Influence of Height on Risk and Outcome of Patients with Early Breast Cancer: A Pooled Analysis of 4,925 Patients from 5 Randomized Trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

Background: Associations between height, cancer risk and worse outcome have been reported for several cancers including breast cancer. We hypothesized that in breast cancer clinical trials, tall women should be overrepresented and might have worse prognosis. Methods: Data of 4,935 women, included from 1990 to 2010 in 5 trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG), were analyzed retrospectively. The primary objective was to determine differences in height distribution between the ABCSG cohort and the Austrian female population according to a cross-sectional health survey conducted by the Austrian Statistic Center in 2006 and 2007. Secondary endpoints were disease-free survival (DFS) and overall survival (OS) in different height classes and differences of body mass index (BMI) distribution. Results: Breast cancer patients in the ABCSG cohort were only slightly but statistically significantly smaller compared to unselected Austrian adult females (mean 164.3 vs. 164.8 cm; p < 0.0001) and significantly more patients were seen in the lower body height class (50 vs. 46%; p < 0.0001) when using the median as a cutoff. However, after adjustment for age, the difference in body height between the two cohorts was no longer significant (p = 0.089). DFS and OS in the two upper height groups (≥170 cm) compared to the two lowest height groups (<160 cm) was not significantly different (5-year DFS: 84.7 vs. 83.0%; HR 0.91, 95% CI 0.73-1.13, p = 0.379; 5-year OS: 94.8 vs. 91.7%; HR 0.74, 95% CI 0.55-1.00, p = 0.051). The BMI of ABCSG patients was significantly higher than in the reference population (mean BMI 24.64 vs. 23.96; p < 0.0001). Conclusions: Our results do not confirm previous findings that greater body height is associated with a higher breast cancer risk and worse outcome.

Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer.

The pathogenesis of hypercoagulability in cancer is not entirely understood. We hypothesized that in cancer patients circulating tissue factor-positive microparticles (TF (+) MPs) are increased and associated with hemostatic system activation. In 20 patients with advanced colorectal cancer and in 20 age- and sex-matched controls, number and cellular origin of TF (+) MPs were determined in plasma by flow cytometry. D-dimer was determined as an indicator of hemostatic system activation. Compared to controls, the median (interquartile range) number of TF (+) MPs was two-fold higher in cancer patients: 25.9 (15.4 - 42.0) x 10 (3) /ml plasma versus 13.1 (11.9 - 19.7) x 10 (3) /ml plasma, p = 0.007. This was mainly due to a higher amount of TF (+) MPs from platelets (13.4 [5.0 - 17.4] x 10 (3) /ml plasma vs. 5.8 [4.5 - 7.5] x 10 (3) /ml plasma, p = 0.017). TF (+) MPs correlated with D-dimer ( ? = 0.48, p = 0.002). High levels of TF (+) MPs in cancer patients and their correlation with D-dimer suggest that TF (+) MPs might be involved in hemostasis activation in cancer patients.

Circulating hematopoietic progenitor cells predict survival in patients with myelofibrosis with myeloid metaplasia.

BACKGROUND AND OBJECTIVES: The levels of circulating hematopoietic progenitor cells are often increased in myelofibrosis with myeloid metaplasia (MMM). The prognostic relevance of this phenomenon is largely unknown. DESIGN AND METHODS: We determined the number of circulating myeloid (CFU-GM), erythroid (BFU-E), and pluripotent (CFU-GEMM) progenitors, in 110 patients with MMM at diagnosis using a semi-solid colony assay. Overall survival was investigated by plots of the Kaplan-Meier estimator; known risk factors and the number of circulating progenitor cells were tested by univariate and multiple Cox regression analysis. RESULTS: Univariate analysis showed that hemoglobin concentration (p=0.019), CFU-GM (p< 0.0001), BFU-E (p=0.002), and age (p=0.002) predicted survival. Numbers of circulating CFU-GM above the 75th percentile were associated with a significantly shorter survival than were CFU-GM levels at or below the 75th percentile (27 vs. 74 months, p=0.0007). Similarly, high numbers of BFU-E in peripheral blood (> 75th percentile) predicted a shorter survival (33 vs. 74 months; p=0.007). When myeloid and erythroid progenitor cells were calculated separately in the multiple Cox regression analysis, both CFU-GM (hazard ratio 2.8, 95% CI, 1.35 to 5.93) and BFU-E (hazard ratio 2.57, 95% CI, 1.26 to 5.21) numbers above the 75th percentile were independent adverse prognostic factors in our patients. INTERPRETATION AND CONCLUSIONS: High levels of circulating myeloid and erythroid progenitor cells are novel risks factors in patients with MMM. The assessment of hematopoietic progenitor cells may be useful to determine risk-adjusted treatment strategies.

Chronic myeloid leukemia: pathophysiology, diagnostic parameters, and current treatment concepts.

Chronic myeloid leukemia (CML) is a stem cell disease characterized by excessive accumulation of clonal myeloid (precursor) cells in hematopoietic tissues. CML cells display the translocation t(9; 22) that creates the bcr/abl oncogene. The respective oncoprotein (= BCR/ABL) exhibits constitutive tyrosine kinase activity and promotes growth and survival in CML cells. Clinically, CML can be divided into three phases: the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP) that resembles acute leukemia. Progression to AP and BP is associated with occurrence of additional genetic defects that cooperate with bcr/abl in leukemogenesis and lead to resistance against antileukemic drugs. The prognosis in CML is variable depending on the phase of disease, age, and response to therapy. The only curative approach available to date is stem cell transplantation. For those who cannot be transplanted, the BCR/ABL tyrosine kinase inhibitor STI571 (Glivec, Imatinib), interferon-alpha (with or without ARAC), or other cytoreductive drugs are prescribed. Currently available data show that STI571 is a superior compound compared to other drugs in producing complete cytogenetic and molecular responses. However, despite superior initial data and high expectations for an effect on survival, long term results are not available so far, and resistance against STI571 has been reported. Forthcoming strategies are therefore attempting to prevent or counteract STI571 resistance by co-administration of other antileukemic drugs. Whether these strategies will lead to curative drug therapy in CML in the future remains at present unknown.

[Treatment of residual disease in chronic myeloid leukemia with STI-571 (Glivec)]. / Therapie der Resterkrankung bei chronisch-myeloischer Leukämie mit STI-571 (Glivec).

Cytoreductive therapy can ameliorate symptoms in chronic myeloid leukemia (CML) but only treatment beyond hematologic remission aiming to affect the leukemic clone can improve prognosis. Up to now bone marrow transplantation is the only established therapy with the potential to completely eliminate the BCR-ABL positive cell population. Interferon-alpha (IFN-alpha) as well as cytosine arabinoside (ARA-C), particularly in combination, have been shown to be effective in achieving cytogenetic remission in some patients. With Glivec (STI-571) there is now a drug available which can induce major cytogenetic response in more than half of the patients who have failed IFN-alpha treatment and thus possibly delay or prevent blast crisis. Recent reports, however, have shown that primitive, quiescent, Philadelphia-positive stem cells are insensitive to STI-571 in vitro. Such cells could be the basis of relapse after termination of Glivec-therapy.