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Purpose: The aim of this study was to evaluate the anastomotic leakage (AL) rate and predictors for AL following minimally invasive restorative rectal resection (RRR) among rectal cancer patients managed according to up-to-date standardized treatment. Furthermore, we explored the impact of symptomatic AL on long-term survival. Methods: The study cohort was rectal cancer patients undergoing minimally invasive RRR in Central Denmark Region between 2013 and 2017. Data was retrieved from a prospective clinical quality database and supplemented with data from medical records. The AL rate was calculated as the proportion of patients who developed symptomatic AL within 30 days. Predictors for AL were identified through logistic regression. The impact of AL on long-term survival was analyzed using Kaplan–Meier methods and Cox regression. Results: AL occurred in 15.1% of 604 patients. The AL rate for males was 20.1% (95% CI 16.3–24.3) and 5.0% (95% CI 2.4–9.0) for females. Odds ratio (OR) of AL in females vs. males was 0.25 (95% CI 0.12–0.51). The use of at least three firings when transecting the rectum was associated with OR of 2.71 (95% CI 1.17–6.26) for AL. The 5-year survival for patients with vs. those without AL was 76.1% (95%CI 65.1–84.0) and 83.6% (95%CI 79.8–86.7), corresponding to adjusted hazard ratio of 1.43 (95%CI 0.84–2.41). Conclusion: Symptomatic AL is still a challenge in a standardized setting using minimally invasive surgery in rectal cancer patients undergoing RRR, especially in men. Multiple firings should be avoided in transection of the rectum with an endoscopic stapler. AL had a statistical non-significant negative impact on survival.

Supplementary Data from Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences

Purpose:Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.Experimental Design:We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.Results:Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.Conclusions:Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.See related commentary by Morris and George, p. 438

Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients.Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients.Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12-2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22-5.03) and Stage II (OR = 1.76, 95%CI: 1.11-2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44-1.53) patients.Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell. Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12–2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22–5.03) and Stage II (OR = 1.76, 95%CI: 1.11–2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44–1.53) patients. Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.

AIM: To 1) develop an assessment tool for laparoscopic complete mesocolic excision (LCME) and 2) report evidence of its content validity.METHOD: Assessment statements were revealed through 1) semi-structured expert interviews and 2) consensus by the Delphi method, both involving an expert panel of five LCME surgeons. All experts were interviewed and then asked to rate LCME describing statements from 1 (strongly disagree) to 5 (strongly agree). Responses were returned anonymously to the panel until consensus was reached. Statements were directly included as content in the assessment tool if ≥60% of the experts responded 'agree' or 'strongly agree' (ratings 4 and 5), with the remaining responses being 'neither agree nor disagree' (rating 3). Interclass correlation coefficient (ICC) was calculated for expert agreement evaluation. All included statements were subsequently reformulated as tool items and approved by the experts.RESULTS: Four Delphi rounds were performed to reach consensus. Disagreement was reported for statements describing instrument handling around pancreas; visualisation of landmarks before inferior mesenteric artery ligation; lymphadenectomy around the inferior mesenteric artery, and division of the terminal ileum and transverse colon. ICC in the last Delphi-round was 0.84. The final tool content included 73 statements, converted to 48 right- and 40 left-sided items for LCME assessment.CONCLUSION: A procedure-specific, video-based tool, named Complete Mesocolic Excision Competency Assessment Tool (CMECAT), has been developed for LCME skill assessment. In the future, we hope it can facilitate assessment of LCME surgeons, resulting in improved patient outcome after colon cancer surgery.

Objective and aims The primary aim of this study was to evaluate the correlation between incidental focal colorectal foci on fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) with colonoscopic and histopathological results. The secondary aim was to determine to what extent these findings led to a change in patient management. Materials and methods A retrospective study was performed among 5850 patients who had an FDG-PT/CT scan from July 2015 to July 2018. Among these patients, we identified patients with a PET/CT description of incidental colorectal FDG uptake, and a colonoscopy within 90 days from the PET/CT scan. PET/CT findings were compared with colonoscopy-detected lesions and eventually histopathology on a per-lesion analysis and a per-person analysis. Results A total of 145 patients were included in the study. A total of 180 foci of colorectal FDG uptake were detected on FDG-PET/CT. Of these, 86 foci corresponded to advanced colorectal neoplasia (ACRN), positive predictive value (PPV) 47.8%; 95% CI: 40.5-55.1%). On a per-patient analysis 81 patients had a least one ACRN at colonoscopy (PPV 55.9%; 95% CI: 47.6-63.8), this group included 20 patients (13.8%) diagnosed with cancer. There was a small positive correlation between focal FDG-uptake and the finding of ACRN at the same colonic segment at colonoscopy, which was statistically significant, rho = 0.2565, p = .002. The findings changed patient management in 67 (46.2%) cases. Conclusions Incidental focal colorectal FDG uptake on PET/CT is associated with a high risk of ACRN and is affecting subsequent patient management. Further evaluation with colonoscopy is recommended when the patient is considered suitable for further treatment.

Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. Results: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making. See related commentary by Morris and George, p. 438

Background Adenoma detection rate (ADR) is the single most important measure of quality in colonoscopy, but little is known about the detection rate of serrated lesions (SLDR). To improve ADR, Endocuff Vision (EV) can be used. Studies have shown differing results as to the effect on ADR; an effect on SLDR has not been shown. To investigate the effect of Endocuff Vision on ADR in a screening population, this randomized controlled open label trial with concealed allocation was performed. Randomization to trial group was carried out by the endoscopist using prepared numbered envelopes. Methods Patients referred as part of the national bowel screening program at Regional Hospital Herning, Denmark were recruited and allocated to one of two groups: Endocuff Vision colonoscopy (EVC) and standard colonoscopy (SC). Outcomes were ADR, mean number, site, and size of lesions per procedure. SLDR as outcome was added after inclusion had begun. Results A total of 1178 participants were included, with 1166 (EVC 583 and SC 583) available for analysis. There was no clinical relevant difference in ADR (59.2% [CI 55.1; 63.1] v 60.5% [CI 56.5; 64.4]) or SLDR (13.0% [CI 10.5; 16.0] v 10.3% [CI 8.0; 13.0]) between groups. More serrated lesions were found per procedure (MSP) (0.2 v 0.1, IRR 57% [CI 17; 109]. Removal rate of EV was similar in the two study groups. Conclusion We found no significant effects of the use of Endocuff Vision on ADR, when compared to standard colonoscopy, but more serrated lesions were detected in the Endocuff group.

Purpose: Anastomotic leakage (AL) continues to be a challenge after restorative rectal resection (RRR). Various treatment options of AL are available; however, their long-term outcomes are uncertain. We explored the impact of AL on the risk of stoma presence 1 year after RRR for rectal cancer and described treatment of AL after RRR including impact on the probability of receiving adjuvant chemotherapy and stoma presence following different treatment options of AL. Methods: We included 859 patients undergoing RRR in Central Denmark Region between 2013 and 2019. Stoma presence was calculated as the proportion of patients with stoma 1 year after RRR. Multivariable logistic regression was conducted to estimate the impact of AL on stoma presence adjusting for potential predictors. Descriptive data of outcomes were stratified for various treatment options of AL. Results: The risk of stoma presence 1 year after surgery was 9.8% (95% CI 7.98–12.0). Predictors for having stoma 1 year after RRR were AL (OR 8.43 (95% CI 4.87–14.59)) and low tumour height (OR 3.85 (95% CI 1.22–13.21)). For patients eligible for adjuvant chemotherapy, the probability of receiving it was 42.9% (95% CI 21.8–66.0) if treated with endo-SPONGE and 71.4% (95% CI 47.8–88.7) if treated with other anastomosis preserving treatment options. The risk of having stoma 1 year after RRR was 33.9% (95% CI 21.8–47.8) for patients treated with endo-SPONGE and 13.5% (95% CI 5.6–25.8) for patients treated with other anastomosis preserving treatment options (p = 0.013). Conclusion: AL is a strong predictor for stoma presence 1 year after RRR. Patients treated with endo-SPONGE seem to have worse outcomes compared to other anastomosis preserving treatment options.

Background In laparoscopic colorectal surgery, higher technical skills have been associated with improved patient outcome. With the growing interest in laparoscopic techniques, pressure on surgeons and certifying bodies is mounting to ensure that operative procedures are performed safely and efficiently. The aim of the present review was to comprehensively identify tools for skill assessment in laparoscopic colon surgery and to assess their validity as reported in the literature. Methods A systematic search was conducted in EMBASE and PubMed/MEDLINE in May 2021 to identify studies examining technical skills assessment tools in laparoscopic colon surgery. Available information on validity evidence (content, response process, internal structure, relation to other variables, and consequences) was evaluated for all included tools. Results Fourteen assessment tools were identified, of which most were procedure-specific and video-based. Most tools reported moderate validity evidence. Commonly not reported were rater training, assessment correlation with variables other than training level, and validity reproducibility and reliability in external educational settings. Conclusion The results of this review show that several tools are available for evaluation of laparoscopic colon cancer surgery, but few authors present substantial validity for tool development and use. As we move towards the implementation of new techniques in laparoscopic colon surgery, it is imperative to establish validity before surgical skill assessment tools can be applied to new procedures and settings. Therefore, future studies ought to examine different aspects of tool validity, especially correlation with other variables, such as patient morbidity and pathological reports, which impact patient survival.

Background Despite increasing focus on the technical performance of total mesorectal excision over recent decades, anastomotic leakage (AL) continues to be a serious complication for many patients, even in the hands of experienced surgical teams. This study describes implementation of standardized surgical technique in an effort to reduce variability, decrease the risk of anastomotic leakage, and improve associated short-term outcomes for rectal cancer patients undergoing robot-assisted restorative rectal resection (RRR). Methods We evaluated all rectal cancer patients undergoing robot-assisted RRR at Aarhus University Hospital between 2017 and 2020. Six standardized surgical steps directed to improve anastomotic healing were mandatory for all RRR. Additional changes were made during the period with prohibition of systemic dexamethasone and limiting the use of endoscopic stapling devices. Results The use of the full standardization, including all six surgical steps, increased from 40.3% (95% CI, 0.28–0.54) to 86.2% (95% CI, 0.68–0.95). The incidence of AL decreased from 21.0% (95% CI, 0.12–0.33) to 6.9% (95% CI, 0.01–0.23). Length of hospital stay (LOS) decreased from 6 days (range 2–50) to 5 days (range 2–26). The rate of patients readmitted within 90 days decreased from 21.0% (95% CI, 0.12–0.33), to 6.9% (95% CI, 0.01–0.23). Conclusion The full standardization was effectively implemented for rectal cancer patients undergoing robot-assisted RRR. The risk of AL, LOS and readmission decreased during the study period. A team focus on high-reliability and peri-operative complications can improve patient outcomes.

Background: Screening for colorectal cancer in Denmark has resulted in more patients being diagnosed with benign adenomas and early-stage rectal cancer. In general, TRUS is accepted as a good modality for evaluating the above mentioned before deciding on surgery. Objective: To investigate the accuracy of TRUS in a clinical setting at the Region Hospital in Herning, Denmark. Study design: Retrospective cohort study from January 2016 to June 2018. Methods: Quantitative method. The cohort (117 patients) was recruited by searching for specific procedure codes. Data were collected by going through the electronic patient files. Results: TRUS predicted T0, T1, T2 and T3 with an accuracy of 91%, 35%, 43% and 20% respectively and an overall accuracy of 68%. A weighted Cohens kappa value of 0.30 (p ≤ .05). TRUS differentiated between T0/T1 with a sensitivity of 70%, specificity of 85% and an accuracy of 85% and kappa value of 0.44 (p ≤ .05). Conclusion: TRUS can with great precision establish whether the tumor is benign so correct local treatment can be instituted.

Background: To describe 24-hour fluid administration in emergency department (ED) patients with suspected infection. Methods: A prospective, multicenter, observational study conducted in three Danish hospitals, January 20 to March 2, 2020. We included consecutive adult ED patients with suspected infection (drawing of blood culture and/or intravenous antibiotic administration within 6 hours of admission). Oral and intravenous fluids were registered for 24 hours. Primary outcome: 24-hour total fluid volume. We used linear regression to investigate patient and disease characteristics' effect on 24-hour fluids and to estimate the proportion of the variance in fluid administration explained by potential predictors. Results: 734 patients had 24-hour fluids available: 387 patients had simple infection, 339 sepsis, eight septic shock. Mean total 24-hour fluid volumes were 3656 mL (standard deviation [SD]:1675), 3762 mL (SD: 1839), and 6080 mL (SD: 3978) for the groups, respectively. Fluid volumes varied markedly. Increasing age (mean difference [MD]: 60-79 years: −470 mL [95% CI: −789, −150], +80 years; −974 mL [95% CI: −1307, −640]), do-not-resuscitate orders (MD: −466 mL [95% CI: −797, −135]), and preexisting atrial fibrillation (MD: −367 mL [95% CI: −661, −72) were associated with less fluid. Systolic blood pressure 120 min (MD: 566 [95% CI: 169, 962]), low (MD: 1963 mL [95% CI: 813, 3112]) and high temperature (MD: 489 mL [95% CI: 234, 742]), SOFA score > 5 (MD: 1005 mL [95% CI: 501, 510]), and new-onset atrial fibrillation (MD: 498 mL [95% CI: 30, 965]) were associated with more fluid. Clinical variables explained 37% of fluid variation among patients. Conclusions: Patients with simple infection and sepsis received equal fluid volumes. Fluid volumes varied markedly, a variation that was partly explained by clinical characteristics.

Background: The efficacy of simulation-based training in surgical education is well known. However, the development of training programs should start with problem identification and a general needs assessment to ensure that the content is aligned with current surgical trainee needs. The objective of the present study is to identify the technical skills and clinical procedures that should be included in a simulation-based curriculum in general surgery. Methods: A national, three-round Delphi process was conducted to achieve consensus on which technical skills and clinical procedures should be included in a simulation-based curriculum in general surgery. In total, 87 key opinion leaders were identified and invited to the study. Results: Round 1 of the Delphi process had a response rate of 64% (56/87) and a total of 245 suggestions. Based on these suggestions, a consolidated list of 51 technical skills or clinical procedures was made. The response rate in Delphi round 2 was 62% (54/87) resulting in a pre-prioritized order of procedures for round 3. The response rate in Delphi round 3 was 65% (35/54). The final list included 13 technical skills and clinical procedures. Training was predominantly requested within general open surgical skills, laparoscopic skills, and endoscopic skills, and a few specific procedures such as appendectomy and cholecystectomy were included in the final prioritized list. Conclusion: Based on the Delphi process 13 technical skills and clinical procedures were included in the final prioritized list, which can serve as a point of departure when developing simulation-based training in surgery.

Transcriptional characterization and classification has potential to resolve the inter-tumor heterogeneity of colorectal cancer and improve patient management. Yet, robust transcriptional profiling is difficult using formalin-fixed, paraffin-embedded (FFPE) samples, which complicates testing in clinical and archival material. We present MethCORR, an approach that allows uniform molecular characterization and classification of fresh-frozen and FFPE samples. MethCORR identifies genome-wide correlations between RNA expression and DNA methylation in fresh-frozen samples. This information is used to infer gene expression information in FFPE samples from their methylation profiles. MethCORR is here applied to methylation profiles from 877 fresh-frozen/FFPE samples and comparative analysis identifies the same two subtypes in four independent cohorts. Furthermore, subtype-specific prognostic biomarkers that better predicts relapse-free survival (HR = 2.66, 95%CI [1.67–4.22], P value, Molecular analysis of archival formalin-fixed clinical tissues can be difficult. Here, researchers have developed MethCORR, an approach that infers gene expression from DNA methylation data and use the approach for molecular characterization and prognostication of colorectal cancer using archival samples.

Background: A prospective study on shoulder and arm morbidity was conducted in Denmark in 2003–2005. This study demonstrated that sentinel lymph node biopsy was associated with better outcomes than axillary lymph node dissection 18 months after surgery. We here aimed to describe subjective symptoms and objective findings in these patients 10+ years after they underwent breast cancer surgery and to assess how symptoms and findings developed during this period. Material and methods: Participants in the prospective study completed a questionnaire and underwent an objective, bilateral examination of their shoulder and arm morbidity, which included measurement of arm volume, range of motion, and sensibility. Results: Seventy participants completed follow-up. Thirty-four (49%) had one or more functional impairments, and 64% had one or more subjective loco regional symptoms like pain, swelling of the arm, and decreased shoulder mobility. Objective evaluation showed 34 ml’s of increased arm volumes and 3–25% had severe reduced shoulder mobility on the operated side. Compared to the findings at 18 months postoperatively, small but significant differences in occurrence of subjective findings were observed. A significant progression regarding most objective findings was revealed. Conclusion: More than 11 years after breast cancer surgery, the majority of participants complained of one or more subjective symptoms of shoulder and arm morbidity. Objective findings were mild or modest in most cases. During the prolonged follow-up period of 10 years, a worsening in symptoms and objective findings was observed.HIGHLIGHTS Shoulder and arm morbidity in relation to breast cancer treatment seems to progress beyond 10 years. The most frequent symptoms were pain, swelling or heaviness of the arm, and decreased shoulder mobility. The objective evaluation showed higher arm volumes and reduced shoulder mobility on the operated side. Objective findings are mild and modest but may affect activities of daily living, and most participants with late symptoms stated that this was a daily problem.

BackgroundIntra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH.MethodsMultiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors).ResultsOverall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; pConclusionOur transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.

BACKGROUND: Goblet cell carcinoma (GCC) of the appendix is a rare disease. Treatment options vary according to disease staging. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) may improve survival in patients with peritoneal spreading.OBJECTIVE: The aim of this study was to examine the prognosis of patients with appendiceal GCC treated per protocol, and to evaluate the results of CRS+HIPEC in cases of peritoneal spreading.METHODS: From 2009 to 2016, a total of 48 GCC patients were referred to the European Neuroendocrine Tumour Center of Excellence, Aarhus University Hospital. All patients received treatment per protocol according to disease staging. In patients with localized disease, the treatment was a right hemicolectomy. Patients with peritoneal spread who met the inclusion criteria for CRS + HIPEC, as well as patients with high-risk features of developing peritoneal spread, received CRS + HIPEC. If too-extensive disease was found, palliative chemotherapy was offered.RESULTS: Overall survival for patients with localized disease (n = 6) or deemed at risk of peritoneal spread (n = 8) was 100% after a median follow-up of 3.5 years. In patients with peritoneal spread and eligible for CRS+HIPEC(n = 27), the median survival was 3.2 years [95% confidence interval (CI) 2.3-4.1] and the 5-year survival rate was 57%. In contrast, the median survival for patients with too-extensive intraperitoneal disease (n = 7) was 1.3 years (95% CI 0.6-2.0), with a 3-year survival rate of 20%.CONCLUSIONS: Long-term survival can be achieved in patients with peritoneal spread treated with CRS + HIPEC. CRS+HIPEC was associated with a favorable outcome in GCC patients at high-risk of developing peritoneal spread.

Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long-time latency of follow-up examinations. Various options for improvement are considered, including increased cut-off values of the fecal blood tests. Results from major clinical studies of blood-based, cancer-associated biomarkers have led to focus, however, on a triage concept for improved selection to colonoscopy. The triage test may include subject age, concentration of hemoglobin in a feces test and a combination of certain blood-based cancer associated biomarkers. Recent results have indicated that triage may reduce the requirements for colonoscopy by around 30%. Such results may be advantageous for the capacity, the heath budgets and in particular, the subjects, who do not need an unnecessary, unpleasant and risk-associated bowel examination.

Background Microsatellite instability (MSI), resulting from a defective mismatch repair system, occurs in approximately 15% of sporadic colorectal cancers (CRC). Since MSI is associated with a poor response to 5-fluorouracile based chemotherapy and is a positive predictive marker of immunotherapy, it is routine practice to evaluate the MSI status of resected tumors in CRC patients. MSIsensor is a novel computational tool for determining MSI status using Next Generation Sequencing. However, it is not widely used in the clinic and has not been independently validated in exome data from CRC. To facilitate clinical implementation of computational determination of MSI status, we compared MSIsensor to current gold standard methods for MSI testing. Methods MSI status was determined for 130 CRC patients (UICC stage I-IV) using immunohistochemistry, PCR based microsatellite stability testing and by applying MSIsensor to exome sequenced tumors and paired germline DNA. Furthermore, we investigated correlation between MSI status, mutational load and mutational signatures. Results Eighteen out of 130 (13.8%) patients were microsatellite instable. We found a 100% agreement between MSIsensor and gold standard methods for MSI testing. All MSI tumors were hypermutated. In addition, two microsatellite stable (MSS) tumors were hypermutated, which was explained by a dominant POLE signature and pathogenic POLE mutations (p.Pro286Arg and p.Ser459Phe). Conclusion MSIsensor is a robust tool, which can be used to determine MSI status of tumor samples from exome sequenced CRC patients.

Importance: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC). Objective: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance. Design, Setting, and Participants: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years. Main Outcomes and Measures: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival. Results: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients (88.5%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P

Background Early detection plays an essential role to reduce colorectal cancer (CRC) mortality. While current screening methods suffer from poor compliance, liquid biopsy-based strategies for cancer detection is rapidly gaining promise. Here, we describe the development of TriMeth, a minimal-invasive blood-based test for detection of early-stage colorectal cancer. The test is based on assessment of three tumour-specific DNA methylation markers in circulating cell-free DNA. Results A thorough multi-step biomarker discovery study based on DNA methylation profiles of more than 5000 tumours and blood cell populations identified CRC-specific DNA methylation markers. The DNA methylation patterns of biomarker candidates were validated by bisulfite sequencing and methylation-specific droplet digital PCR in CRC tumour tissue and peripheral blood leucocytes. The three best performing markers were first applied to plasma from 113 primarily early-stage CRC patients and 87 age- and gender-matched colonoscopy-verified controls. Based on this, the test scoring algorithm was locked, and then TriMeth was validated in an independent cohort comprising 143 CRC patients and 91 controls. Three DNA methylation markers, C9orf50, KCNQ5, and CLIP4, were identified, each capable of discriminating plasma from colorectal cancer patients and healthy individuals (areas under the curve 0.86, 0.91, and 0.88). When combined in the TriMeth test, an average sensitivity of 85% (218/256) was observed (stage I: 80% (33/41), stage II: 85% (121/143), stage III: 89% (49/55), and stage IV: 88% (15/17)) at 99% (176/178) specificity in two independent plasma cohorts. Conclusion TriMeth enables detection of early-stage colorectal cancer with high sensitivity and specificity. The reported results underline the potential utility of DNA methylation-based detection of circulating tumour DNA in the clinical management of colorectal cancer.

Item does not contain fulltext Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer(1). However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.

11 Background: Timely detection of recurrence, as well as identification of patients at high risk of recurrence after surgery and after completion of adjuvant therapy, are major challenges in the treatment of colorectal cancer (CRC). Postsurgical circulating tumor DNA (ctDNA) analysis is a promising tool for the identification of patients with minimal residual disease (MRD) and a high risk of recurrence. The objective of this prospective, multicenter study was to determine whether serial postsurgical ctDNA analysis could identify the patients at high risk of recurrence, provide an assessment of adjuvant therapy efficacy and detect relapse earlier than standard-of-care radiological imaging. Methods: The cohort comprises 265 stage I-III CRC patients, the to-date largest cohort assessed for ctDNA. All patients had the tumor resected and a subset of 62.6% (166 /265) was additionally treated with ACT. Plasma samples (n = 1503) were collected at various time points for a median follow-up of 28.4 months (range: 1.2-51.0 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) were identified. Personalized multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in each patient’s plasma sample. Results: Postoperative ctDNA status prior to ACT was assessed in 218 patients, of which 9.17% (20/218) were identified to be MRD-positive and 75% (15/20) eventually relapsed. The remaining 25% (5/20) of MRD-positive patients that did not relapse, received ACT. In contrast, only 13.6% (27/198) of MRD-negative cases relapsed (HR: 11: 95% CI: 5.7-20; p < 0.001). Longitudinal ctDNA-positive status, post-definitive therapy (n = 202) was associated with a HR of 36 (95% CI: 16-81; p < 0.001). For a subset of 155 patients postoperative CEA and ctDNA measurements were compared, wherein, ctDNA-positive status was found to be significantly associated with RFS (HR, 7.1; 95% CI, 3.4-15; P < 0.001) compared to CEA (HR, 1.2; 95% CI, 0.46-3.1; P = 0.73). Serial ctDNA analysis detected MRD up to a median of 8 months (0.56 - 21.6 months) ahead of radiologic relapse. Conclusion: Postoperative ctDNA positive status was associated with markedly reduced RFS compared to CEA. The study also shows that effective therapy can be curative in a portion of MRD-positive patients. In a longitudinal setting, ctDNA analysis predicted the risk of recurrence and is a more reliable biomarker for treatment response monitoring.

Udgivelsesdato: 2008-null BACKGROUND: Diagnostic and treatment of breast cancer has steadily improved in the last decades; mammography-screening, more aggressive axillary surgery and finally sentinel lymph node biopsies. This study analyses the impact of time trends in diagnostic and surgical procedures on stage at diagnosis and survival in three Danish counties in three decades. METHODS: We compare extent of disease and outcome in three complete population-based patient cohorts with primary invasive breast cancer, diagnosed in 1986, 1996-1997 and 2002-2003; 3 385 patients, thereby comparing populations with and without centralised breast cancer management, mammography-screening, sentinel lymph node biopsies and the effect of time-period. RESULTS: The 5-year over-all survival increased significantly (p

Udgivelsesdato: 2008-null BACKGROUND: The validation series of sentinel lymph node biopsy (SLNB) in the treatment of breast cancer have shown that 10-20% more lymph node metastases are detected. However, their impact has never been studied in populations where the method has been fully implemented. In a population-based setting, the objective of the current study was to estimate the increased risk of metastases after introduction of the sentinel lymph node biopsy technique. METHODS: We identified all new breast cancer patients in three different counties in two time periods (1996-1997 and 2002-2003). The study cohort was comprised of 2 932 patients. The main outcome was the frequency of patients with metastases. The frequencies of patients with metastases were compared as well as adjusted (using a multivariate logistic regression) and unadjusted odds-ratio for detecting lymph node metastases. RESULTS: In counties where sentinel lymph node biopsy was implemented, the frequency of patients with lymph node metastases increased significantly 7.3% (95% CI: 1.0-13.7%) and 13.3% (95% CI: 7.3-19.3%), respectively. In the county without sentinel lymph node biopsy, an insignificant increase of 6.9% (-0.1-13.9%) in the frequency of patients with metastases was seen. The adjusted odds- ratio for detecting lymph node metastases was 1.41 (1.07-1.87) and 1.70 (1.30-2.23) in the counties with SLNB. Conclusion: The frequency of patients with metastases increased significantly in counties where sentinel lymph node biopsy was implemented.

OBJECTIVES:The treatment of peptic ulcer bleeding (PUB) is complex, and mortality remains high. We present results from a nationwide initiative to monitor and improve the quality of care (QOC) in PUB.METHODS:All Danish hospitals treating PUB patients between 2004 and 2011 prospectively registered demographic, clinical, and prognostic data. QOC was evaluated using eight process and outcome indicators, including time to initial endoscopy, hemostasis obtainment, proportion undergoing surgery, rebleeding risks, and 30-day mortality.RESULTS:A total of 13,498 PUB patients (median age 74 years) were included, of which one-quarter were in-hospital bleeders. Preadmission use of anticoagulants, multiple coexisting diseases, and the American Society of Anesthesiologists scores increased between 2004 and 2011. Considerable improvements were observed for most QOC indicators over time. Endoscopic treatment was successful with primary hemostasis achieved in more patients (94% in 2010-2011 vs. 89% in 2004-2006, relative risk (RR) 1.06 (95% confidence intervals 1.04-1.08)), endoscopy delay for hemodynamically unstable patients decreased during this period (43% vs. 34% had endoscopy within 6 h, RR 1.33 (1.10-1.61)), and fewer patients underwent open surgery (4% vs. 6%, RR 0.72 (0.59-0.87)). After controlling for time changes in prognostic factors, rebleeding rates improved (13% vs. 18%, adjusted RR 0.77 (0.66-0.91)). Crude 30-day mortality was unchanged (11% vs. 11%), whereas adjusted mortality decreased nonsignificantly over time (adjusted RR 0.89 (0.78-1.00)).CONCLUSIONS:QOC in PUB has improved substantially in Denmark, but the 30-day mortality remains high. Future initiatives to improve outcomes may include earlier endoscopy, having fully trained endoscopists on call, and increased focus on managing coexisting disease.Am J Gastroenterol advance online publication, 4 June 2013; doi:10.1038/ajg.2013.162.

Adult intussusception is rare and most often not identified until surgery. We report a case involving a 59-year-old woman admitted to the surgical ward. Computed tomography identified intestinal obstruction caused by intussusception of the terminal ileum. Exploratory laparotomy was performed - an intussusception was identified 30 cm from the ileocoecal valve. The intussusception was caused by what looked like a 6 x 2 cm tumour. Histology revealed no tumour but ectopic ventricular mucosa and no indication of malignancy. The case and literature on the subject are discussed.

After implementation of the sentinel lymph node biopsy technique as a standard procedure in the treatment of breast cancer the indications and technique used has changed. This review gives a brief, comprehensive update of the method regarding surgical techniques, histopathology, morbidity, recurrence and mortality.

Udgivelsesdato: 2008-Apr BACKGROUND: Sentinel lymph node biopsy was implemented in the treatment of early breast cancer with the aim of reducing shoulder and arm morbidity. Relatively few prospective studies have been published where the morbidity was assessed by clinical examination. Very few studies have examined the impact on shoulder mobility of node positive patients having a secondary axillary dissection because of the findings of metastases postoperatively. AIM: We aimed to investigate the objective and subjective arm morbidity in node negative and node positive patients. METHODS AND MATERIALS: In a prospective study, 395 patients with tumors less than 4 cm, were included. Patients were recruited from seven Danish breast cancer clinics. Both subjective and objective arm and shoulder morbidity were measured before, 6 and 18 months after the operation. RESULTS: Comparing node negative patients having a sentinel lymph node biopsy with node negative patients having a lymph node dissection of levels I and II of the axilla, we found significant increase in arm volume among the patients who had an axillary dissection. Only minor, but significant, differences in shoulder mobility were observed comparing the two groups of node negative patients. Highly significant difference was found comparing sensibility. Comparing the morbidity in node positive patients who had a one-step axillary dissection with patients having a two-step procedure (sentinel lymph node biopsy followed by delayed axillary dissection) revealed no difference in objective or subjective arm morbidity. CONCLUSION: Node negative patients operated with sentinel lymph node biopsy have less arm morbidity compared with node negative patients operated with axillary lymph node dissection. Node positive patients who had a secondary axillary lymph node dissection after sentinel lymph node biopsy had no difference in either objective or subjective morbidity compared with node positive patients having a one-step axillary dissection.

Staging of the axilla in breast cancer is essential because lymph node status is the most important prognostic factor [1]. On patients with unifocal breast cancer the sentinel lymph node biopsy technique (SLNB) is a reliable tool to detect lymph node metastases and perhaps even more importantly to identify patients without metastases [2 6]. Patients without metastases can avoid a total axillary dissection and the related complications [7 12]. The method has rapidly been implemented as standard procedure despite there being no documented evidence of a beneficial effect on overall survival and relapse rate. However, trials with the aim of investigating these important issues are ongoing [13 15]. Compared with the numerous studies of the SLNB on patients with unifocal breast cancer relatively few validation studies have been made on patients having multifocal or multicentric tumors (Table I). Unfortunately, the published works are not comparable. This is mainly because different definitions of multifocal and multicentric breast cancer are used, but also that the inclusion criteria used in the studies are not uniform. Few of the studies have been performed as prospective studies, and with the only aim to investigate the methods reliability. Despite these facts, it is now generally accepted, that the method works among patients with more than one tumor in the same breast [16]. The aim of the present study was to validate the use of SLNB in patients, who preoperatively had been diagnosed with more than one tumor on either mammography and/or ultrasonography.