Daniela Dunkler

Prediction of venous thromboembolism in cancer patients

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients - results from the Vienna Cancer and Thrombosis Study (CATS)

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.

D-Dimer and Prothrombin Fragment 1 + 2 Predict Venous Thromboembolism in Patients With Cancer: Results From the Vienna Cancer and Thrombosis Study

PURPOSE Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE. PATIENTS AND METHODS In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE. RESULTS VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001). CONCLUSION High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.

Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intraluminal thrombus organization and fibrous obliteration of pulmonary arteries. Recently, associated medical conditions such as splenectomy, ventriculoatrial shunt for the treatment of hydrocephalus, permanent central intravenous lines, inflammatory bowel disease, and osteomyelitis were found to be associated with the development of CTEPH. The study aim was to define the impact of these novel risk factors on survival. Methods and Results— Between January 1992 and December 2006, 181 patients diagnosed with CTEPH were tracked with the use of our centers customized computer database. A Cox regression model was used to examine relations between survival and associated medical conditions, age, sex, hemodynamic parameters, modified New York Heart Association functional class at diagnosis, CTEPH type, pulmonary endarterectomy, and anti-cardiolipin antibodies/lupus anticoagulant. During a median observation time of 22.1 (range, 0.03 to 152) months, the clinical end point of cardiovascular death or lung transplantation occurred in 48 cases (27%). Pulmonary endarterectomy (hazard ratio, 0.14; 95% CI, 0.05 to 0.41; P=0.0003), associated medical conditions (hazard ratio, 3.17; 95% CI, 1.70 to 5.92; P=0.0003), and pulmonary vascular resistance (hazard ratio, 1.02; 95% CI, 1.00 to 1.04; P=0.04) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions. Conclusions— CTEPH-predisposing medical conditions, such as splenectomy, permanent central intravenous lines, and certain inflammatory disorders, predict poor survival in CTEPH.

Sex-Specific Prevalence of Adenomas, Advanced Adenomas, and Colorectal Cancer in Individuals Undergoing Screening Colonoscopy

CONTEXT Although some studies have shown that men are at greater age-specific risk for advanced colorectal neoplasia than women, the age for referring patients to screening colonoscopy is independent of sex and usually recommended to be 50 years. OBJECTIVE To determine and compare the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas (AAs), and colorectal carcinomas (CRCs) for different age groups in men and women. DESIGN, SETTING, AND PATIENTS Cohort study of 44,350 participants in a national screening colonoscopy program over a 4-year period (2007 to 2010) in Austria. MAIN OUTCOME MEASURES Prevalence and NNS of adenomas, AAs, and CRCs in different age groups for men and women. RESULTS The median ages were 60.7 years (interquartile range [IQR], 54.5-67.5 years) for women and 60.6 years (IQR, 54.3-67.6 years) for men, and the sex ratio was nearly identical (51.0% [22,598] vs 49.0% [21,572]). Adenomas were found in 19.7% of individuals screened (95% CI, 19.3%-20.1%; n = 8743), AAs in 6.3% (95% CI, 6.1%-6.5%; n = 2781), and CRCs in 1.1% (95% CI, 1.0%-1.2%; n = 491); NNS were 5.1 (95% CI, 5.0-5.2), 15.9 (95% CI, 15.4-16.5), and 90.9 (95% CI, 83.3-100.0), respectively. Male sex was significantly associated with a higher prevalence of adenomas (24.9% [95% CI, 24.3%-25.4%] vs 14.8% [95% CI, 14.3%-15.2%]; P < .001; unadjusted odds ratio [OR], 1.9 [95% CI, 1.8-2.0]), AAs (8.0% [95% CI, 7.6%-8.3%] vs 4.7% [95% CI, 4.4%-4.9%]; P < .001; unadjusted OR, 1.8 [95% CI, 1.6-1.9]), and CRCs (1.5% [95% CI, 1.3%-1.7%] vs 0.7% [95% CI, 0.6%-0.9%]; P < .001; unadjusted OR, 2.1 [95% CI, 1.7-2.5]). The prevalence of AAs in 50- to 54-year-old individuals was 5.0% (95% CI, 4.4%-5.6%) in men but 2.9% (95% CI, 2.5%-3.4%) in women (adjusted P = .001); the NNS in men was 20 (95% CI, 17.8-22.6) vs 34 in women (95% CI, 29.1-40; adjusted P = .001). There was no statistical significance between the prevalence and NNS of AAs in men aged 45 to 49 years compared with women aged 55 to 59 years (3.8% [95% CI, 2.3%-6.1%] vs 3.9% [95% CI, 3.3%-4.5%] and 26.1 [95% CI, 16.5-44.4] vs 26 [95% CI, 22.5-30.2]; P = .99). CONCLUSION Among a cohort of Austrian individuals undergoing screening colonoscopy, the prevalence and NNS of AAs were comparable between men aged 45 to 49 years and women aged 55 to 59 years.

High D-dimer levels are associated with poor prognosis in cancer patients

Background Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. Design and Methods In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay Results The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1st, 2nd and 3rd quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4–1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. Conclusions High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.

Renal Function and Outcome After Continuous Flow Left Ventricular Assist Device Implantation

BACKGROUND Renal dysfunction as a risk factor with the use of left ventricular assist devices (LVAD) is controversial. We determined the effect of renal function on outcomes after continuous flow LVAD implantation. METHODS Eighty-six patients with advanced heart failure undergoing continuous flow LVAD implantation as bridge to transplantation from November 1998 to July 2007 were retrospectively analyzed. Renal function was assessed using the Modification of Diet in Renal Disease study-derived glomerular filtration rates (GFR [mL x min(-1) x 1.73 m(-2)]). Patients were categorized into two groups based on pre-LVAD GFR: those with normal renal function (GFR > 60, n = 46), and those with renal dysfunction (GFR < 60, n = 40). RESULTS Post-LVAD survival at 1, 3, and 6 months for GFR greater than 60 was 91.3%, 79.9%, 72.6%, respectively, and for GFR less than 60, it was 92.5%, 66.5%, 47.9%, respectively (p = 0.038). Bridge-to-transplant rate was lower for GFR less than 60 than for GFR greater than 60 (40.0% versus 63.0%, p = 0.033). For GFR less than 60, GFR improved on LVAD support: implant to month 6, 41.7 +/- 11.5 to 62.7 +/- 25.0 (p = 0.021). Post-LVAD survival was improved in GFR less than 60 patients who after LVAD implantation recovered renal function to GFR greater than 60 (p < 0.001). Patients with post-LVAD renal failure had significantly lower post-LVAD survival regardless of pre-LVAD renal function (p < 0.001). CONCLUSIONS Patients with renal dysfunction have poorer outcomes after continuous flow LVAD implantation. However, renal function improves after LVAD implantation and is associated with improved survival. Our data underscore the importance of end-organ function in patient selection for LVAD therapy.

High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS).

Summary.  Background: In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti‐cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels. Design and methods: The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients’ anti‐cancer treatment during follow‐up were recorded. Results: Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 × 109/L compared with 5.9% in those below 443 × 109/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52–8.06, P = 0.0032], soluble P‐selectin [HR: 2.66, 95% CI: 1.42–4.96, P = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74–9.46, P = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio‐ and CHT. We found no correlation between platelet count and TPO levels. Conclusions: High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.

High Factor VIII Levels Independently Predict Venous Thromboembolism in Cancer Patients: The Cancer and Thrombosis Study

Objective—Patients with cancer are at an increased risk for venous thromboembolism (VTE). Clotting factor VIII activity (FVIII) has been established as risk factor of primary and recurrent VTE. We investigated FVIII as predictive parameter of VTE in cancer patients. Methods and Results—The prospective observational Cancer and Thrombosis Study (CATS) includes patients with newly diagnosed cancer or disease progression, study end point is symptomatic VTE. FVIII was measured on a Sysmex CA 7000 analyzer. Data on 840 patients (median age: 62 years, 25th to 75th percentile 53 to 68, 378 women) were available for analyses, of these 111 patients had hematologic malignancies and 729 solid cancer. During a median observation time of 495 days 62 events occurred. Cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII-levels and 4% in those with normal levels (P=0.001). The association was strongest in younger patients: whereas in 40-year-old patients a 2-fold VTE risk per factor VIII increase of 20% was observed (HR=2.0 [95% CI: 1.5 to 2.7], P<0.0001), this association was still present but attenuated in older patients. Conclusions—FVIII is independently associated with an increased risk of VTE in cancer patients. The association between FVIII and VTE risk declines with increasing age.

Development of Proteinuria After Switch to Sirolimus‐Based Immunosuppression in Long‐Term Cardiac Transplant Patients

Calcineurin‐inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long‐term cardiac transplant patients were switched from cyclosporine to Srl‐based IS. Concomitant IS consisted of mycophenolate mofetil ± steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0–5.7) preswitch to 0.23 g/day (0–9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high‐grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin‐releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high‐grade proteinuria showed decreased renal function at the end of follow‐up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.