Anders Christian Larsen

Treatment-related frequency of venous thrombosis in lower esophageal, gastro-esophageal and gastric cancer--a clinical prospective study of outcome and prognostic factors.

INTRODUCTION Prospective studies of chemotherapy-associated VTE in cancer patients undergoing neoadjuvant chemotherapy in combination with curative intended surgery have not been reported for upper gastrointestinal cancer. In this clinical prospective study, we sought to estimate the incidence of VTE in esophagogastric cancer (OEC) patients scheduled for a specific perioperative chemotherapy regime: oxaliplatin, capecitabine, and epirubicin, (EXE) and curative intended surgery. MATERIAL AND METHODS A total of 129 consecutive OEC patients were examined using state-of-the-art bilateral compression ultrasound (biCUS) for deep vein thrombosis (DVT) before undergoing preoperative chemotherapy, surgery, and postoperative chemotherapy. In addition 79 were also consecutively scanned at baseline for pulmonary embolism (PE) using state-of-the-art computer tomography pulmonary angiography (CTPA). RESULTS There were 21 VTE cases throughout the course of treatment (16%, 95% confidence interval [95% CI]: 10 - 24%) among the patients examined using both biCUS and CTPA. Fourteen of 21 VTE was incidental (68%, 95% CI: 43 -85) and 7 VTE events was symptomatic (33%, 15 - 57). The median overall survival was 18months (95% CI: 13 - 24) in patients without any VTE and 14months (95% CI: 7 -30, P = 0.820) in patients with VTE. The cancer stage (adjusted odds ratio [OR]: 5.2, 95% CI: 1 - 21, p=0.002) and gastric cancer (OR 6.4, 95% CI: 2 - 21, P = 0.002) was a significant predictor of VTE. CONCLUSION The incidence of VTE in patients undergoing EXE neoadjuvant chemotherapy was high, particularly among patients with initial stage III and IV cancers. In addition, a substantial number of chemotherapy-related VTE cases were asymptomatic.

Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

BackgroundPancreatic 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.MethodsPatients 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.ResultsPatients 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 < 0.001). A diagnostic prediction model (age >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.ConclusionsCell-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 registrationClinicalTrials.gov, NCT02079363

Prevalence of venous thromboembolism at diagnosis of upper gastrointestinal cancer

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.

Venous thrombosis in pancreaticobiliary tract cancer: outcome and prognostic factors.

The differences in outcome among cancer patients with incidental vs. symptomatic venous thromboembolism (VTE) are unknown. In this study, patients with extrahepatic pancreaticobiliary tract cancer (PBC) were selected for a prospective cohort study between February 2008 and February 2011.

Promoter Hypermethylation in Plasma-Derived Cell-Free DNA as a Prognostic Marker for Pancreatic Adenocarcinoma Staging

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.

D-Dimer predicts prognosis and non-resectability in patients with pancreatic cancer: a prospective cohort study

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.

Comparative investigation of postoperative complications in patients with gastroesophageal junction cancer treated with preoperative chemotherapy or surgery alone

Background and aim: Gastroesophageal junction cancer is one of the leading causes to cancer-related death and the prognosis is poor. However, progress has been made over the last couple of decades with the introduction of multimodality treatment and optimized surgery. Three-year survival rates have improved to 50% in patients receiving neoadjuvant therapy. Only a few studies have focused on the difference of postoperative complications in patients receiving neoadjuvant therapy in relation to a comparative surgery-only group. The aim of this study was to compare the prevalence of postoperative complications of patients with cancer at the gastroesophageal junction treated with either neoadjuvant chemotherapy or surgery alone in patients from “The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach.” Materials and methods: A historical follow-up study, comparing postoperative complications between two cohorts before and after implementation of chemotherapy was completed. Results: In all, 180 consecutive patients treated with perioperative chemotherapy and a comparative surgery-only group of patients were identified from The Danish Clinical Registry of Carcinomas of the Esophagus, the Gastro-Esophageal Junction and the Stomach. No difference was found in demographics between the two groups, except for alcohol consumption and a lower T and N stage in the surgery-only group, and no difference in complication rates was found. Furthermore, no variable in the multivariate analysis was significantly associated with anastomotic leakage which was considered the most severe complication. Conclusion: Since perioperative chemotherapy does not appear to increase surgical complications, the future challenges include defining the optimal combination of chemo- and/or radiotherapy, but more importantly also to select the patients who will benefit the most from the different neoadjuvant strategies.

Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma

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.

Quality of endoscopic surveillance of Barrett’s esophagus

Abstract Objectives: The aim of this study was to evaluate adherence to Barrett’s esophagus (BE) surveillance guidelines in Denmark. Methods: The Danish Pathology Registry was used to identify 3692 patients. A total of 300 patients were included by drawing a simple random sample. Description of the BE segment, biopsy protocol, communication with the pathologist and planned follow-up endoscopy, was evaluated. Results: Thirty-one patients were excluded due to missing reports and 83 patients (28%) due to no endoscopic evidence of BE. Endoscopists suspected BE in 186 patients (62%) and these patients were included. Prague C&M classification was used in 34% of the endoscopy reports. The median number of biopsies was 4 (interquartile range (IQR), 3–6). The BE segment was stratified by lengths of 1–5, 6–10 and 11–15 cm and endoscopists obtained a sufficient number of biopsies in 12, 8 and 0% of cases, respectively. 28% of endoscopists described the exact location of the biopsy site in the pathology requisition. Patients with nondysplastic BE had endoscopic surveillance performed after a median of 24 months (IQR, 6–24). Conclusions: Adherence to the Danish guidelines was poor. This may be associated with insufficient quality of BE surveillance. Lack of endoscopic evidence of BE in the Danish Pathology Registry may have underestimated the incidence of adenocarcinoma in BE patients in previous studies.

PO-04 Prevalence of venous thromboembolism in upper gastrointestinal cancer at time of diagnosis

PO-04 Prevalence of venous thromboembolism in upper gastrointestinal cancer at time of diagnosis A.C. Larsen *, T. Dabrowski, R. Vincents Fisker, S. Risom Kristensen, B. Kuno Møller, O. Thorlacius-Ussing. Department of Gastroenterological Surgery, Department of Radiology, Department of Nuclear Medicine, and Department of Biochemistry, Aalborg Hospital, Department of Clinical Immunology, Aarhus University Hospital, Skejby, Denmark