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

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

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

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

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

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

Colorectal cancer commonly metastasizes into multiple liver foci, but intermetastatic heterogeneity remains poorly described. Here, we demonstrate that mutations of RAS/BRAF/TP53 are homogeneous within patients, while DNA copy number aberrations can vary greatly. RAS/BRAF/TP53 co‐mutations conferred a dismal prognosis, and co‐mutations combined with a high burden and heterogeneity of copy number aberrations identified patients with the poorest outcome., Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAF V600, and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high‐level amplifications of cancer‐critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAF V600E and TP53 co‐mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome‐wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAF V600E/TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co‐mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, P = 0.013; co‐mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co‐mutated RAS/BRAF V600E/TP53.

Background Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. Methods More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. Findings 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72–5·43; p

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

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

Background Colorectal cancer (CRC) is prevalent in the older population, and surgery is the mainstay in curative treatment. A preoperative geriatric assessment (GA) can identify frail older patients at risk for developing postoperative complications. In this randomised controlled trial we wanted to investigate whether tailored interventions based on a preoperative GA could reduce the frequency of postoperative complications in frail patients operated for CRC. Methods Patients >65 years scheduled for elective CRC surgery and fulfilling predefined criteria for frailty were randomised to either a preoperative GA followed by a tailored intervention, or care as usual. Primary endpoint was postoperative complications grade II-V. Secondary endpoints included complications of any grade, reoperation, length of stay, readmittance and survival. Results 122 patients with a mean age of 78.6 years were randomised. We found no statistically significant differences between the intervention group and the control group for grade II-V complications (68% vs 75%, p=0.43), reoperation (19% vs 11%, p=0.24), length of stay (8 days in both groups), readmittance (16% vs 6%, p=0.12) or 30-day survival (4% vs 5%, p=0.79). Complications grade I-V occurred in 76% of intervention group patients compared to 87% in the control group (p=0.10). In secondary analyses adjusting for prespecified prognostic factors, there was a statistically significant difference in favour of the intervention for reducing the total number of grade I-V complications (p=0.05). Conclusion A preoperative GA and tailored interventions did not reduce the rate of complications grade II-V, reoperations, readmittance or mortality in frail older patients electively operated for CRC. This article is protected by copyright. All rights reserved.

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

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5-markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni- and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (

Objective: Older patients with cancer value functional outcomes as much as survival, but surgical studies lack functional recovery (FR) data. The value of a standardized frailty assessment has been confirmed, yet it's infrequently utilized due to time restrictions into everyday practice. The multicenter GOSAFE study was designed to (1) evaluate the trajectory of patients' quality of life (QoL) after cancer surgery (2) assess baseline frailty indicators in unselected patients (3) clarify the most relevant tools in predicting FR and clinical outcomes. This is a report of the study design and baseline patient evaluations. Materials & Methods: GOSAFE prospectively collected a baseline multidimensional evaluation before major elective surgery in patients (≥70 years) from 26 international units. Short−/mid−/long-term surgical outcomes were recorded with QoL and FR data. Results: 1003 patients were enrolled in a 26-month span. Complete baseline data were available for 977(97.4%). Median age was 78 years (range 70–94); 52.8% males. 968(99%) lived at home, 51.6% without caregiver. 54.4% had ≥ 3 medications, 5.9% none. Patients were dependent (ADL < 5) in 7.9% of the cases. Frailty was either detected by G8 ≤ 14(68.4%), fTRST ≥ 2(37.4%), TUG > 20 s (5.2%) or ASAIII-IV (48.8%). Major comorbidities (CACI > 6) were detected in 36%; 20.9% of patients had cognitive impairment according to Mini-Cog. Conclusion: The GOSAFE showed that frailty is frequent in older patients undergoing cancer surgery. QoL and FR, for the first time, are going to be primary outcomes of a real-life observational study. The crucial role of frailty assessment is going to be addressed in the ability to predict postoperative outcomes and to correlate with QoL and FR.

Structured Abstract Background The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF and PIK3CA, as well as their prognostic impact. Materials and Methods We analyzed mutation status among 371 liver metastases and 78 primary tumors from 106 patients by several methods used in clinical routine testing, Sanger sequencing, next-generation sequencing (NGS) and/or droplet digital PCR. Three-year cancer-specific survival (3y-CSS) was analyzed with the Kaplan-Meier method. Results Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14/96 patients (15%), almost all cases were refuted by high-sensitive NGS, and heterogeneity among metastatic deposits were concluded only for PIK3CA in two patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8/78 patients (10%) using Sanger sequencing, but concluded for only two patients after NGS, showing the emergence of one KRAS and one PIK3CA mutation in the metastatic lesions. In total, KRAS mutations were present in 53/106 patients (50%) and associated with a poorer 3y-CSS after liver resection (37% versus 61% for KRAS wild type; p=0.004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations in comparison with triple wild type (p=0.002). Conclusion Intra-patient mutation heterogeneity was virtually non-detected, neither between the primary tumor and liver metastases, nor among metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with a poor patient survival after partial liver resection.

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

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

Treatment of early stage rectal cancer has excellent oncological results. To reduce treatment-related mortality and morbidity and improve functional results, a focus on local resections is increasingly important.The purpose of this study was to compare outcomes after transanal endoscopic microsurgery and total mesorectal excision for early stage rectal cancer (T1 + T2) in Norway.This was an observational study based on prospective data from the Norwegian Colorectal Cancer Registry.The study was conducted as a national, population-based study.All 543 patients with T1 and 1593 patients with T2 rectal cancer without distant metastases that was treated by transanal endoscopic microsurgery or total mesorectal excision without radiochemotherapy during 2000-2009 were included.The primary outcomes were 5-year relative survival and 5-year local recurrence rate.Among 543 patients with T1 cancer, the 5-year overall survival rate was 65.3% after transanal endoscopic microsurgery versus 81.5% after total mesorectal excision (p = 0.012). Adjusted for age and sex there was no excess mortality for transanal endoscopic microsurgery (HR = 1.28 (95% CI, 0.8-1.9); p = 0.22). The 5-year relative survival rate was 96.8% after transanal endoscopic microsurgery versus 98.2% after total mesorectal excision (p = 0.603), and the 5-year local recurrence rate was 14.5% versus 1.4% (p0.001). Among 1593 patients with T2 cancer, 5-year overall survival was 42.1% versus 76.1% (p0.001), 5-year relative survival was 65.4% versus 93.9% (p0.001), and 5 year local recurrence rate was 11.4% versus 4.4% in the 2 groups.The study is limited by its observational design and that the 2 groups were different according to patient and tumor characteristics. Another limitation was the low number of transanal endoscopic microsurgery procedures.Transanal endoscopic microsurgery had comparable 5-year relative survival to total mesorectal excision in T1 rectal cancer but inferior 5-year relative survival in T2 rectal cancer. Transanal endoscopic microsurgery was associated with higher local recurrence rates for both T1 and T2 tumors.

Stent treatment of large bowel obstruction is still controversial. There are concerns regarding complications, particularly bowel perforation, as well as long-term outcome in curable patients. Through a 10-year retrospective study, we have evaluated efficacy, complications, delay in surgical interventions and stent patency in cases of palliative treatment. We treated 183 patients, 85 as bridge to surgery and 98 as definitive, palliative treatment. At presentation, 58 % of patients had advanced local or metastatic disease. Seventeen patients required more than one stent insertion. The total number of procedures was 213. We recorded technical and clinical success or failure, complications, necessity of restenting or surgical intervention, mortality and stent patency in the palliation group. Stenting was clinically successful in 89 % of the bridge to surgery group and 86 % of the palliative group. Complications occurred in 7 %, including 12 perforations. Six patients suffered an early perforation, of which two died. Half of the six late perforations were silent. Procedure related mortality was 1 %. The clinical success rate was high in both the palliative and bridge to surgery setting. The complication rate was low, and the sum of early and late perforations was 5.6 %. Procedure related mortality was low.

BACKGROUND: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.METHODS: We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.FINDINGS: Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; pINTERPRETATION: POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.FUNDING: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Patients with metastatic colorectal cancer (CRC) have few targeted treatment options compared with other major malignancies, and both over- and undertreatment with cytostatic drugs remain a challenge. Recent studies show that patient-derived organoids (PDOs) can predict clinical responses to systemic therapies in a personalized manner, but tumor heterogeneity may limit the clinical benefit of anticancer therapies, as well as the accuracy of preclinical predictions. PDO lineage establishment from multiple distinct lesions per patient presents a novel opportunity for preclinical investigation of intrapatient pharmacotranscriptomic heterogeneity. From September 2017 until November 2019, we have established a living biobank of 107 PDOs from 53 patients who underwent resection of CRC liver metastases at Oslo University Hospital, Norway, 31 of whom had multiple (2-5) metastases. All PDOs were screened for sensitivity to 40 anticancer agents, including clinically relevant targeted drugs and conventional chemotherapies. Molecular profiling by gene expression and mutation analyses is ongoing and currently completed for 27 PDOs. Recapitulation of known pharmacogenomic/transcriptomic associations was confirmed in PDOs for EGFR inhibition and RAS/BRAFV600E mutation status, as well as TP53-MDM2 inhibition and TP53 mutation status and TP53 transcriptional activity. Antimetabolites such as gemcitabine and methotrexate, or small-molecule inhibitors in late-stage clinical development targeting Aurora A, PLK1, and HSP90, showed strong differential activities, enabling identification of sensitive subgroups. Strong sensitivity to HSP90 inhibition was associated with low protein expression of Heat Shock Transcription Factor 1, which had a homogenous intrapatient intermetastatic expression pattern. Principal component analyses revealed a clear patient-wise separation of PDOs based on both their pharmacologic and transcriptomic profiles separately, indicating only modest intrapatient heterogeneity among distinct metastatic lesions. Accurate prediction of clinical responses to 5-FU and oxaliplatin was shown in PDOs from one patient treated for recurrent liver metastases. Additionally, PDOs from recurrent liver metastases showed an increased sensitivity to off-label drugs compared to PDOs from the first liver resection, supporting therapy repurposing in later lines of treatment. In summary, patient-derived models of CRC liver metastases reveal modest intrapatient pharmacotranscriptomic heterogeneity—an encouraging result for further efforts to develop personalized drug repurposing strategies for this poor-prognosis patient group. Citation Format: Kushtrim Kryeziu, Jarle Bruun, Peter W. Eide, Seyed H. Moosavi, Ina A. Eilertsen, Jonas Langerud, Bård Røsok, Tuva H. Brunsell, Marianne G. Guren, Andreas Abildgaard, Arild Nesbakken, Bjørn Atle Bjørnbeth, Anita Sveen, Ragnhild A. Lothe. Modeling intrapatient pharmacotranscriptomic heterogeneity with organoids derived from colorectal cancer liver metastases [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A19.

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

Background The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression–based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods Totally 1197 primary tumors from a Norwegian series of CRC stage I–IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results BRAF V600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P

Background We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13–2.77) and HR = 2.95 (95% CI: 1.73–5.03), P Conclusion A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.

We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early-stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF. This work was financially supported by the Cancer Clinic, Oslo University Hospital (Grant No.: 2017-19 supporting JB with researcher fellowship), the Norwegian Cancer Society (Grant No.: 182759-2016, to RAL; and Grant No.: 6824048-2016, to AS), the foundation K. G. Jebsen Colorectal Cancer Research Centre, Stiftelsen Kristian Gerhard Jebsen, the South-Eastern Health Regional Authorities of Norway, and the Research Council of Norway, in cooperation with the University of Oslo, through the ?Toppforsk? grant (RAL, Project Number 250993/F20). This work was financially supported by the projects NORTE-01-0145-FEDER-000029 and NORTE-01-0145-FEDER-000003, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was also supported by FEDER?Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020?Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT?Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Inova??o in the framework of the project ?Institute for Research and Innovation in Health Sciences? (POCI-01-0145-FEDER-007274). RB acknowledges FCT for financial support (SFRH/BPD/68276/2010).

Altres ajuts: This work was partially supported by grant UM1 CA167551 from the National Cancer Institute (NCI), National Institutes of Health (NIH), and through cooperative agreements with members of the Colon Cancer Family Registry (CCFR) and Principal Investigators. Centers contributing to this analysis include the Seattle Colorectal Cancer Family Registry (U01/U24CA074794), Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800), and Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783). This work was also supported by NCI/NIH grant K07CA172298 and K05CA152715 (to AIP). The content of this article does not necessarily reflect the views or policies of the NIH or any of the collaborating centers in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This study was partly supported by the "Norwegian Cancer Society" and the "Research Council of Norway" (no grants apply). TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation. After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782). TNM staging, MSI and BRAF V600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R 2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively. Incorporation of MSI, BRAF V600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

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

Gastrointestinal cancers include malignancies arising in the esophagus, liver and bile ducts, gallbladder, pancreas, stomach, small intestine, colon and rectum. Their incidence and mortality differ significantly, however, together they account for approximately one-fifth of the cancer incidence and nearly one-fourth of the cancer related deaths in the US.1 Colorectal and gastric cancers are the most common gastrointestinal tumors worldwide, accounting for ∼2.2 million new cases and an estimated 1.3 million deaths annually.2 When these malignancies are detected at an early, localized stage, the 5-year survival is 90% and 63%, respectively.3 However, more than 60% of the patients with colorectal cancer and 75% of the patients with gastric cancer have regional or distant metastases at the time of diagnosis, resulting in a significant drop in survival.3 Cholangiocarinoma and pancreatic cancer are less prevalent.2,4 However, these malignancies are often “clinically silent” and thus diagnosed at an advanced stage with a corresponding poor prognosis.2,4 Early detection, particularly of colorectal and gastric cancer, may significantly reduce the number of gastrointestinal cancer deaths, and identification of suitable biomarkers for this purpose is therefore warranted. In humans, DNA methylation occurs predominantly at the 5′ position of cytosine, within CpG dinucleotides. Approximately 70% of the human genes have a CpG island—an enrichment of such dinucleotides—in the promoter region.5 In normal cells these islands are usually unmethylated, but several of them become hypermethylated in cancer and this is associated with repressed or lost gene expression.6 Using genome-wide analyzes, DNA methylation was recently shown to be more frequent than genetic changes in colorectal cancer.7 In addition to being frequent, aberrant DNA methylation has been shown to be an early event in tumorigenesis.8 Finally, several examples of genes with promoter DNA hypermethylation have been detected in various bodily fluids from cancer patients, including bile, feces, plasma and urine,9–13 indicating that methylation biomarkers may be useful for non- or minimally invasive cancer diagnostics. Although cancer is a highly heterogeneous disease, comprising more than 200 different conditions, it is believed that tumors arising in the gastrointestinal tract share several molecular alterations. Gut derived adenocarcinomas have indeed been found to display similar copy-number changes, forming tissue-specific clusters when various cancer types were clustered according to amplification activated oncogenes.14,15 Gastrointestinal tumors further show extremely high frequencies of transition mutations at CpG dinucleotides,16 and several genes, including APC, MLH1, MGMT, p16INK4a, CDH1, SFRP1, RASSF1A and VIM have been shown to be epigenetically dysregulated across malignancies of the gastrointestinal tract.17–21 With increased focus on cross-tumor analysis, exemplified by The Cancer Genome Atlas (TCGA) Pan-Cancer project, more shared abnormalities among the gastrointestinal cancers are expected to be uncovered. In the present study we have investigated whether the recently identified methylation biomarkers for cholangiocarcinoma (CDO1, DCLK1, ZSCAN18 and SFRP1)22 were methylated also in other malignancies of the gastrointestinal tract. The promoter methylation frequency of these genes, in addition to ZNF331, previously shown to be methylated across several gastrointestinal cancer cell lines,22 was analyzed in tissue samples from colorectal-, gastric- and pancreatic cancer patients.

Colorectal cancer is a global health challenge with high incidence rate and mortality. The patients' prognosis is strongly associated with disease stage and currently there is a need for improved prognostic and predictive biomarkers. In this study, novel colorectal cancer-specific transcript structures were nominated from whole transcriptome sequencing of seven colorectal cancer cell lines, two primary colorectal carcinomas with corresponding normal colonic mucosa and 16 normal tissues. The nominated transcripts were combined with gene level outlier expression analyses in a cohort of 505 colorectal cancers to identify biomarkers with capacity to stratify colorectal cancer subgroups. The transcriptome sequencing data and outlier expression analysis revealed 11 novel colorectal cancer-specific exon-exon junctions, of which 3 were located in the gene VNN1. The junctions within VNN1 were further characterized using rapid amplification of cDNA ends (RACE) and the prevalence of the subsequently characterized novel transcript, VNN1-AB, was investigated by real-time RT-PCR in 291 samples of miscellaneous origins. VNN1-AB was not present in any of the 43 normal colorectal tissue samples investigated, but in 5 of the 6 polyps, and 102 of the 136 (75%) colorectal cancers. We have identified a novel transcript of the VNN1 gene, with an organ-confined complete specificity for colorectal neoplasia.

Objectives The number of older survivors from colorectal cancer is increasing, but little is known regarding long-term consequences of cancer treatment in this patient group. Physical function is an important outcome for older patients, affecting both autonomy and quality of life. We aimed to investigate physical function in older patients with colorectal cancer before and after surgery, and to examine the role of individual frailty indicators as predictors of functional decline. Material and Methods We present 16–28 months follow-up data of older patients after elective surgery for colorectal cancer. During a home-visit, physical function was evaluated by activities of daily living (ADL), instrumental activities of daily living (IADL), the timed up-and-go (TUG) test, and grip strength. Measurements were compared with those obtained preoperatively using the Wilcoxon signed rank test. Frailty indicators were dichotomized and implemented in logistic regression models to explore their associations to a decline in the physical function scores. Results Eighty-four patients were included and the median age was 82 years. There was a significant decrease in ADL (p = 0.04) and IADL scores (p ≤ 0.001) at follow-up. We found no associations between frailty indicators and the risk of decline in physical functioning. Conclusion In our population of older patients with surgically treated colorectal cancer, there was a significant decline in ADL- and IADL-scores at follow-up. No change was found in TUG or grip strength, and frailty indicators did not predict decline in physical function.

Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group.We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8In QUASAR2, intratumoural CD8The prognostic value of intratumoural CD8

Purpose: According to current recommendations for adjuvant treatment, patients with colon cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of relapse based on specific clinicopathological parameters. Following these criteria, it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but due to expected adverse effects and frailty, elderly patients are often excluded from standard protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear. In these two clinical settings, improved risk stratification has great potential impact on patient care, anticipating that high-risk patients will benefit from chemotherapy. However, microsatellite instability is the only molecular prognostic marker recommended for clinical use. Experimental Design: In this perspective, we provide an updated view on the status and clinical potential of the many proposed prognostic gene expression–based tests for colon cancer stage II and III. Results: The main limitation for clinical implementation is lack of prospective validation. For patients with stage II, highly promising tests have been identified and clinical trials are ongoing. For elderly patients with stage III, the value of such tests has received less focus, but promising early results have been shown. Conclusion: Although awaiting results from prospective trials, improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future. Clin Cancer Res; 19(24); 6669–77. ©2013 AACR.

Aim There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified 'liver-first' approach. Method This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short-term surgical outcome, overall survival and recurrence-free survival are reported. Results Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty-four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7-116) and 60 (range 31-156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien-Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence-free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent. Conclusion The modified liver-first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases.

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

Published version. Source at http://dx.doi.org/10.1002/cam4.766 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.

BACKGROUND: Microsatellite instability (MSI) was suggested as a marker for good prognosis in colorectal cancer in 1993 and a systematic review from 2005 and a meta-analysis from 2010 support the initial observation. We here assess the prognostic impact and prevalence of MSI in different stages in a consecutive, population-based series from a single hospital in Oslo, Norway. PATIENTS AND METHODS: Of 1274 patients, 952 underwent major resection of which 805 were included in analyses of MSI prevalence and 613 with complete resection in analyses of outcome. Formalin-fixed tumor tissue was used for PCR-based MSI analyses. RESULTS: The overall prevalence of MSI was 14%, highest in females (19%) and in proximal colon cancer (29%). Five-year relapse-free survival (5-year RFS) was 67% and 55% (P = 0.030) in patients with MSI and MSS tumors, respectively, with the hazard ratio (HR) equal to 1.60 (P = 0.045) in multivariate analysis. The improved outcome was confined to stage II patients who had 5-year RFS of 74% and 56% respectively (P = 0.010), HR = 2.02 (P = 0.040). Examination of 12 or more lymph nodes was significantly associated with proximal tumor location (P < 0.001). CONCLUSIONS: MSI has an independent positive prognostic impact on stage II colorectal cancer patients after complete resection.

Purpose: Improved prognostic stratification of patients with stage II and III colorectal cancer is warranted for postoperative clinical decision making. This study was conducted to develop a clinically feasible and robust prognostic classifier for these patients independent of adjuvant treatment. Experimental Design: Global gene expression profiles from altogether 387 stage II and III colorectal cancer tissue samples from three independent patient series were included in the study. ColoGuidePro, a seven-gene prognostic classifier, was developed from a selected Norwegian learning series (n = 95; no adjuvant treatment) using lasso-penalized multivariate survival modeling with cross-validation. Results: The expression signature significantly stratified patients in a consecutive Norwegian test series, in which patients were treated according to current standards [HR, 2.9 (1.1–7.5); P = 0.03; n = 77] and an external validation series [HR, 3.7 (2.0–6.8); P < 0.001; n = 215] according to survival. ColoGuidePro was also an independent predictor of prognosis in multivariate models including tumor stage in both series (HR, ≥3.1; P ≤ 0.03). In the validation series, which consisted of patients from other populations (United States and Australia), 5-year relapse-free survival was significantly predicted for stage III patients only (P < 0.001; n = 107). Here, prognostic stratification was independent of adjuvant treatment (P = 0.001). Conclusions: We present ColoGuidePro, a prognostic classifier developed for patients with stage II and III colorectal cancer. The test is suitable for transfer to clinical use and has best prognostic prediction potential for stage III patients. Clin Cancer Res; 18(21); 6001–10. ©2012 AACR.

An alternative transcript variant of SLC39A14, caused by pre-mRNA splicing, was recently suggested as a biomarker for colorectal cancer (CRC). In our study, we have validated the cancer-specific splicing pattern of the mutually exclusive exons 4A and 4B in altogether 244 colorectal tissue samples. Exon-specific quantitative RT-PCR analyses across 136 Stage I-IV CRC samples and 44 normal colonic mucosa samples showed complete cancer-specificity, as well as 94% sensitivity of SLC39A14-exon4B relative to SLC39A14-exon4A expression. However, across 20 samples from a range of healthy tissues, 18 expressed the CRC variant. This was true also for ten benign lymph nodes, demonstrating that the cancer-specificity is mainly confined to the colon and rectum. Hence, clinical use of SLC39A14-exon4B as a detection marker for CRC other than in samples taken from the bowel wall is diminished. Prognostic value by detection of metastasis to lymph nodes is also abated, elucidating an important pitfall to biomarker discovery. However, analyses of ten nondysplastic biopsies from patients with active inflammatory bowel disease showed negative results in seven samples and only weakly positive results in three samples, suggesting value of SLC39A14-exon4B as a marker to distinguish CRC from other pathologic conditions of the colon. In conclusion, the SLC39A14-exon4B transcript variant is a CRC biomarker with high sensitivity and organ-confined specificity. Further use of the transcript and its encoded protein isoform should be explored in an organ-confined context.

Background Measuring frailty in older adults with cancer may identify patients with an increased risk of treatment complications. As it remains controversial how to identify frailty, the aim of this study was to compare a pre-operative multi-domain frailty measure based on a comprehensive geriatric assessment (CGA) to a modified version of the physical phenotype of frailty (PF) in a cohort of older adults with colorectal cancer, and to analyze the ability of the two classifications to predict post-operative complications and survival. Methods A prospective longitudinal study including 176 patients aged 70–94years electively operated for colorectal cancer in three Norwegian hospitals. A pre-operative CGA, self-reported quality of life, and measurements of grip strength and gait speed were performed. CGA-frailty was defined as fulfilling one or more of the following criteria: dependency in activities of daily living, severe comorbidity, cognitive dysfunction, depression, malnutrition, or >seven daily medications. PF was defined with three or more of the following criteria: unintentional weight loss, exhaustion, low physical activity, impaired grip strength, or slow gait speed. Outcome measures were post-operative complications and survival. Results The agreement between the classifications was poor. CGA-frailty was identified in 75 (43%) patients, while PF was identified in 22 (13%) patients. Only CGA-frailty predicted post-operative complications [P=0.001]. Both measures predicted survival. Conclusions A multi-domain frailty measure based on a CGA was more useful than frailty identified from a modified version of the PF criteria in predicting post-operative complications. For overall survival, both frailty measures were predictive.

This article is the first to show that loss of connexin43 (Cx43) expression in colorectal tumors is correlated with significantly shorter relapse-free and overall survival. Cx43 was further found to negatively regulate growth of colon cancer cells, in part by enhancing apoptosis. In addition, Cx43 was found to colocalize with β-catenin and reduce Wnt signaling. The study represents the first evidence that Cx43 acts as a colorectal cancer tumor suppressor and that loss of Cx43 expression during colorectal cancer development is associated with reduced patient survival. The study has important implications for the assessment of Cx43 as a prognostic marker and target in colorectal cancer prevention and therapy. Gap junctions consist of intercellular channels that permit direct transfer of ions and small molecules between adjacent cells. The gap junction channel protein Cx43 plays important roles in cell growth control and differentiation and is frequently dysregulated in human cancers. However, the functional importance and clinical relevance of Cx43 in cancer development has remained elusive. Here, we show that Cx43 is downregulated or aberrantly localized in colon cancer cell lines and colorectal carcinomas, which is associated with loss of gap junction intercellular communication. The in situ protein expression of Cx43 was analyzed in colorectal tumors in a cohort of 674 patients and related to established clinicopathological variables and survival. A subgroup of the patients had weak or no expression of Cx43 in tumors. Loss of Cx43 expression was significantly correlated with shorter relapse-free and overall survival. Loss of Cx43 further identified a high-risk subgroup among stage I and stage II patients with reduced relapse-free and overall survival. Ectopic expression of Cx43 in the colon cancer cell line HT29 was associated with reduced growth in monolayer and soft agar cultures and in tumor xenografts. Cx43 was found to colocalize with β-catenin and negatively regulate the Wnt signaling pathway, and expression of Cx43 was associated with increased levels of apoptosis. Altogether, these data indicate that Cx43 is a colorectal cancer tumor suppressor protein that predicts clinical outcome.

Background and Objectives : The aim of the study was to evaluate the incidence of peritoneal carcinomatosis (PC) in a prospectively recorded series of colon cancer patients from a defined cohort and to compare clinicopathological characteristics, survival, and TP53 mutation status in primary tumors from patients with and without PC. Methods : Clinical data from all colon cancer patients admitted in 1993–2006 were registered prospectively (n = 1,124). In a subset of PC patients, DNA was retrieved from tumor tissue and TP53 mutations analyzed and compared to the mutation status in a historical series. Results : In the prospective series 10% of female and 7% of male patients had PC (P = 0.05). The PC patients were younger than those without PC (median 4 years, P = 0.002). The incidence of PC was 10.3% and 6.2% (P = 0.03) in patients with primary tumors in the right and left colon, respectively. TP53 was mutated in 57% of the PC patients as compared to 41% in the series of patients without PC (P = 0.05). Conclusions : The incidence of PC was higher in right-sided colon cancer and among women. PC patients were younger than non-PC patients, and PC was independently associated with TP53 mutation in the primary tumor. J. Surg. Oncol. © 2011 Wiley Periodicals, Inc.

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

Aim The study aimed to evaluate long-term health-related quality of life (HRQOL) and functional outcome in patients who had undergone restorative proctocolectomy with ileo-anal anastomosis (IPAA) for ulcerative colitis and familial adenomatous polyposis. Method A total of 156 patients who underwent IPAA during the period 1984–2003 and who still had an intact pouch were included. The HRQOL score was compared with 4152 individuals from the general Norwegian population using the SF-36 questionnaire, and function was evaluated using the Wexner Continence Grading Scale. Results One hundred and ten (71%) patients answered the questionnaires, 60 (55%) of whom were men. All except five patients had ulcerative colitis. Median (range) age at interview was 47 (19–66) years, and time after surgery was 12 (2–22) years. The IPAA patients scored slightly, but significantly, lower in four of six SF-36 health domains than the control subjects, adjusted for age and gender. Multiple regression analysis showed frequency of nocturnal defaecation, faecal incontinence and urgency to be independent negative prognostic factors of quality of life. Frequency of defaecation was a median of 7 (3–12) bowel movements during the day and 2 (0–6) at night. The majority had some degree of faecal incontinence, median (range) Wexner score of 8 (0–17), and 40% reported urgency of defaecation necessitating alterations in lifestyle. Conclusion Patients with IPAA reported slightly lower HRQOL rates than the general population and had an inferior functional outcome.

Objective To examine the association between the outcomes of a pre-operative comprehensive geriatric assessment (CGA) and the risk of severe post-operative complications in elderly patients electively operated for colorectal cancer. Methods One hundred seventy-eight consecutive patients ≥70 years electively operated for all stages of colorectal cancer were prospectively examined. A pre-operative CGA was performed, and patients were categorized as fit, intermediate, or frail. The main outcome measure was severe complications within 30 days of surgery. Results Twenty-one patients (12%) were categorized as fit, 81 (46%) as intermediate, and 76 (43%) as frail. Eighty-three patients experienced severe complications, including three deaths; 7/21 (33%) of fit patients, 29/81 (36%) of intermediate patients and 47/76 (62%) of frail patients (p = 0.002). Increasing age and ASA classification were not associated with complications in this series. Conclusion CGA can identify frail patients who have a significantly increased risk of severe complications after elective surgery for colorectal cancer.

Objectives To identify independent predictors of post-operative complications and early mortality in elderly patients operated for colorectal cancer from a comprehensive geriatric assessment [CGA] and Eastern Cooperative Oncology Group performance status [PS]. Patients and Methods Patients ≥ 70 years electively operated for all stages of colorectal cancer from 2006 to 2008 in three hospitals were consecutively included. CGA addressed the following domains pre-operatively: personal and instrumental activities of daily living [IADL], comorbidity, polypharmacy, nutrition, cognition, and depression. The associations between elements of CGA as well as PS and morbidity and mortality were analyzed using multivariate regression models. Results Patients (182) with a median age of 80 years (range, 70–94 years) were included. Severe comorbidity was an independent predictor of severe complications (odds ratio [OR] 5.62; 95% CI 2.18 to 14.50) and early mortality (hazard ratio [HR] 2.78; 95% CI 1.50 to 5.17). IADL-dependency and depression were predictors of any complication (OR 4.02; 95% CI 1.24 to 13.09 and OR 3.68; 95% CI 0.96 to 14.08, respectively) while impaired nutrition predicted early mortality (HR 2.39, 95% CI 1.24 to 4.61). When added to the models, PS independently predicted both morbidity and early mortality, and PS was a more powerful predictor than IADL-dependency, depression, and impaired nutrition. Conclusions In elderly patients with colorectal cancer, severe comorbidity, IADL-dependency, depression, and impaired nutrition seem to be the most important CGA-elements predictive of post-operative complications and early mortality. As PS predicts all outcomes, a consistent use of PS in studies of cancer surgery is recommended.

Major rectal resection for T1 rectal cancer offers more than 95% cancer specific five-year survival to patients surviving the first 30 days after surgery. A significant further improvement by development of the surgical technique may not be possible. Improvements in the total survival rate have to come from a more differentiated treatment modality, taking patient and procedure related risk factors into account. Subgroups of patients have operative mortality risks of 10% or more. Operative complications and long-term side effects after rectum resection are frequent and often severe.Local treatment of T1 cancers combined with close follow-up, early salvage surgery or later radical resection of local recurrences or with chemo-radiation may lead to fewer severe complications and comparable, or even better, long-term survival. Accurate preoperative staging and careful selection of patients for local or non-operative treatment are mandatory. As preoperative staging, at present, is not sufficiently accurate, strategies for completion, salvage or rescue surgery is important, and must be accepted by the patient before local treatment for cure is initiated.It is recommended that polyps with low-risk T1 cancers should be treated with endoscopic snare resection in case of Haggitt's stage 1 or 2. TEM is recommended if resection margins are uncertain after snare resection for Haggitt's stage 3 and 4, and for sessile and flat, low-risk T1 cancers. Average risk patients with high-risk T1 cancers should be offered rectum resection, but old and comorbid patients with high-risk T1 cancers should be treated individually according to objective criteria as age, physical performance as well as patient's preference. All patients treated for cure with local resection or non-surgical methods should be followed closely.

The Norwegian Rectal Cancer Project was initated in 1993 with the aims of improving surgery, decreasing local recurrence rates, improving survival, and establishing a national rectal cancer registry. Here we present results from the Norwegian Colorectal Cancer Registry (NCCR) from 1993 to 2010.A total of 15 193 patients were diagnosed with rectal cancer in Norway 1993-2010, and were registered with clinical data regarding diagnosis, treatment, locoregional recurrences and distant metastases. Of these, 10 796 with non-metastatic disease underwent tumour resection. The results were stratified into five time periods, and the treatment outcomes were compared. Recurrence rates are presented for the 9785 patients who underwent curative major resection (R0/R1).Among all 15 193 patients, relative five-year survival increased from 54.1% in 1993-1997 to 63.4% in 2007-2010 (p0.001). Among the 10 796 patients with stage I-III disease who underwent tumour resection, from 1993-1997 to 2007-2010, relative five-year survival improved from 71.2% to 80.6% (p0.001). An increasing proportion of these patients underwent surgery at large-volume hospitals; and 30- and 100-day mortality rates, respectively, decreased from 3.0% to 1.4% (p0.001) and from 5.1% to 3.0% (p0.011). Use of preoperative chemoradiotherapy increased from 6.5% in 1993 to 39.0% in 2010 (p0.001). Estimated local recurrence rate after major resection (R0/R1) decreased from 14.5% in 1993-1997 to 5.0% in 2007-2009 (p0.001), and distant recurrence rate decreased from 26.0% to 20.2% (p0.001).Long-term outcomes from a national population-based rectal cancer registry are presented. Improvements in rectal cancer treatment have led to decreased recurrence rates of 5% and increased survival on a national level.

Purpose: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis. Experimental Design: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903). Results: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5′ UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer. Conclusions: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. Clin Cancer Res; 21(16); 3759–70. ©2015 AACR.

Aims The aims of the study were (1) to evaluate quality of life (QoL) and functional outcome in patients following anterior resection (AR) or abdominoperineal resection (APR) for rectal cancer, and (2) whether these outcomes were dependent on the level of anastomosis. Methods Patients who were without recurrent or metastatic disease were identified from the Norwegian Rectal Cancer Registry. QoL was assessed by the EORTC questionnaires QLQ-C30 and QLQ-CR38, and rectal function by a short questionnaire. Of 319 patients studied, 229 had undergone AR and 90 APR. The median age was 73 years, and the median time since surgery was 64 months. Results Mean QoL scores for body image and male sexual problems were better following AR than APR (P