Significance of Cytokeratin Fragment M65 and Cytokines IL6, IL8 and IL17A in Bone Marrow Aspirates of Colorectal Cancer Patients

Aims: Soluble cytokeratin (CK) fragments and inflammatory interleukins (ILs) in bone marrow (BM) aspirates of colorectal cancer (CRC) patients are expected to indicate presence of disseminated tumor cells (DTCs) and anticancer response of the host, respectively. The present study investigated the relations of CK18 fragment M65, IL6, IL8, and IL17A in BM samples to the presence of DTCs and prognosis. Place and Duration of Study: Department of Medicine (Medical Unit II) and Department of Surgery, Donauspital Vienna, between 2002 and July 2005. Methodology: BM aspirates were obtained immediately prior to and one and two years after tumor surgery, respectively, and M65 and cytokines were quantified by ELISA assays. Results: 16/66 patients revealed tumor-positive BM aspirates, and 10/46 evaluable patients relapsed within five years. M65 levels exhibited no relation to either positive biopsies, relapses or methylation status of O6-methyl guanine methyl transferase (MGMT). In contrast, IL17A concentrations of BM aspirates were elevated in nonrelapsed versus relapsed, as well as MGMT-wildtype versus MGMT-methylated patients. Due to large individual variations, IL6 and IL8 levels of BM showed no significant differences for non-relapsed versus relapsed patients. Conclusion: M65 levels of BM samples of CRC patients exhibited no correlation with micrometastases or disease recurrence, respectively; however, patients who achieved disease-free survival revealed increases of IL17A in BM aspirates, possibly indicating immune response to tumor cells

Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients.

In an international collaborative study, a central histologic review identified 891 patients with essential thrombocythemia, strictly defined by World Health Organization criteria. After a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. In multivariable analysis, predictors of arterial thrombosis included age more than 60 years (P = .03; hazard ratio [HR] = 1.7), thrombosis history (P = .003; HR = 2.1), cardiovascular risk factors including tobacco use, hypertension, or diabetes mellitus (P = .007; HR = 1.9), leukocytosis (> 11 7 10(9)/L; P = .04; HR = 1.7), and presence of JAK2V617F (P = .009; HR = 2.6). In contrast, only male gender predicted venous thrombosis. Platelet count more than 1000 7 10(9)/L was associated with a lower risk of arterial thrombosis (P = .007; HR = 0.4). These associations, except the one with leukocytosis, remained significant (or near significant) when analysis was restricted to JAK2V617F-positive cases. The current study clarifies the contribution of specific disease and host characteristics to the risk of arterial versus venous thrombosis in essential thrombocythemia

Development and validation of an International Prognostic Score of thrombosis in WHO-Essential Thrombocythemia (IPSET-thrombosis).

Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is two-tiered and considers low- and high-risk categories, based on the respective absence or presence of either age >60 years or history of thrombosis. In an international study of 891 patients with WHO-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HR) to age >60 years (HR 1.5; one point), thrombosis history (HR 1.9; two points), cardiovascular risk factors (HR 1.6; one point) and JAK2V617F (HR 2.0; two points) and subsequently devised a three-tiered prognostic model (low-risk, 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n=356; internal validation set) as well as in an external validation set (n=329). Considering all three cohorts (n=1,220), the three-tiered new prognostic model (low-risk n=474 vs. intermediate-risk n=471 vs. high-risk n=275), with a respective thrombosis risk of 1.03%pts/yr vs. 2.35%pts/yr vs. 3.56%pts/yr, outperformed the two-tiered (low-risk 0.95%pts/yr vs. high-risk 2.86%pts/yr) conventional risk stratification in predicting future vascular events

Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria.

In an international study of 1104 patients with essential thrombocythemia (ET), a histological review according to the 2008 World Health Organization (WHO) criteria confirmed ET in 891 patients (WHO-ET, 81%), and revised the diagnosis to prefibrotic primary myelofibrosis (PMF) in 180 patients (PMF, 16%). Major bleeding during follow-up occurred in 55 (6%) WHO-ET and 21 (12%) PMF patients (P = 0.009), at a rate of 0.79 and 1.39% patients per year, respectively, (P = 0.039). In a multivariable analysis, predictors of bleeding included diagnosis of PMF (P = 0.05; hazard ratio (HR) 1.74), leukocytosis (P = 0.04; HR 1.74), previous hemorrhage (P = 0.025; HR 2.35) and aspirin therapy (P=0.001; HR 3.16). The analysis restricted to patients with WHO-ET confirmed previous hemorrhage (P = 0.043; HR 1.92) and aspirin (P=0.027; HR 2.24) as independent risk factors. The current study reveals that major bleeding associated with thrombocytosis might be relatively specific to PMF, as opposed to WHO-defined ET. Furthermore, it shows that low-dose aspirin exacerbates these hemorrhagic events of PMF. In contrast, thrombocytosis per se was not a risk factor for bleeding; however, low-dose aspirin had a synergistic hemorrhagic effect unmasking the bleeding tendency of patients with extreme thrombocytosis. These observations carry significant therapeutic implications in these two WHO entities

Development and validation of an International Prognostic Score of thrombosis in WHO-Essential Thrombocythemia (IPSET-thrombosis).

Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is two-tiered and considers low- and high-risk categories, based on the respective absence or presence of either age >60 years or history of thrombosis. In an international study of 891 patients with WHO-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HR) to age >60 years (HR 1.5; one point), thrombosis history (HR 1.9; two points), cardiovascular risk factors (HR 1.6; one point) and JAK2V617F (HR 2.0; two points) and subsequently devised a three-tiered prognostic model (low-risk, 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n=356; internal validation set) as well as in an external validation set (n=329). Considering all three cohorts (n=1,220), the three-tiered new prognostic model (low-risk n=474 vs. intermediate-risk n=471 vs. high-risk n=275), with a respective thrombosis risk of 1.03%pts/yr vs. 2.35%pts/yr vs. 3.56%pts/yr, outperformed the two-tiered (low-risk 0.95%pts/yr vs. high-risk 2.86%pts/yr) conventional risk stratification in predicting future vascular events