SummaryThe 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) × 103 /ml plasma versus 13.1 (11.9 – 19.7) × 103 /ml plasma, p = 0.007. This was mainly due to a higher amount of TF+ MPs from platelets (13.4 [5.0 – 17.4] × 103 /ml plasma vs. 5.8 [4.5 – 7.5] × 103 /ml plasma, p = 0.017). TF+ MPs correlated with D-dimer (ρ = 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.

Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib, and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33 patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P ¼ 0.66), and rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a 450% paraprotein reduction. Median duration of response was 12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P ¼ 0.25), and survival was also not different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

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.

We have originally shown that spontaneous granulocyte/macrophage colony (CFU-GM) formation in semisolid medium is a characteristic in vitro feature of chronic myelomonocytic leukemia (CMML). However, the clinical significance of spontaneous CFU-GM growth in CMML is unknown so far. CFU-GM growth characteristics were studied in semisolid cultures in the absence of exogenous cytokines using peripheral blood mononuclear cells in 30 patients with CMML at first presentation. The median number of CFU-GM/10(5) MNC of all patients was 48.5 (range 0-622) with 18 patients having colony numbers below 100 (low CFU-GM growth) and 12 patients above 100 (high CFU-GM growth). Kaplan-Meier analysis revealed that patients with high CFU-GM growth had a significantly shorter survival than patients with low CFU-GM growth (median 6.5 vs. 44.5 months, p<0.00002). The probability of survival after 2 years was 60.5% for patients with low colony growth but 0% in those with high colony formation. Patients with CFU-GM >100 had a significantly higher WBC count, a higher LDH, and a higher number of blast cells in blood and bone marrow than patients with low colony growth. Moreover, patients with high colony growth had more often splenomegaly and lower platelet counts. In seven patients, in whom semisolid in vitro cultures were performed after transformation into RAEBT/AML, spontaneous colony growth was significantly increased as compared to CFU-GM growth in patients before transformation (median number/10(5) MNC 533, range 212-4553, p<0.005). This study demonstrates that high (>100) spontaneous CFU-GM formation in CMML at presentation correlates with increased disease activity and represents a novel and important prognostic factor predicting for short survival of CMML patients.