Detection of colorectal cancer and advanced neoplasia during first surveillance interval after detection of adenomas in fecal immunochemical test cancer screening: a nationwide study.

BACKGROUND: Adenoma surveillance guidelines are based on non-fecal immunochemical test (FIT)-based screening settings. However, colorectal cancer (CRC) risk may be different in FIT-positive screening populations. We evaluated the CRC and advanced adenoma risk within the recommended surveillance periods in the Danish FIT-based CRC screening program for participants with intermediate or high risk adenomas according to 2010 European guidelines. Furthermore, we estimated CRC risk for those who were not recommended surveillance according to European Society of Gastrointestinal Endoscopy (ESGE) 2020 guidelines. METHODS: Using nationwide health registries, we identified 17 936 FIT-screening participants from 2014-2017 with adenomas undergoing surveillance (high risk 1 year, intermediate risk 3 years). Participants with a follow-up examination were included (N = 10 068). Relative risk (RR) of CRC and advance adenoma was compared between intermediate and high risk groups and between intermediates who were recommended surveillance (S) or no surveillance (NS) according to 2020 ESGE guidelines. RESULTS: During surveillance, CRC occurred in 0.59% of the high risk group and 1.11% of the intermediate risk group (RR 0.53 [95%CI 0.34-0.84]). The high risk group had a 24% increased risk of advanced adenoma. CRC occurred in 1.69% of the intermediateNS group and 0.87% of the intermediateS group (RR 1.94 [95%CI 1.18-3.21]), and RR for advanced adenoma was 1.19 (95%CI 1.03-1.37). CONCLUSION: CRC detection was lower among participants rated at higher risk at initial CRC screening. Findings at first screen-derived colonoscopy might not be as good a predictor of CRC risk in a FIT-positive screening population.

Significant Individual Variation Between Pathologists in the Evaluation of Colon Cancer Specimens After Complete Mesocolic Excision.

BACKGROUND: After the introduction of complete mesocolic excision, a new pathological evaluation of the resected colon cancer specimen was introduced. This concept has quickly gained acceptance and is often used to compare surgical quality. The grading of colon cancer specimens is likely to depend on both surgical quality and the training of the pathologist. OBJECTIVE: The purpose of this study was to validate the principles of the pathological evaluation of colon cancer specimens. DESIGN: This was an exploratory study. SETTINGS: The study was conducted in Aarhus, Denmark, and Leeds, United Kingdom. PATIENTS: Colon cancers specimens were used. MAIN OUTCOME MEASURES: The agreement of gradings between participants was of interest. Four specialist GI pathologists and 2 abdominal surgeons evaluated 2 rounds of colon cancer specimens, each at 2 separate time points. Each round contained 50 specimens. After the first round, a protocol of detailed principles for the grading procedure was agreed on. Results from an experienced pathologist were considered as the reference results. RESULTS: In the first round, the distribution of gradings between participants showed substantial variation. In the second round, the variation was reduced. Intraobserver agreement was mostly fair to good, whereas interobserver agreement was frequently poor. This did not significantly change from round 1 to round 2. LIMITATIONS: The small sample size of 100 specimens provided a very small number of specimens resected in the muscularis propria plane, which renders the evaluation of this group potentially unreliable. The evaluations were made on photos and not on fresh specimens. CONCLUSIONS: This study demonstrates significant variation in the pathological evaluation of colon cancer specimens. It demonstrates that it cannot be used in clinical studies, and care should be taken when comparing results between different hospitals.

Objective measurement of the distal resection margin by MRI of the fresh and fixed specimen after partial mesorectal excision for rectal cancer: 5 cm is not just 5 cm and depends on when measured.

BACKGROUND: Most studies have directly established the optimal perioperative in situ clearance margin in surgery for rectal cancer from the histologically observed extent of distal spread, neglecting the tissue variability that occurs after resection and fixation of the rectal specimen. PURPOSE: To measure the length of the distal resection margin in the fresh and fixed specimen following partial mesorectal excision for rectal cancer using magnetic resonance imaging (MRI) to document tissue shrinkage after surgical removal and fixation. MATERIAL AND METHODS: The length of the distal resection margin was measured by MRI of the fresh and fixed specimen and at histopathological examination of the fixed specimen in 10 patients who underwent surgery for upper rectal cancer. In addition, tissue shrinkage was estimated by measuring the total length of the fresh and fixed specimen and distance from the peritoneal reflection anteriorly to the distal cut edge of the specimen. RESULTS: Measured by MRI, the distal resection margin was in the range of 0.6-10.2 cm (mean, 4.6 cm) in the fresh specimen, and 0.5-6.2 cm (mean, 3.2 cm) in the fixed specimen. The tissue shrinkage ratio was a mean of 69% (interquartile range, 61-77%). Taking all ratios from MRI and histopathological examination of tissue shrinkage into account, the collective tissue shrinkage ratio was 70% (95% confidence interval, 67-73%) CONCLUSION: The length of the distal resection margin was reduced by 30% after surgical removal and fixation of the specimen.

Early and Late Outcomes of Surgery for Locally Recurrent Rectal Cancer: A Prospective 10-Year Study in the Total Mesorectal Excision Era.

AIM: The aim of this study was to assess the outcome of all locally recurrent rectal cancer (LRRC) patients who were referred to a tertiary care center. The study examined LRRC patients who underwent surgery after prior total mesorectal excision. METHOD: The data of 213 consecutive LRRC patients who were registered in a database between 2001 and 2010 were accessed. RESULTS: A total of 115 patients (54 %) with a median age of 63 (range 34-81) years underwent tumor resection. The 30-day mortality rate was 0.8 % (95 % CI 0.02-4 %), and the complication rate was 42 % (95 % CI 33-51 %). R0 resection was achieved in 70 patients (61 %), R1 resection in 38 patients (33 %), and R2 resection in 7 patients (6 %). The 3- and 5-year survival rates for R0 resections were 55 % (95 % CI 41-66) and 40 % (95 % CI 26-53), respectively; 42 % (95 % CI 26-58) and 16 % (95 % CI 5-31), respectively, for R1 resections; no patients who received an R2 resection survived to the 3-year mark. Patients with prior abdominoperineal excision (APE) had significantly poorer survival rates than patients with prior resection with anastomosis (p = 0.02). CONCLUSION: Acceptable long-term survival can be achieved for patients undergoing surgery for LRRC, but radical resection is mandatory. Prior APE was associated with poorer survival rates.

MiRNA-362-3p induces cell cycle arrest through targeting of E2F1, USF2 and PTPN1 and is associated with recurrence of colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer deaths in Western countries. A significant number of CRC patients undergoing curatively intended surgery subsequently develop recurrence and die from the disease. MicroRNAs (miRNAs) are aberrantly expressed in cancers and appear to have both diagnostic and prognostic significance. In this study, we identified novel miRNAs associated with recurrence of CRC, and their possible mechanism of action. TaqMan(®) Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosas and 46 microsatellite stable CRC tumors. Four miRNAs (miR-362-3p, miR-570, miR-148 a* and miR-944) were expressed at a higher level in tumors from patients with no recurrence (p<0.015), compared with tumors from patients with recurrence. A significant association with increased disease free survival was confirmed for miR-362-3p in a second independent cohort of 43 CRC patients, using single TaqMan(®) microRNA assays. In vitro functional analysis showed that over-expression of miR-362-3p in colon cancer cell lines reduced cell viability, and proliferation mainly due to cell cycle arrest. E2F1, USF2 and PTPN1 were identified as potential miR-362-3p targets by mRNA profiling of HCT116 cells over-expressing miR-362-3p. Subsequently, these genes were confirmed as direct targets by Luciferase reporter assays and their knockdown in vitro phenocopied the effects of miR-362-3p over-expression. We conclude that miR-362-3p may be a novel prognostic marker in CRC, and hypothesize that the positive effects of augmented miR-362-3p expression may in part be mediated through the targets E2F1, USF2 and PTPN1.

[Collagenous sprue in a patient with severe diarrhoea, malnutrition and acute renal failure].

Collagenous sprue is a rare enteropathy affecting the small intestinal mucosa and can resemble and coincide with coeliac disease or collagenous colitis. To our knowledge, less than 175 cases of collagenous sprue have been described. Both clinicians and pathologists should be aware of the condition in order to adequately target their investigations and treatment. This is a case report of severe collagenous sprue in a 78-year-old male resulting in severe diarrhoea, weight loss, malnutrition and acute kidney failure. The disorder improved on a lactose and gluten-free diet, loperamide and corticosteroids.

Magnetic Resonance Enterography and Histology in Patients With Fibrostenotic Crohn's Disease: A Multicenter Study.

INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients.

Postoperative MRI Findings Following Conventional and Extralevator Abdominoperineal Excision in Low Rectal Cancer.

Aim: The disparity in outcomes for low rectal cancer may reflect differences in operative approach and quality. The extralevator abdominoperineal excision (ELAPE) was developed to reduce margin involvement in low rectal cancers by widening the excision of the conventional abdominoperineal excision (c-APE) to include the posterior pelvic diaphragm. This study aimed to determine the prevalence and localization of inadvertent residual pelvic diaphragm on postoperative MRI after intended ELAPE and c-APE. Methods: A total of 147 patients treated with c-APE or ELAPE for rectal cancer were included. Postoperative MRI was performed on 51% of the cohort (n = 75) and evaluated with regard to the residual pelvic diaphragm by a radiologist trained in pelvic MRI. Patient records, histopathological reports, and standardized photographs were assessed. Pathology and MRI findings were evaluated independently in a blinded fashion. Additionally, preoperative MRIs were evaluated for possible risk factors for margin involvement. Results: Magnetic resonance imaging-detected residual pelvic diaphragm was identified in 45 (75.4%) of 61 patients who underwent ELAPE and in 14 (100%) of 14 patients who underwent c-APE. An increased risk of margin involvement was observed in anteriorly oriented tumors with 16 (22%) of 73 anteriorly oriented tumors presenting with margin involvement vs. 7 (9%) of 74 non-anteriorly oriented tumors (p = 0.038). Conclusion: Residual pelvic diaphragm following abdominoperineal excision can be depicted by postoperative MRI. Inadvertent residual pelvic diaphragm (RPD) was commonly found in the series of patients treated with the ELAPE technique. Anterior tumor orientation was a risk factor for circumferential resection margin (CRM) involvement regardless of surgical approach.

Improving the quality of colon cancer surgery through a surgical education program.

PURPOSE: Recent evidence has demonstrated the importance of dissection in the correct tissue plane for the resection of colon cancer. We have previously shown that meticulous mesocolic plane surgery yields better outcomes and that the addition of central vascular ligation produces an oncologically superior specimen compared with standard techniques. We aimed to assess the effect of surgical education on the oncological quality of the resection specimen produced. METHODS: We received clinicopathological data and specimen photographs from 263 resections for primary colon cancer from 6 hospitals in the Capital and Zealand regions of Denmark before a national training program. Ninety-three cases were from Hillerød Hospital, where surgeons had previously implemented a surgical educational training program in complete mesocolic excision with central vascular ligation and adopted the procedure as standard practice. The specimen photographs were assessed for the plane of surgery and tissue morphometry was performed. RESULTS: Hillerød specimens had a higher rate of mesocolic plane surgery (75% vs 48%; P < .0001) compared with the other hospitals. The surgeons at Hillerød Hospital also removed a greater length of colon in both fresh (median, 315 vs 247 mm; P < .0001) and fixed (269 vs 207 mm; P < .0001) specimens with a greater distance between the tumor and the closest vascular tie in both fresh (105 vs 84 mm; P = .006) and fixed (82 vs 67 mm; P = .002) specimens. This resulted in the removal of more mesentery in both fresh (14,466 vs 8706 mm; P < .0001) and fixed (9418 vs 6789 mm; P < .0001) specimens and a greater median lymph node yield (28 vs 18; P < .0001). CONCLUSIONS: We have shown that adoption of complete mesocolic excision with central vascular ligation results in a change to the production of an oncologically superior specimen compared with standard techniques. This should improve outcomes toward those reported by centers that have long practiced meticulous colon cancer surgery.

The Validity of Registered Synchronous Peritoneal Metastases from Colorectal Cancer in the Danish Medical Registries.

INTRODUCTION: Treatment options for peritoneal metastases (PM) from colorectal cancer (CRC) have increased, their efficiency should be monitored. For this purpose, register-based data on PM can be used, if valid. PURPOSE: We aimed to evaluate the completeness and positive predictive value (PPV) of synchronous peritoneal metastases (S-PM) registered among CRC patients in the Danish National Patient Register (DNPR) and/or the Danish National Pathology Register (the DNPatR) using the Danish Colorectal Cancer Group database (DCCG) as a reference. PATIENTS AND METHODS: We identified Danish patients with newly diagnosed primary CRC in the DCCG during 2014-2015. S-PM were routinely registered in the DCCG. We excluded patients with non-CRC cancers and identified S-PM using all three registries. We estimated the completeness and the PPV of registered S-PM in the DNPR, the DNPatR and the DNPR and/or the DNPatR (DNPR/DNPatR) in combination using the DCCG as the reference. We stratified by age, gender, WHO performance status, tumour location and distant metastases to liver and/or lungs. RESULTS: We identified 9142 patients with CRC in DCCG. In DCCG, 366 patients were registered with S-PM, among whom 213 in DCCG only, whereas 153 in DCCG and in at least one of DNPR and/or DNPatR. In DNPR/DNPatR, S-PM was registered with a completeness of 42% [95% CI: 37-47] and a PPV of 60% [95% CI: 54-66]. In the DNPR only, the completeness was 32% [95% CI: 27-37] and the PPV 57% [95% CI: 50-64]. The completeness in the DNPatR was 19% [95% CI: 15-23] and the PPV was 76% [95% CI: 68-85]. In the DNPR/DNPatR patients aged <60 years (57% [95% CI: 46-69]), patients with WHO performance status 0 (46% [95% CI: 37-54]) and patients with no distant metastases (58% [95% CI: 50-65]) were registered with a higher completeness. CONCLUSION: Our algorithm demonstrates that the DNPR/DNPatR captures less than half of CRC patients with S-PM. Potential candidates for curative treatment options are registered with a higher completeness. Clinicians should be encouraged to register the presence of S-PM to increase the validity of register-based S-PM data.

Validity of Contrast-enhanced Ultrasonography and Dynamic Contrast-enhanced MR Enterography in the Assessment of Transmural Activity and Fibrosis in Crohn's Disease.

BACKGROUND AND AIMS: Increased small intestinal wall thickness correlates with both inflammatory activity and fibrosis in Crohn's disease [CD]. Assessment of perfusion holds promise as an objective marker distinguishing between the two conditions. Our primary aim was to determine if relative bowel wall perfusion measurements correlate with histopathological scores for inflammation or fibrosis in CD. METHODS: A total of 25 patients were investigated before elective surgery for small intestinal CD. Unenhanced ultrasonography [US] and magnetic resonance enterography [MRE] were applied to describe bowel wall thickness. Perfusion was assessed with contrast-enhanced US [CEUS] and dynamic contrast-enhanced MRE [DCE-MRE]. Histopathology was used as gold standard. RESULTS: Compared with histopathology, the mean wall thickness was 0.4 mm greater on US [range -0.3 to 1.0, p = 0.24] and 1.4 mm greater on MR [0.4 to 2.3, p = 0.006]. No correlation was found between the severity of inflammation or fibrosis on histopathology, and either DCE-MRE [r = -0.13, p = 0.54 for inflammation and r = 0.41, p = 0.05 for fibrosis] or CEUS [r = 0.16, p = 0.45 for inflammation and r = -0.28, p = 0.19 for fibrosis]. Wall thickness assessed with US was correlated with both histological inflammation [r = 0.611, p = 0.0012] and fibrosis [r = 0.399, p = 0.048]. The same was not true for MR [r = 0.41, p = 0.047 for inflammation and r = 0.29, p = 0.16 for fibrosis]. CONCLUSIONS: Bowel wall thickness assessed with US is a valid marker of inflammation in small intestinal CD. However, relative contrast enhancement of US or of MRE cannot distinguish between inflammatory activity and fibrosis.

[The development of a generic guideline for multidisciplinary team conferences in Denmark].

Since 2005 multidisciplinary team conferences (MDT) has been a crucial pivot for the Danish national integrated cancer pathways. Despite the formal decision to implement MDT-conferences, many aspects of this complex organization have never been addressed. In 2014, The Danish Multidisciplinary Cancer Groups (DMCG) provided a workgroup with the task of drafting a Danish national guideline for keeping MDT-conferences. This article presents the process of the workgroup, the background for the final content of the guideline as well as minutes from different parts of the guideline.

Treatment of Clostridium difficile infection in mice with vancomycin alone is as effective as treatment with vancomycin and metronidazole in combination.

OBJECTIVE: Clostridium difficile is a major cause of nosocomial infectious diarrhoea. Treatment of C. difficile infection (CDI) depends on disease severity. A combination of vancomycin and metronidazole is often recommended in severe cases. The aim of this study was to examine, in a murine model of CDI, if mice treated with a combination of vancomycin and metronidazole had a better clinical outcome than mice treated with vancomycin or metronidazole alone. DESIGN: C57BL/6J mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or phosphate-buffered saline by oral gavage. After the challenge, the mice were treated with placebo, vancomycin, metronidazole or a combination of vancomycin and metronidazole for 10 days. The mice were monitored for 20 days with weight and a clinical score. Stool samples were examined for C. difficile spore load and presence of C. difficile toxins. RESULTS: None of the mice in the vancomycin-treated group died during the treatment phase compared to a mortality of 17%, 33% and 55% in the combination, metronidazole and infected control group, respectively. Mice treated with vancomycin alone or in combination with metronidazole recovered from CDI faster than mice treated with metronidazole alone. However, after discontinuation of treatment, vancomycin-treated and combination-treated mice succumbed to clinical and bacteriological relapse. CONCLUSIONS: Mice treated with vancomycin alone had a better clinical outcome in the treatment phase of CDI than mice treated with metronidazole alone. A combination of vancomycin and metronidazole did not improve the clinical outcome when compared to treatment with vancomycin alone. TRIAL REGISTRATION NUMBER: The trial registration number from the Danish Experimental Animal Inspectorate is J number 2012-15-2934-00422.

Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer.

MicroRNAs (miRNAs) play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal cancer (CRC) only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional screening was carried out in six CRC cell lines transfected with a pre-miR library including 319 synthetic human pre-miRs. Phenotypic alterations were evaluated by immunostaining of cleaved cPARP (apoptosis) or MKI67 (proliferation). Additionally, TaqMan Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosa and 46 microsatellite stable stage II CRC patients. Among the miRNAs that induced growth arrest and apoptosis in the CRC cell lines, and at same time were dys-regulated in the clinical samples, miR-375 was selected for further analysis. Independent in vitro analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1. Finally, in vivo analysis of mouse xenograft tumors showed that miR-375 expression significantly reduced tumor growth. We conclude that the high-throughput screening successfully identified miRNAs that induce apoptosis and/or inhibit proliferation in CRC cells. Finally, combining the functional screening with profiling of CRC tissue samples we identified clinically relevant miRNAs and miRNA targets in CRC.

[Close teamwork between pathologist and surgeon can improve results in colorectal cancer treatment]. / Tæt samarbejde mellem patolog og kirurg kan forbedre resultaterne efter kolorektal cancer.

Colorectal cancer is common in the Western world and is a leading cause of cancer related mortality. The introduction of multidisciplinary teams and focus on quality control has led to improved outcomes in which pathologists play a central role through feedback to surgeons, radiologists, and oncologists. This review focuses on the importance of pathological examination of the resection specimen and subsequent feedback to the surgical team regarding quality. Specific markers of oncological quality including grading the plane of surgery, tissue morphometry and lymph node yields are discussed.

Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients.

Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity of the missense mutations, we carried out in vitro functional analyses. The missense mutations were analyzed for their effect on protein expression and repair efficiency. The results of the functional analysis were correlated with clinical data on the families carrying these mutations. Eight missense mutations resulted in proteins with expression and repair efficiency similar to the wild type. One missense mutation (MSH2 p.Met688Val) caused reduced protein expression and one (MSH2 p.Leu187Arg) caused both reduced protein expression and repair deficiency. The MSH2 p.Leu187Arg mutation was found in an Amsterdam II family presenting with high microsatellite instability and loss of MSH2 and MSH6 proteins in tumours. In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded.