and their payload. Fulltekst i vitenarkiv
• Hyldbakk, Astrid; Fleten, Karianne Giller; Snipstad, Sofie; Åslund, Andreas; Davies, Ruth Catharina de Lange & Flatmark, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2022). ENPERITO: polymeric nanoparticles for treatment of peritoneal metastases - a toxicity, biodstribution and efficacy study. Fulltekst i vitenarkiv
• Meltzer, Sebastian; Negård, Anne; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva & Guren, Marianne Grønlie [Vis alle 9 forfattere av denne artikkelen] (2022). Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). Fulltekst i vitenarkiv
• Fleten, Karianne Giller; Flatmark, Kjersti; Åslund, Karl Olof Andreas; Snipstad, Sofie; Borgos, Sven Even F. & Mørch, Yrr Asbjörg (2022). The in vivo fate of poly(alkyl cyanoacrylate) (PACA) nanoparticles and their payload. Fulltekst i vitenarkiv
• Knuth, Franziska Hanna; Adde, Ingvild Askim; Huynh, Bao Ngoc; Grøndahl, Aurora Rosvoll; Winter, René & Negård, Anne [Vis alle 15 forfattere av denne artikkelen] (2021). MRI-based automatic segmentation of rectal cancer using 2D U-Net on two independent cohorts. Fulltekst i vitenarkiv
• Ree, Anne Hansen; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva; Guren, Marianne Grønlie & Sørbye, Halfdan [Vis alle 10 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv
• Aghayan, Davit; Dagenborg, Vegar Johansen; Grzyb, Krzysztof; Fretland, Åsmund Avdem; Kazaryan, Airazat & Yaqub, Sheraz [Vis alle 8 forfattere av denne artikkelen] (2021). Histopathologic Growth Patterns of Colorectal Liver Metastases for Predicting Survival after Liver Resection: Data from the OSLO-COMET RCT. HPB. ISSN 1365-182X. doi: 10.1016/j.hpb.2020.11.040. Fulltekst i vitenarkiv
• Sørensen, Olaf; Andersen, Anders Mikal; Larsen, Stein Gunnar; Giercksky, Karl-Erik & Flatmark, Kjersti (2021). Correction to: Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of highgrade pseudomyxoma peritonei (Clinical & Experimental Metastasis, (2019), 36, 6, (511-518), 10.1007/s10585-019-09991-0). Clinical and Experimental Metastasis. ISSN 0262-0898. 38(2), s. 253–253. doi: 10.1007/s10585-021-10084-0. Fulltekst i vitenarkiv
• Hyldbakk, Astrid; Fleten, Karianne Giller; Snipstad, Sofie; Åslund, Andreas; Folkesson, Evelina & Flatmark, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2021). ENPERITO: Polymeric nanoparticles for treatment of peritoneal metastases. Fulltekst i vitenarkiv
• Fromm, Bastian; Domanska, Diana; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing & Aparicio-Puerta, Ernesto [Vis alle 13 forfattere av denne artikkelen] (2020). Erratum: MirGeneDB 2.0: The metazoan microRNA complement (Nucleic Acids Research (2019) DOI: 10.1093/nar/gkz885). Nucleic Acids Research (NAR). ISSN 0305-1048. 48(1), s. D1172–D1172. doi: 10.1093/nar/gkz1016. Fulltekst i vitenarkiv
• Meltzer, Sebastian; Redalen, Kathrine; Dueland, Svein; Kristensen, Annette Torgunrud; Solbakken, Arne Mide & Flatmark, Kjersti [Vis alle 7 forfattere av denne artikkelen] (2019). Circulating angiogenic factors predict metastatic liver progression in rectal cancer patients given curative-intent oxaliplatin-containing neoadjuvant therapy. Fulltekst i vitenarkiv
• Meltzer, Sebastian; Bakke, Kine Mari; Rød, Karina Lund; Dueland, Svein; Flatmark, Kjersti & Kristensen, Annette Torgunrud [Vis alle 12 forfattere av denne artikkelen] (2019). Gender disparities in outcome after neoadjuvant chemoradiotherapy for locally advanced rectal cancer are associated with hemodynamic differences. Fulltekst i vitenarkiv
• Bakke, Kine Mari; Hole, Knut Håkon; Dueland, Svein; Grøholt, Krystyna Kotanska; Ree, Anne Hansen & Flatmark, Kjersti [Vis alle 8 forfattere av denne artikkelen] (2017). Diffusion-weighted MRI of rectal cancer: baseline tumour perfusion fraction predicts chemoradiotherapy response and survival. Fulltekst i vitenarkiv
• Bousquet, Paula; Meltzer, Sebastian; Sønstevold, Linda; Esbensen, Qin Ying; Lyckander, Lars Gustav & Dueland, Svein [Vis alle 10 forfattere av denne artikkelen] (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, s. 1782–1782. doi: 10.1158/1538-7445.AM2017-1782. Fulltekst i vitenarkiv
• Goscinski, Mariusz Adam; Hole, Knut Håkon; Tønne, Elin; Ryder, Truls; Kotanska-Grøholt, Krystyna & Flatmark, Kjersti (2016). Fibromatosis in vertical rectus abdominis myocutaneous flap imitating tumor recurrence after surgery for locally advanced rectal cancer: case report. World Journal of Surgical Oncology (WJSO). 14(63). doi: 10.1186/s12957-016-0818-4. Fulltekst i vitenarkiv

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