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Campylobacter concisus is an emerging pathogen associated with inflammatory bowel disease (IBD), yet little is known about the genetic diversity of C. concisus in relation to host niches and disease. We isolated 104 C. concisus isolates from saliva, mucosal biopsies and faecal samples from 41 individuals (26 IBD, 3 Gastroenteritis (GE), 12 Healthy controls (HC)). Whole genomes were sequenced and the dataset pan-genome examined, and genomic information was used for typing using multi-locus-sequence typing (MLST). C. concisus isolates clustered into two main groups/genomospecies (GS) with 71 distinct sequence types (STs) represented. Sampling site (p C. concisus and provides evidence that genomic variation is related to the source of isolation, but not clinical phenotype.

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

// Stine Dam Henriksen 1, 2, 3, 4 , Poul Henning Madsen 5 , Anders Christian Larsen 1 , Martin Berg Johansen 6 , Inge Sokilde Pedersen 5 , Henrik Krarup 4, 5 and Ole Thorlacius-Ussing 1, 3, 4 1 Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark 2 Department of General Surgery, Hospital of Vendsyssel, Hjorring, Denmark 3 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 4 Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark 5 Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark 6 Unit of Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark Correspondence to: Stine Dam Henriksen, email: stdh@rn.dk Keywords: biomarker, epigenetics, methylation, pancreatic cancer, prognosis Received: December 12, 2016 Accepted: September 13, 2017 Published: September 30, 2017 ABSTRACT Introduction: Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA. Methods: Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection. Results: Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1 , SFRP2 , BNC1 , SFRP1 , TFPI2, and WNT5A ) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2 ) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; ( BMP3 , NPTX2 , SFRP1 , and MGMT ) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1. Conclusion: Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.

Objectives: We aimed to clarify if endometrial cancer patients are at higher risk of venous thromboembolism (VTE) following hysterectomy, compared to patients undergoing hysterectomy for benign gynecological disease. Methods: In a nationwide registry-based cohort study, patients undergoing hysterectomy for endometrial cancer or benign disease were followed 30 days after surgery. The Danish Gynecological Cancer Database (DGCD) and the Danish National Patient Register (DNPR) were linked with four other administrative registries to describe the population and retrieve data on venous thromboembolism and mortality. Multivariable logistic regression models were used to estimate odds ratios (ORs) for 30-day postoperative VTE. Results: We identified 5513 patients with endometrial cancer, and 45,825 patients with benign disease undergoing hysterectomy in the period 2005–2014. The overall incidence of 30-day VTE following hysterectomy was 0.2% (103/51,338). Thirty (0.5%) patients with endometrial cancer and 73 (0.16%) patients with benign disease developed VTE. In a multivariable logistic regression analysis, significant predictors of 30-day OR for VTE were open surgery (minimally invasive surgery vs. open: OR = 0.46; 95% CI, 0.30–0.71; p < 0.001), lymphadenectomy (OR = 4.00; 95% CI, 1.89–8.46; p < 0.001), BMI > 40 (OR = 2.34;95% CI, 1.10–5.01; p = 0.03) and previous VTE (OR = 34; 95% CI, 22.7–51.3; p < 0.001). There was no statistically significant difference in the 30-day OR for VTE in endometrial cancer compared to benign disease (OR = 1.47; 95% CI, 0.74–2.91; p = 0.27). Conclusions: This study did not identify endometrial cancer to be an independent risk factor for VTE following hysterectomy compared to benign disease. We identified open surgery, lymphadenectomy, BMI above 40 and previous VTE as independent risk factors for 30-day postoperative VTE.

Background Among men and women diagnosed with colorectal cancer (CRC), 20–50% will develop a cancer recurrence. Cancer recurrences are not routinely captured by most population-based registries; however, linkage across Danish registries allows for the development of predictive models to detect recurrence. Successful application of such models in population-based settings requires validation against a gold standard to ensure the accuracy of recurrence identification. Objective We apply a recently developed validation study design for prospectively collected validation data to validate predicted CRC recurrences against gold standard diagnoses from medical records in an actively followed cohort of CRC patients in Denmark. Methods We use a Bayesian monitoring framework, traditionally used in clinical trials, to iteratively update classification parameters (positive and negative predictive values, and sensitivity and specificity) in an adaptive validation substudy design. This design allows determination of the sample size necessary to estimate the corresponding parameters and to identify when validation efforts can cease based on predefined criteria for parameter values and levels of precision. Results Among 355 men and women diagnosed with CRC in Denmark and actively followed semi-annually, there were 63 recurrences diagnosed by active follow-up and 70 recurrences identified by a predictive algorithm. The adaptive validation design met stopping criteria for the classification parameters after 120 patients had their recurrence information validated. This stopping point yielded parameter estimates for the classification parameters similar to those obtained when the entire cohort was validated, with 66% less patients needed for the validation study. Conclusion In this proof of concept application of the adaptive validation study design for outcome misclassification, we demonstrated the ability of the method to accurately determine when sufficient validation data have been collected. This method serves as a novel validation substudy design for prospectively collected data with simultaneous implementation of a validation study.

BACKGROUND: The risk of pelvic sepsis following IPAA for ulcerative colitis may have changed with changes in medical and surgical treatment, but data are scarce.OBJECTIVES: This study aims to examine temporal changes in the risk of pelvic sepsis following IPAA for ulcerative colitis and to ascertain risk factors associated with pelvic sepsis.DESIGN: This is a nationwide cohort study.SETTING: This study was conducted in Denmark from 1996 to 2013.PATIENTS: Patients were operated on with an IPAA for ulcerative colitis.MAIN OUTCOME MEASURES: Pelvic sepsis was defined and validated as the occurrence of anastomotic leakage, pelvic abscesses or fistulas, or an operation for these conditions, recorded in a nationwide registry. Cumulative risks were calculated by using death as a competing risk. Multivariate Cox regression was used to examine the effects of calendar periods (1996-1999, 2000-2004, 2005-2009, and 2010-2013) on hazards ratios for pelvic sepsis, adjusting for age, sex, comorbidity, annual hospital volume, pelvic sepsis in the 12 months preceding surgery, operative stage (1-, 2-, modified 2-, or 3-stage), laparoscopy, and preoperative treatment with biological medicine within 12 weeks before surgery.RESULTS: Of 1456 patients, 244 (16.8%) experienced pelvic sepsis. The 1-year risk increased by calendar period (1996-1999: 2.5%, 2000-2004: 4.5%, 2005-2009: 7.4%, and 2010-2013: 9.6%). The adjusted hazard ratio for pelvic sepsis increased by an average 4.4% (95% CI, 1.3-7.6) per year in the study period. In general, patients were older and had more comorbidities at IPAA in recent years than in earlier years, and more had experienced pelvic sepsis in the 12 months preceding the operation.LIMITATIONS: This study was register based. There were no data on important clinical variables to determine the causes of an increased risk over calendar periods.CONCLUSION: In this nationwide cohort study, the 1-year risk of pelvic sepsis following primary IPAA for ulcerative colitis increased 4-fold from 1996 to 2013. See Video Abstract at http://links.lww.com/DCR/A956.

PURPOSE: To validate prescription registry data as a measurement of adherence to statins through a direct method using assays for selected statins in serial blood samples collected from two prospective cohorts of Danish colorectal cancer patients.METHODS: We linked information on statin prescriptions from the Aarhus University Prescription Database with the cancer cohorts from Aalborg University Hospital. For statin-prescribed patients, we calculated a prescription window covering the anticipated duration of the prescription. For each statin-prescribed patient with at least one blood sample in a prescription window, we selected without replacement a never-statin-prescribed patient matched on sex, age, and calendar year of surgery. Each of the selected blood samples were analyzed using assays to detect statins. We calculated the positive and negative predictive value of the prescription registry reporting using the assay result as the gold standard.RESULTS: We identified 73 ever-statin-prescribed patients with a total of 253 blood samples and 74 blood samples among never-statin-prescribed patients. The positive predictive value for prescribed patients, with presence of statins in at least one blood sample as the gold standard, was 93% (95% CI, 86%-97%) and the negative predictive value was 93% (95% CI, 86%-97%). Stratified results did not reveal substantial differences in predictive values. Fifty-two (71%) of the statin-prescribed patients had statins in every blood sample, suggesting continuous adherence.CONCLUSION: This study showed a high adherence with treatment with statins among colorectal cancer patients.

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.

The impact of antibiotic prophylaxis on fecal carriage of ESBL-/AmpC-/carbapenemase-producing Enterobacteriaceae (CPE) was investigated. Patients admitted for elective surgery or diagnostic procedure in a Department of Surgical Gastroenterology (SG) (n= 450) and Orthopedic Surgery (OS) (n= 300) provided a fecal swab at admission and responded to a questionnaire on possible exposures. SG patients received gentamicin/penicillin G (±metronidazole); OS patients received cefuroxime. Two days after surgery a second swab was taken. From SG patients, 6% of first swabs and 9% of second swabs were positive for ESBL-/AmpC-producers. A similar carriage rate was observed in OS patients (6% and 8%, respectively). No CPE were detected. Escherichia coli was the predominant species and blaCTX-M-15 (29% and 22%) and blaCTX-M-14 (11% and 17%) were the most prevalent ESBL genotypes among SG and OS patients. Two different prophylactic antibiotic regimens had no impact on carriage rates. Previous hospitalization and antimicrobial treatment were associated with carriage for SG patients.

Background Gene expression profiles of normal and tumor tissue reflect both differences in biological processes taking place in vivo and differences in response to stress during surgery and sample handling. The effect of cold (room temperature) ischemia in the time interval between surgical removal of the specimen and freezing is described in a few studies. However, not much is known about the effect of warm (body temperature) ischemia during surgery. Methods Three women with primary operable breast cancer underwent in situ biopsies from normal breast and tumor tissue prior to radical mastectomy. Ex vivo biopsies from normal and tumor tissue were collected immediately after surgical excision. The putative effects on gene expression of malignancy (tumor versus normal), surgical manipulation (post- versus pre-surgical) and interaction between the two (differences in effect of surgical manipulation on tumor and normal samples) were investigated simultaneously by Generalized Estimating Equation (GEE) analysis in this self-matched study. Results Gene set enrichment analysis (GSEA) demonstrates a marked difference in effect of surgical manipulation on tumor compared to normal tissue. Interestingly, a large proportion of pathways affected by ischemia especially in tumor tissue are pathways considered to be specifically up regulated in tumor tissue compared to normal. Conclusion The results of this study suggest that a large contribution to this differential expression originates from altered response to stress in tumor cells rather than merely representing in vivo differences. It is important to bear this in mind when using gene-expression analysis to deduce biological function, and when collecting material for gene expression profiling. Electronic supplementary material The online version of this article (10.1186/s10020-018-0058-x) contains supplementary material, which is available to authorized users.

Background: The overall risk of cancer following ileal pouch-anal anastomosis [IPAA] is unknown, and pouch cancer surveillance is controversial. We evaluated long-term risk of cancer in a national cohort of patients with ulcerative colitis and IPAA, with emphasis on pouch cancer.Methods: Data on incident cancers were extracted from the national Danish Cancer Registry. Incidence rates for all site-specific cancers were compared between patients with IPAA and a gender- and age-matched comparison cohort from the background population to obtain incidence rate ratios [IRRs].Results: A total of 1723 patients with IPAA, operated for ulcerative colitis in the period 1980-2010, were matched to 8615 individuals from the background population. During a median follow-up of 12.9 years (interquartile range [IQR] 7.7-19.6 years), two pouch cancers [0.12%] were found after 16 and 27 years, respectively. In the population comparison cohort, 38 intestinal cancers [0.45%] were found, of which 35 were colorectal. The risk of hepatobiliary cancer was higher for patients with IPAA {IRR = 13.0 (95% confidence interval [CI]: 3.1-76.1)}, and half of the affected patients had coexisting primary sclerosing cholangitis. The risk of cancer overall following IPAA was identical to that of the comparison cohort: IRR = 1.05 [0.84-1.31].Conclusions: Pouch cancer following IPAA is very rare, questioning the need for general, rather than selective, surveillance. The overall cancer risk is comparable to that of the background population, and the increased risk of hepatobiliary cancer is likely an effect of coexisting liver disease and not causally related to IPAA.

BACKGROUND AND PURPOSE: Defining margins around the Gross Tumour Volume (GTV) to create a Clinical Target Volume (CTV) for head and neck cancer radiotherapy has traditionally been based on presumed knowledge of anatomical routes of spread. However, using a concentric geometric expansion around the GTV may be more reproducible. The purpose of this study was to analyse the inter-observer consistency of geometric CTV delineation with adaptation for anatomical boundaries versus anatomically defined CTVs.MATERIAL AND METHODS: Radiation oncologists at four Danish cancer centres delineated high, intermediate and elective dose CTVs (CTV1, CTV2 and CTV3, respectively) in a patient-case template (stage IV squamous cell carcinoma of the oropharynx), first using mainly anatomical margins (original standard) and then using concentric geometric expansion (new standard). Each centre made a dummy-run radiotherapy plan based on the delineated CTVs. The difference between the CTV contours and the radiotherapy plans was evaluated across the centres.RESULTS: Anatomy-based contours were significantly more heterogenous and showed larger volume differences between centres than geometric margins. Dice similarity coefficient increased by 0.29 and mean surface distance decreased by 4mm for CTV1. Use of consistent CTV volumes resulted in more consistent irradiated volumes between centres.CONCLUSION: Introduction of geometric margins resulted in more uniform CTV1 and CTV2 delineation. Geometric CTV expansion was easier, left less room for misinterpretation, and resulted in more uniform treatment plans with similar irradiated high and intermediate dose volumes across all centres.

Background The ileal pouch-anal anastomosis is a procedure offered to patients with ulcerative colitis who opt for restoration of bowel continuity. The aim of this study was to determine the risk of pouch failure and ascertain risk factors associated with failure. Method 1,991 patients with ulcerative colitis operated with ileal pouch-anal anastomosis in Denmark in the period 1980–2013 were included. Pouch failure was defined as excision of the pouch or presence of a stoma un-reversed within one year after its creation. We used Cox proportional hazards regression to explore the association between pouch failure and age, gender, synchronous colectomy, primary fecal diversion, annual hospital volume (very low=1-5 cases/year, low=6-10/year, intermediate=11-20/year, high>20/year), calendar year, laparoscopy, and primary sclerosing cholangitis. Results Over a median 11.4 years, 295 failures occurred, corresponding to 5-, 10-, and 20-year cumulative risks of 9.1%, 12.1%, and 18.2%, respectively. The risk of failure was higher for females (adjusted hazard ratio [aHR] 1.39, 95% CI: 1.10-1.75). Primary non-diversion (aHR 1.63, 95% CI: 1.11-2.41) and a low hospital volume (aHR, very low-volume vs. high-volume 2.30, 95% CI: 1.26-4.20) were also associated with a higher risk of failure. The risk of failure was not associated with calendar year, primary sclerosing cholangitis, synchronous colectomy, or laparoscopy. Conclusion In a cohort of patients with ulcerative colitis and ileal pouch-anal anastomosis from Denmark, where pouch surgery is centralized, females had a higher risk of pouch failure. Of modifiable factors, low hospital volume and non-diversion were associated with a higher risk of pouch failure. This article is protected by copyright. All rights reserved.

AIM: Permacol™ collagen paste (Permacol™ paste) is an acellular cross-linked porcine dermal collagen matrix suspension for use in soft tissue repair. The use of Permacol™ paste in the filling of anorectal fistula tract is a new sphincter-preserving method for fistula repair. The MASERATI100 study was a prospective, observational clinical study with the objective to assess the efficacy of Permacol™ collagen paste for anal fistula repair in 100 patients.METHOD: Patients (N=100) with anal fistula were treated at ten European surgical sites with a sphincter-preserving technique using Permacol™ paste. Fistula healing was assessed at 1, 3, 6, and 12 months post-treatment, with the primary endpoint being healing at 6 months. Faecal continence and patient satisfaction were surveyed at each follow-up; adverse events (AEs) were monitored throughout the follow-up.RESULTS: At 6 months post-surgery, 56.7% of patients were healed, and the percentage healed was largely maintained, with 53.5% healed at 12 months. 29.0% of patients had at least one AE, and 16.0% of patients had one or more procedure-related AE. Most AEs reported were minor and similar to those commonly observed after fistula treatment, and the incidence of serious adverse events was low (4.0% of patients). Regardless of treatment outcome, 73.0% of patients were satisfied or very satisfied with the procedure.CONCLUSION: Permacol™ paste provides a promising sphincter-preserving treatment for anal fistulas with minimal adverse side-effects. This article is protected by copyright. All rights reserved.

A method is provided for determining colorectal cancer, or the prognosis of a colorectal cancer in a subject, said method comprising in a sample from said subject determining the methylation status of a specific gene marker panel.

OBJECTIVES: The aim is to review genes aberrantly methylated in pancreatic cancer. This review focuses on DNA promoter hypermethylation in plasma and serum to describe the most promising genes that may be useful as minimally invasive diagnostic blood-based markers for pancreatic cancer.METHODS: A systematic search of the literature was performed using the PubMed and EMBASE databases. The following MeSH terms and free text were used: pancreatic disease, pancreatic cancer, pancreatic neoplasm, methylation, DNA hypermethylation, CG rich sequence, CpG island, cell-free DNA, blood, plasma, serum, fluids, and secretions.RESULTS: In total, 720 articles were found. Eight studies on cell-free DNA promoter hypermethylation in plasma or serum and 2 studies on hypermethylation in whole blood/leukocyte DNA from patients with pancreatic cancer were identified. The search for a hypermethylated marker in cell-free DNA is characterized by a few small studies lacking well-defined control groups. No single gene has been identified as a diagnostic marker.CONCLUSION: Because of insufficient power, none of the genes examined have the potential to work as an individual diagnostic marker, suggesting that a panel of several genes is needed. Further research is warranted before a blood-based diagnostic marker for pancreatic cancer based on promoter hypermethylation can be applied clinically.

In earlier studies of the influence of hydroxymethylglutaryl-coenzyme A reductase inhibitors (also known as statins) on colorectal cancer prognosis, investigators reported a reduced rate of cancer-specific mortality. Studies of recurrence are few and small. Using data from Danish registries, we followed 21,152 patients diagnosed with stage I-III colorectal cancer from 2001 to 2011. We estimated the association between statin use in the preceding year and cancer recurrence, cancer-specific mortality, and all-cause mortality rates. We identified 5,036 recurrences, 7,084 deaths from any cause, and 4,066 deaths from colorectal cancer. After adjustment for potential confounders, statin use was not associated with recurrence (adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.93, 1.09), but it was associated with death from colorectal cancer (aHR = 0.72, 95% CI: 0.65, 0.79) and death from any cause (aHR = 0.72, 95% CI: 0.67, 0.76). Statin use in the year preceding recurrence was associated with a reduced risk of cancer-specific mortality (aHR = 0.83, 95% CI: 0.74, 0.92) but also a reduced risk of death from any other cause (aHR = 0.78, 95% CI: 0.61, 1.00). Statin use was not associated with a reduced rate of colorectal cancer recurrence, but it was associated with a reduced rate of cancer-specific mortality, which suggests that there is no cancer-directed benefit; therefore, there is no basis to prescribe statins to colorectal cancer patients who do not have cardiovascular indications.

// Simon Ladefoged Rasmussen 1, 2, 3 , Henrik Bygum Krarup 2, 4 , Kare Gotschalck Sunesen 1 , Martin Berg Johansen 5 , Mogens Tornby Stender 1 , Inge Sokilde Pedersen 2, 4 , Poul Henning Madsen 2, 4 and Ole Thorlacius-Ussing 1, 2, 3 1 Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark 2 Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark 3 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 4 Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark 5 Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark Correspondence to: Simon Ladefoged Rasmussen, email: simon.rasmussen@rn.dk Keywords: colorectal cancer; DNA hypermethylation; prognosis; staging Received: September 08, 2017 Accepted: January 03, 2018 Published: January 09, 2018 ABSTRACT Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC). We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information. The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival. The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.

Study Objective: To estimate the risk of venous thromboembolic complications after abdominal, laparoscopic, and vaginal hysterectomy when performed for benign disorders. Design: A nationwide cohort study (Canadian Task Force classification II-2). Setting: Data from Danish national registers on all women undergoing hysterectomy for benign conditions from 1996 to 2015. Patients: Women aged 18 years and older who underwent hysterectomy for benign disease were stratified into 3 groups according to the hysterectomy approach: abdominal, laparoscopic, or vaginal. Interventions: Hysterectomy. Measurements and Main Results: Eighty-nine thousand nine hundred thirty-one women met the inclusion criteria. Venous thromboembolism (VTE) as a diagnosis or cause of death was identified. The risk of postoperative VTE was examined with Cox proportional hazard models adjusting for age, surgical approach, and relevant comorbidities. The mean age was 49.9, 47.9, and 54.3 years for women with abdominal, laparoscopic, and vaginal hysterectomy, respectively. The crude incidences of VTE within 30 days after hysterectomy were 0.24% (n = 142), 0.13% (n = 12), and 0.10% (n = 21). The most important predictors of VTE were the approach to hysterectomy and a history of thromboembolic disease. In the multivariable analysis, the risk of VTE was significantly reduced with laparoscopic hysterectomy (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.28–0.92; p =.03) and vaginal hysterectomy (HR = 0.39; 95% CI, 0.24–0.63; p

BACKGROUND: Recurrence is a common outcome among patients that have undergone an intended curative resection for colorectal cancer. However, data on factors that influence colorectal cancer recurrence are sparse. We report descriptive characteristics of both colon and rectal cancer recurrence in an unselected population.MATERIAL AND METHODS: We identified 21,152 patients with colorectal cancer diagnosed between May 2001 and December 2011 and registered with the Danish Colorectal Cancer Group. Recurrences were identified in 3198 colon and 1838 rectal cancer patients during follow-up. We calculated the frequency, proportion, and incidence rates of colon and rectal cancer recurrence within descriptive categories, and the cumulative five- and ten-year incidences of recurrence, treating death as a competing risk. We used a Cox proportional hazard model to calculate hazard ratios (HR) and 95% confidence intervals (CI).RESULTS: Recurrence risk was highest in the first three years of follow-up. Patients CONCLUSIONS: In this population, increases in colorectal cancer recurrence risk were associated with younger age and increasing stage at diagnosis. Cumulative incidence of recurrence did not differ by cancer type. Descriptive characteristics of colon and rectal cancer recurrence may help to inform patient-physician decision-making, and could be used to determine adjuvant therapies or tailor surveillance strategies so that recurrence may be identified early, particularly within the first 3 years of follow-up.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection.METHODS: We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC.RESULTS: None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5.CONCLUSIONS: Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.

OBJECTIVES: Biochemical studies suggest that patients who have had a colectomy or restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) are at an increased risk of developing gallstone disease, but epidemiological studies are lacking. We evaluated the risk of gallstone disease following colectomy and IPAA.METHODS: Individuals who had a colectomy were identified from a national cohort of patients with ulcerative colitis (UC), and controls without colectomy were sampled from within the same cohort, matching on gender, calendar year, and year of birth. We used Cox regression to examine the effect of colectomy on the hazard rates of gallstone disease and cholecystectomy, adjusting for alcoholism, stroke, chronic obstructive pulmonary disease, cancer, cardiac disease, diabetes mellitus, hypothyroidism, hyperlipidemia, cirrhosis, obesity, renal failure, and transient ischemic attacks. The effect of an IPAA was determined for patients who had colectomy by including the procedure as a time-dependent variable.RESULTS: We identified 4548 patients and matched these to 44 372 controls without colectomy. During a median follow-up of 11.9 years, 1963 patients were hospitalized for gallstone disease. Patients who had a colectomy were at an increased risk (adjusted hazard ratio (HR)=1.63 (1.39-1.91)), and sensitivity analyses of the risk of undergoing cholecystectomy revealed a similar association (adjusted HR=1.55 (1.22-1.98)). An IPAA did not affect the risk of developing gallstones among patients who had a colectomy (adjusted HR=1.03 (0.77-1.37)).CONCLUSION: The risk of gallstone disease increases following colectomy for UC.Am J Gastroenterol advance online publication, 24 January 2017; doi:10.1038/ajg.2016.564.

BACKGROUND: The main treatment for non-metastatic rectal cancer (RC) is surgical resection. Late adverse effects that are highly prevalent and negatively impact patients' symptom burden and quality of life are: bowel-, urological and sexual dysfunctions; psychological distress; fear of recurrence. Patients and clinicians have requested a more patient-centred follow-up, balancing the focus on detection of recurrence, and physiological and psychological late adverse effects. The current follow-up program primarily focuses on detection of recurrence, with less attention on late adverse effects. As a consequence, the randomized controlled trial Follow-up after Rectal Cancer (FURCA) has been launched, testing the effect of a new patient-led, follow-up program. The aim of this paper is to describe the methodology used in the FURCA study and to report results from the development of the patient-led, follow-up program. Adult patients, treated with curative intent for primary adenocarcinoma in the rectum are included from four Danish centers.MATERIAL AND METHODS: Patients are randomized into an intervention group, receiving standardized education and access to self-referral to an assigned project nurse, or a control group following the current follow-up program with routine medicals. The primary outcomes are symptom burden and quality of life, measured by the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) questionnaire. Other outcome and demographic data are collected as patient-reported measures and register-based data. Results from developing the intervention: The education program is based on data from two focus group interviews and the feedback from experts. An algorithm is developed in order to qualify the research nurses' responses to patients' self-referral. Discussion and perspectives: The results of the FURCA study will strengthen the evidence base for RC follow-up, and qualify the ongoing transformation in cancer follow-up programs.

Colorectal cancer recurrences are difficult to ascertain accurately and efficiently. We developed and validated an algorithm to identify recurrences that uses Danish medical registries. The algorithm uses metastasis and chemotherapy codes in the Danish National Patient Registry and codes indicating cancer recurrence in the Danish Pathology Registry. We applied the algorithm to a cohort (n = 21,246) of colorectal cancer patients diagnosed 2001-2011 and followed through 2012. In a cohort (n = 355) of two groups of actively followed patients, we compared the imputed recurrence data with recurrences diagnosed by regular follow-up. We compared cumulative incidence curves of imputed recurrence in local and regional stage patients from the large cohort, and of imputed and diagnosed recurrences in the actively followed cohort. In the 355 members of the actively followed cohort, our algorithm correctly identified 60 of 63 recurrences [sensitivity = 95%; 95% confidence interval (CI) 87-99%] and misclassified only 10 of 292 without recurrence (specificity = 97%; 95% CI 94-98%). Cumulative incidence curves showed that members of the large cohort with regional disease had much higher incidence of imputed recurrence than those with local disease. In the actively followed cohort, the cumulative incidence of recurrence overlapped substantially when recurrence was imputed by our algorithm or using the follow-up data. Despite some limitations regarding ambiguous pathology codes, our algorithm showed excellent performance against actively followed recurrence data, and the expected relation between recurrence risk and cancer stage. It can be used in the Danish registries and adapted to similar registries elsewhere.

PURPOSE: Carcinoembryonic antigen (CEA) has limited value as an isolated predictor for survival among colorectal cancer (CRC) patients. D-dimer (DD) is a strong predictor of survival among metastatic CRC patients, but the prognostic value in non-metastatic CRC patients remains controversial. We examined the prognostic value of preoperative DD levels in relation to CEA levels in non-metastatic, resectable CRC patients.METHODS: Between October 2003 and November 2005, 166 patients were included. We used the Kaplan-Meier method to compute 5-year mortality rates, stratified by preoperative DD and CEA levels. Adjusted Cox regression analysis was used to compute mortality rate ratios (MRRs) during postoperative years 0-1 and 1-5 based on the preoperative CEA and DD levels.RESULTS: The cumulative 5-year mortality rate was 15 % (95 % confidence interval [CI], 9-25 %) in patients with normal DD and CEA levels, 30 % (CI, 16-53 %) in patients with isolated elevated CEA levels, 37 % (CI, 25-53 %) in patients with isolated elevated DD levels, and 60 % (CI, 37-83 %) in patients with elevated CEA and DD levels. Elevated CEA was associated with an approximately ten-fold increase in mortality within the first postoperative year (adjusted MRR 9.8, CI 2.5-38.3); this association was lost during postoperative years 1-5 (adjusted MRR 1.1, CI 0.5-2.7). Elevated DD was associated with a greater than two-fold increase in mortality during postoperative years 0-1 (adjusted MRR 2.8, CI 0.7-11.0) and 1-5 (adjusted MRR 2.2, CI 1.1-4.8).CONCLUSION: DD is a strong predictor of survival among non-metastatic curatively resected CRC patients, particularly in combination with CEA.

Background Venous thromboembolism (VTE) in patients with upper gastrointestinal (GI) cancer increases morbidity and mortality. This study aimed to determine the prevalence of VTE at diagnosis of upper GI cancer. Methods Patients admitted between February 2008 and February 2011 with upper GI cancer (pancreatic, extrahepatic biliary, lower oesophageal, gastro-oesophageal junction or gastric cancer) were investigated in a cross-sectional cohort study. At cancer diagnosis, all patients were examined for deep vein thrombosis (DVT) by means of bilateral compression ultrasonography. From February 2009 and onwards, computed tomographic pulmonary angiography (CTPA) was also performed for the diagnosis of pulmonary embolism (PE). Results Some 250 patients had ultrasonography; CTPA was performed in 143 patients on admission. DVT was detected in 13 (5·2 per cent) of the 250 patients, eight (3·2 per cent) of whom were asymptomatic. DVT was correlated with tumour location in the pancreaticobiliary tract (odds ratio (OR) 6·27, 95 per cent confidence interval 1·18 to 33·38; P = 0·031) and tumour stage IV (OR 19·34, 2·33 to 160·70; P = 0·006). PE was detected in 11 (7·7 per cent) of 143 patients, eight (5·6 per cent) of whom were asymptomatic. PE embolism was also significantly more common in patients with pancreaticobiliary tract cancer (OR 7·81, 1·28 to 47·62; P = 0·026) and in those with stage IV disease (OR 17·19, 1·83 to 161·50; P = 0·013). Conclusion The prevalence of VTE at cancer diagnosis was significantly higher in patients with pancreaticobiliary tract cancer than in those with other forms of upper GI cancer, and in patients with advanced cancer stage.

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

Background Campylobacter concisus is a commensal of the human oral flora that has been linked to prolonged diarrhea and inflammatory bowel disease (IBD). It has been detected more often from intestinal biopsies in patients with IBD compared to healthy controls using PCR-based techniques, whereas the number of C. concisus culture-positive biopsies in previous studies has been very limited. Determining the rate of viable isolates present in the gut mucosa is of great importance when evaluating the role in different disease presentations. We therefore investigated a novel two-step cultivation procedure combining anaerobic and microaerobic incubation from several gut mucosal sites to improve isolate yield, and compared this to PCR results, from IBD patients and healthy controls. Results Cultivation with the novel two-step procedure yielded a higher rate of C. concisus isolates from mucosal biopsies than previously reported by other methods. From 52 IBD patients, 52/245 (21 %) biopsies were culture positive for C. concisus, while 121/245 (49 %) of biopsies were PCR positive. For 26 healthy controls, the numbers were 23/182 (13 %) and 66/182 (36 %), respectively (p

AIM: Permacol(™) collagen paste (Permacol(™) paste) is a new option for the treatment of anorectal fistula. It functions by filling the fistula tract with an acellular crosslinked porcine dermal collagen matrix suspension. The MASERATI 100 study group was set to evaluate the clinical outcome of Permacol(™) paste in the treatment of anorectal fistula. This paper reports the results from the initial 30 patients enrolled in the MASERATI 100 prospective, observational clinical trial.METHOD: Patients (N=30) with anal fistula presenting to ten European academic surgical units were treated with a sphincter-preserving technique using Permacol(™) paste. Fistula healing was assessed at 1, 3, 6, and 12 months after treatment, with the primary endpoint of fistula healing at 6-months post-surgery. Faecal continence and patient satisfaction were recorded at each follow-up visit and adverse events were monitored throughout the follow-up.RESULTS: Of the 28 patients with data at six months post-surgery, 15 (54%) were healed, and the healing rate was maintained at 12 months. Healing after treatment with Permacol(™) paste was similar for intersphincteric to transsphincteric fistulas and primary or recurrent fistulas. Only one patient exhibited an adverse event (perianal abscess) that was possibly related to the treatment. At the last outpatient visit, over 60% of patients were satisfied or very satisfied with the operation.CONCLUSION: Permacol(™) paste is was shown to be effective in treating primary and recurrent cryptoglandular anorectal fistula with minimal unwanted side effects. This article is protected by copyright. All rights reserved.

To examine the impact of plasma D-dimer levels in predicting 3-year survival and nonresectability in pancreatic cancer patients. Ninety-five patients were divided into three groups according to plasma D-dimer levels. Kaplan-Meier survival curves and hazard ratios were computed, and diagnostic indices of D-dimer in the prediction of resectability were assessed. The median survival among patients with low, medium and high D-dimer levels was 13.7 [95% confidence interval (CI): 10.2-19.6], 6.2 (95% CI: 2.0-15.1) and 2.4 months (95% CI: 1.4-3.3), respectively. The adjusted hazard ratio of death in the group of patients with high D-dimer levels was 2.2 (95% CI: 1.1-4.2). The positive and negative predictive values of D-dimer in the prediction of nonresectability were 89% (95% CI: 77-96%) and 48% (95% CI: 33- 63%), respectively. An elevated D-dimer level is associated with reduced survival in pancreatic cancer and predicts nonresectability.

Background Pancreatic cancer has a 5-year survival rate of only 5–7%. Difficulties in detecting pancreatic cancer at early stages results in the high mortality and substantiates the need for additional diagnostic tools. Surgery is the only curative treatment and unfortunately only possible in localized tumours. A diagnostic biomarker for pancreatic cancer will have a major impact on patient survival by facilitating early detection and the possibility for curative treatment. DNA promoter hypermethylation is a mechanism of early carcinogenesis, which can cause inactivation of tumour suppressor genes. The aim of this study was to examine promoter hypermethylation in a panel of selected genes from cell-free DNA, as a diagnostic marker for pancreatic adenocarcinoma. Methods Patients with suspected or biopsy-verified pancreatic cancer were included prospectively and consecutively. Patients with chronic/acute pancreatitis were included as additional benign control groups. Based on an optimized accelerated bisulfite treatment protocol, methylation-specific PCR of a 28 gene panel was performed on plasma samples. A diagnostic prediction model was developed by multivariable logistic regression analysis using backward stepwise elimination. Results Patients with pancreatic adenocarcinoma (n = 95), chronic pancreatitis (n = 97) and acute pancreatitis (n = 59) and patients screened, but negative for pancreatic adenocarcinoma (n = 27), were included. The difference in mean number of methylated genes in the cancer group (8.41 (95% CI 7.62–9.20)) vs the total control group (4.74 (95% CI 4.40–5.08)) was highly significant (p 65, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) had an area under the curve of 0.86 (sensitivity 76%, specificity 83%). The model performance was independent of cancer stage. Conclusions Cell-free DNA promoter hypermethylation has the potential to be a diagnostic marker for pancreatic adenocarcinoma and differentiate between malignant and benign pancreatic disease. This study brings us closer to a clinical useful diagnostic marker for pancreatic cancer, which is urgently needed. External validation is, however, required before the test can be applied in the clinic. Trial registration ClinicalTrials.gov, NCT02079363 Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0286-2) contains supplementary material, which is available to authorized users.

Summary. Background: Fibrin formation is required for tumor angiogenesis, metastasis and invasion. Cancer discovered at the same time as or shortly after venous thromboembolism (VTE) tends to be advanced, and the prognosis poor. Previous studies have demonstrated that plasma D-dimer – a degradation product of cross-linked fibrin – correlates with tumor stage and prognosis in patients with colorectal cancer. However, it remains unclear whether D-dimer is of prognostic significance in colorectal cancer patients with absence of VTE. Objective: To examine whether the preoperative plasma D-dimer level predicts 1-year survival in pre- and postoperative VTE-negative colorectal cancer patients admitted for surgery. Methods: We measured preoperative D-dimer levels in 157 patients, and computed Kaplan-Meier survival curves according to the levels of D-dimer. Cox proportional-hazard regression analysis was used to compute hazard ratio as a measure of 1-year mortality rate ratio, controlling for potential confounding factors. The Aalborg Hospital’s standard cut-off level of 0.3 mg L−1 was used to distinguish negative and positive D-dimer results. Results: The overall 1-year survival rate was 87.3% (95% confidence interval (CI), 81.0–91.6%), with 78.1% survival (95% CI, 65.9–86.4%) in the positive D-dimer group compared with 93.6% survival (95% CI, 86.2–97.1%) in the negative D-dimer group. The adjusted hazard ratio of death in the positive D-dimer group compared with the negative D-dimer group was 3.6 (95% CI, 1.3–9.9). Conclusion: A positive preoperative D-dimer is associated with a poor prognosis in colorectal cancer patients with absence of VTE.

The large number of colorectal cancer survivors, coupled with the financial burden of colorectal cancer, makes it critical to identify factors associated with cancer recurrence. The human gut microbiome is one of the most densely populated bacterial communities known to exist. It plays a vital role in the host's gut physiology and potentially contributes to colorectal cancer progression. Given the prevalence and often overuse of antibiotics in the population, and their effects on the gut microbiome, the potential influence of antibiotics on the clinical course of colorectal cancer is of great public health importance. Using data from Danish medical registries, we followed 21,152 patients (5,036 with recurrences) diagnosed with stage I-III colorectal cancer from 2001 to 2011. We examined the association between pre- and post-diagnostic antibiotic use and cancer recurrence. After adjustment for potential confounders (age at diagnosis, sex, year of diagnosis, stage, tumor location, cancer treatment, comorbidities, inflammatory bowel disease, and use of statins, non-steroidal anti-inflammatory drugs and aspirin), any antibiotic prescription 90 days prior to colorectal cancer diagnosis was not associated with recurrence [adjusted hazard ratio (aHR) = 1.06, 95% confidence interval (CI): 0.98, 1.14]. However, antibiotic use after cancer diagnosis was associated with a higher risk of recurrence (aHR = 1.23, 95% CI: 1.16, 1.31). Additional ongoing analyses address cancer-specific and all-cause mortality and different time-lag periods. Their results also will be presented at the meeting. Our preliminary findings support further investigation into the possible roles of the gut microbiome and agents that alter its composition and diversity in colorectal cancer progression. Citation Format: Veronika Fedirko, Deirdre Cronin-Fenton, Anders Hammerich Riis, Henrik Toft Sørensen, Claus Lindbjerg Andersen, Ole Thorlacius-Ussing, Timothy Lash. Antibiotic prescriptions and colorectal cancer recurrence risk: A Danish nationwide prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-166.

Background Deep venous thrombosis (DVT) is a major complication of cancer and a predictor of reduced survival. The postoperative prevalence of DVT in colorectal cancer surgery is high, but the preoperative prevalence is unknown. The aim of this observational study was to estimate the preoperative prevalence of DVT in patients with colorectal cancer. Methods Some 193 consecutive patients with newly diagnosed colorectal cancer admitted for intended curative surgery were examined with compression ultrasonography for DVT before surgery. Results DVT was detected in 15 (7·8 per cent) of the 193 patients, with a prevalence of 16 per cent in women (12 of 76) versus 2·6 per cent in men (three of 117 (adjusted odds ratio (OR) 5·8 (95 per cent confidence interval (c.i.) 1·4 to 23·2)). The risk of DVT was strongly correlated with increasing American Society of Anesthesiologists (ASA) risk score: adjusted OR 6·8 (95 per cent c.i. 1·6 to 28·7 for ASA group III or IV versus ASA group I or II). Pulmonary embolism was detected in two patients (1·0 per cent). Conclusion A high preoperative prevalence of DVT was observed in patients with colorectal cancer, especially among women and patients in ASA groups III and IV.

Respiratory disease in the very preterm infant is frequent and often severe. Bilirubin is both a potent neurotoxin and antioxidant, and may have a clinical impact on preterm respiratory disease. The Gilbert genotype, the UGT1A1*28 allele, is the major known genetic cause of variation in bilirubin.To study the association between respiratory disease in the very preterm infant and the UGT1A1*28 allele.This is a cohort study of 1,354 very preterm infants (gestational age32 weeks) born in Jutland, Denmark in 1997-2011. Genotypes were obtained from the Danish Neonatal Screening Biobank, and clinical information was obtained from the databases of two tertiary neonatal intensive care units. Outcomes were the need for surfactant therapy, any need for and duration of supplementary oxygen and bronchopulmonary dysplasia (BPD).Per UGT1A1*28 allele, odds were increased for any need of supplementary oxygen (odds ratio 1.26; 1.05-1.50) and for BPD (odds ratio 1.71; 1.23-2.39), the need of supplementary oxygen increased by 6.38 days (1.87-10.89), and chance per day of no longer needing supplementary oxygen was reduced (hazard rate 0.84; 0.76-0.93). No effect was observed for need of surfactant treatment (odds ratio 1.08; 0.91-1.28). Hardy-Weinberg equilibrium was unlikely for the cohort (p0.012). This could be explained by death prior to genotype sampling. In tests of robustness this failed to explain the primary results.Compared to the common genotype, UGT1A1*28 genotypes were associated with an increased need of oxygen supplementation and risk of BPD in very preterm newborns.

BACKGROUND: The diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) as the first imaging approach in the evaluation of rising carcinoembryonic antigen (CEA) is not clear. The objective of this study was to investigate the value of (18)F-FDG PET/CT in patients with colorectal cancer (CRC) and suspected recurrence based on rising CEA.METHODS: A total of 73 patients with CRC were referred to PET/CT after radical surgery. Generally, all patients were scheduled to follow a CT-based post-surgical follow-up regimen. In the case of rising CEA, (18)F-FDG PET/CT was performed in most patients with contrast-enhanced CT. The PET/CT images were independently reviewed by two readers. The presence or absence of recurrence was based on histology and/or standardized clinical follow-up.RESULTS: Among 35 patients who had confirmed recurrence of CRC, PET/CT demonstrated recurrence with a sensitivity of 85.7 %, a specificity of 94.7 %, a positive predictive value of 93.8 %, and a negative predictive value of 87.8 %. The SUVmax ranged from 1.3 to 19.9. The mean time since the last postoperative imaging and PET/CT was 8 months (median 4 months). CEA values at referral ranged from 1.5 to 164.0 μg/L (median 5.6 μg/L). The diagnostic properties of PET/CT were analyzed in subgroups of patients with a single rising CEA sample (30 patients, 41 %), 31 patients (43 %) with two or more consecutive increases, and 12 patients (16 %) with persistently elevated values.CONCLUSIONS: (18)F-FDG PET/contrast-enhanced CT has high diagnostic accuracy in the diagnosis of recurrent CRC, even in patients in a conventional CT-based follow-up program.

BACKGROUND: Recent clinical trials have demonstrated the benefit and feasibility of perioperative chemotherapy for treatment of gastroesophageal adenocarcinoma (GEA). Despite convincing results, patients entering such trials usually represent only a fraction of those who are candidates for treatment. Confirmation of trial-reported effects and tolerability in unselected cohorts is therefore required. The aims of this study were to confirm the safety and efficacy of perioperative chemotherapy for resectable GEA and to delineate risks of treatment failure.METHODS: We conducted a national retrospective cohort analysis of patients admitted for perioperative chemotherapy for resectable GEA. Regimens were epirubicin and capecitabine combined with oxaliplatin or cisplatin.RESULTS: The intention-to-treat analysis included 271 patients. Eighty-seven percent of patients completed preoperative chemotherapy, and 63 % received radical resection. Age >70 years (odds ratio 2.58) and hypoalbuminemia (odds ratio 4.10) were independent predictors of not undergoing scheduled surgery (P = 0.033). Grade 3 or higher febrile neutropenia, fatigue, and diarrhea were common in the oxaliplatin group (n = 128), but hypomagnesaemia and tinnitus/hearing loss were more common in the cisplatin group (n = 135). The median overall survival was 26.4 months, and the 1- and 2-year survival rates were 76 and 53 %, respectively. Performance status >0 (hazard ratio 1.64) and elevated serum lactate dehydrogenase (hazard ratio 3.03) were independent predictors of poor prognosis (P ≤ 0.05).CONCLUSIONS: Perioperative chemotherapy is feasible and well tolerated in patients with good performance status and low incidence of comorbidities.

OBJECTIVE: To examine whether preadmission glucocorticoid use increases the risk of anastomotic leakage after colon and rectal cancer resections.DESIGN: A population-based cohort study.SETTING: Denmark (2001-2011).PARTICIPANTS: We identified patients who had undergone a primary anastomosis after a colorectal cancer resection by linking medical registries. Participants who filled their most recent glucocorticoid prescription ≤90, 91-365 and >365 days before their surgery date were categorised as current, recent and former users, respectively.MAIN OUTCOME MEASURES: We calculated 30-day absolute risk of anastomotic leakage and computed ORs using logistic regression models with adjustment for potential confounders.RESULTS: Of the 18 190 patients with colon cancer, anastomotic leakage occurred in 1184 (6.5%). Glucocorticoid use overall was not associated with an increased risk of leakage (6.4% vs 6.9% among never-users; OR 1.05; 95% CI 0.89 to 1.23). Categories of oral, inhaled or intestinal-acting glucocorticoids did not greatly affect risk of leakage. Anastomotic leakage occurred in 695 (13.2%) of 5284 patients with rectal cancer. Glucocorticoid use overall slightly increased risk of leakage (14.6% vs 12.8% among never-users; OR 1.36, 95% CI 1.08 to 1.72). Results did not differ significantly within glucocorticoid categories.CONCLUSIONS: Preadmission glucocorticoids modestly increased the risk of anastomotic leakage mainly after rectal cancer resection. However, absolute risk differences were small and the clinical impact of glucocorticoid use may therefore be limited.