Mogens Tornby Stender

Preoperative plasma D-dimer is a predictor of postoperative deep venous thrombosis in colorectal cancer patients: a clinical, prospective cohort study with one-year follow-up

PURPOSE: The study examined if preoperative plasma D-dimer level was associated with the postoperative cumulative incidence of deep venous thrombosis in patients with colorectal cancer admitted for intended curative surgery. METHODS: In 176 consecutive patients with newly-diagnosed colorectal cancer and absence of preoperative deep venous thrombosis, we measured the preoperative plasma D-dimer levels and performed compression ultrasonography for deep venous thrombosis prior to surgery, as well as one week, one month, and one year after surgery. RESULTS: The cumulative incidence of deep venous thrombosis up to one year after surgery was 20 percent (95 percent confidence interval, 12 to 31 percent) in the positive D-dimer group compared with 5 percent (95 percent confidence interval, 2 to 12 percent) in the negative D-dimer group. The adjusted hazard ratio of deep venous thrombosis in the positive vs. the negative D-dimer group was 6.53 (95 percent confidence interval, 1.58 to 27.0). CONCLUSIONS: A positive preoperative D-dimer was associated with a higher cumulated incidence of postoperative deep venous thrombosis. D-dimer might be useful in identifying those colorectal cancer patients who fail to respond to standard prophylaxis for deep venous thrombosis.

High preoperative prevalence of deep venous thrombosis in patients with colorectal cancer.

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.

Increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and colorectal adenocarcinoma determined by a newly developed ELISA using a specific monoclonal antibody

Citrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 ± 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 ± 237.6 ng/ml and 36.8 ± 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma.

Preoperative plasma D-dimer predicts 1-year survival in colorectal cancer patients with absence of venous thromboembolism (VTE): a prospective clinical cohort study

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.

Combined use of clinical pre-test probability and D-dimer test in the diagnosis of preoperative deep venous thrombosis in colorectal cancer patients

The preoperative prevalence of deep venous thrombosis (DVT) in patients with colorectal cancer may be as high as 8%. In order to minimize the risk of pulmonary embolism, it is important to rule out preoperative DVT. A large study has confirmed that a negative D-dimer test in combination with a low clinical pre-test probability (PTP) can be safely used to rule out the tentative diagnosis of DVT in cancer patients. However, the accuracy in colorectal cancer patients is uncertain. This study assessed the diagnostic accuracy of a quantitative D-dimer assay in combination with the PTP score in ruling out preoperative DVT in colorectal cancer patients admitted for surgery. Preoperative D-dimer test and compression ultrasonography for DVT were performed in 193 consecutive patients with newly diagnosed colorectal cancer. Diagnostic accuracy indices of the D-dimer test were assessed according to the PTP score. The negative predictive value, positive predictive value, sensitivity and specificity were 99% (95% confidence interval (CI), 95-100%), 17% (95% CI, 9-26), 93% (95% CI, 68-100%) and 61% (95% CI, 53-68%), respectively. In conclusion, the combined use of pre-test probability and D-dimer test may be useful in ruling out preoperative DVT in colorectal cancer patients admitted for surgery.

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection

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.

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.

Haemostatis activity in rectal cancer patients exposed to preoperative radiotherapy: a clinical prospective cohort study

To investigate whether markers of haemostasis activity increased during preoperative radiotherapy and whether postoperative marker levels were increased in irradiated rectal cancer patients when compared with nonirradiated rectal and colon cancer patients. In 45 rectal cancer patients, we measured plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin complex, and D-dimer during radiotherapy. Postoperative levels of F1 + 2, thrombin–antithrombin complex, and D-dimer in irradiated patients were compared with postoperative levels in 123 nonirradiated colon and rectal cancer patients. A small oscillation in F1 + 2 levels was observed during radiotherapy among long-term low-intensity radiotherapy recipients. Postoperative levels of F1 + 2 and D-dimer were significantly higher among patients who received short-term high-intensity radiotherapy. This study provided no evidence for activation of the haemostatic system during preoperative radiotherapy in patients with rectal cancer. Some evidence was provided for increased postoperative haemostatic activity among rectal cancer patients who received short-term high-intensity radiotherapy, when compared with patients who received long-term low-intensity radiotherapy, and nonirradiated patients.

The prognostic efficacy of cell-free DNA hypermethylation in colorectal cancer

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.