Atilla Yalçin

The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide.

Bisphosphonates have recently been introduced in the therapeutic armamentarium for long-term treatment of patients with multiple myeloma. These pyrophosphate analogs not only reduce the occurrence of skeletal events but also provide clinical benefit to patients and improve the survival of some of them. The existence of these capabilities raises the possibility that these compounds may have a direct antiproliferative effect on tumor cells. To investigate whether these drugs exert a direct antitumor effect, we exposed human myeloma cell lines ARH-77 and RPMI-8226 to increasing concentrations of zoledronic acid (ZOL) in vitro. A concentration- but not time-dependent cytotoxic effect was detected with drug treatment of ARH-77 and RPMI-8226 cell lines (30% and 60% at 48 hours and 38% and 62% at 72 hours, respectively, for 50µM of ZOL). Cytotoxicity was not due to ZOL-induced chelation of extracellular calcium as shown by control experiments with the calcium chelator ethylene glycol-bis(β-aminoethylether)-N,N,N’,N’-tetraacetic acid. Addition of the competitive inhibitor of the nitric oxide synthase Nω-nitro-L-arginine methyl ester did not modulate ZOL-induced cytotoxicity. However, a decrease in the number of apoptotic cells was detected when protein kinase C was inhibited by addition of staurosporine to ZOL-containing cultures. Cytotoxicity also was increased by addition of dexamethasone (Dex) and thalidomide (Thal) to ARH-77 and RPMI-8226 cultures. We demonstrated that exposing myeloma cell lines ARH-77 and RPMI-8226 to ZOL inhibits cell growth in a dose-dependent but not a time-dependent manner and that combination of Dex and Thal with ZOL induces apoptotic cell death, providing a rationale for potential applications in vivo.

Total parenteral nutrition delays platelet engraftment in patients who undergo autologous hematopoietic stem cell transplantation

OBJECTIVES One of the major challenges in the post-transplant period is nutrition. In this prospective, non-randomized study, total parenteral nutrition (TPN) was given to 31 patients and partial parenteral nutrition (PPN) was given to 30 patients undergoing autologous hematopoietic stem cell transplantation for solid tumors or hematologic malignancies to compare the effects of these parenteral nutrition modalities on post-transplant hematological engraftment, blood chemistry, and supportive therapy requirements. METHODS All patients in the TPN group and 17 patients in the PPN group received growth factor in the post-transplant period. Both groups did not differ with respect to sex, age, and reinfused CD34(+) cell numbers. RESULTS After transplantation body mass index and body weight decreased significantly in both groups (P < 0.001). Whereas serum albumin concentrations did not decrease significantly in the TPN group, it fell markedly in the PPN group at the end of parenteral nutrition (P = 0.019). After parenteral nutrition, blood chemistry was also remarkable for serum urea and glucose levels, which were elevated significantly in the TPN group (P < 0.001 and P = 0.03, respectively). Patients receiving TPN had a higher incidence of positive microbial cultures and clinical infection than did patients receiving PPN (64.5% versus 40%, P = 0.05). The most striking result was a delay in platelet engraftment for the TPN group compared with the PPN group (15.54 and 12.93 d, respectively; P = 0.014). This difference was also noted in patients using growth factor in the PPN group (P = 0.017). Parallel to these results, platelet transfusion requirement increased in the TPN group compared with the PPN group (1.93 versus 1.16 U, P = 0.004). Both groups were unremarkable for leukocyte recovery and red blood cell transfusion requirement. CONCLUSIONS Consequently, TPN has some pitfalls of hyperglycemia, infection tendency, delayed platelet engraftment, and increased platelet transfusion requirement. Therefore, it should not be used as a standard nutrition support for patients undergoing autotransplantation.

The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane

Abstract:  Objectives: Bisphosphonates (BPs) are mostly used in the palliative care of myeloma‐associated osteolytic lesions. Recent studies have suggested that BPs may also exert direct antitumor effects on myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid (ZOL), on the development of pristane (2,6,10,14‐tetramethylpentadecane)‐induced plasmacytoma (PCT) in six‐week‐old BALB/c mice. Methods: Different groups of pristane‐treated mice also received ZOL (100 μg/kg) commencing after the development of PCT or ZOL (20 μg/kg) from the first day. Control groups received pristane alone, ZOL alone (20 μg/kg), or phosphate‐buffered saline. The study was terminated on day 300, and the remaining mice were autopsied and abdominal tissues were examined histologically for PCT. Results and conclusions: Statistical analysis revealed a significant delay in PCT development in the group receiving pristane plus ZOL (20 μg/kg) from the first day compared to the groups receiving pristane alone and pristane combined with ZOL (100 μg/kg) after the appearance of PCT (Log‐rank, P = 0.0001 and 0.0001; respectively). Kaplan–Meier analysis revealed a significant difference in survival between the group treated with pristane alone and the groups receiving pristane plus ZOL (20 μg/kg) from the first day or ZOL (100 μg/kg) after the appearance of PCT (Log‐rank, P = 0.016 and 0.023; respectively). These results indicate a direct anti‐tumor effect of ZOL in pristane‐induced PCT development BALB/c mice, which may contribute to their significantly increased survival. This hypothesis should now be further investigated in clinical trials.

Treatment with Cerivastatin in Primary Mixed Hyperlipidemia Induces Changes in Platelet Aggregation and Coagulation System Components

Platelet activation, impairment of fibrinolysis, activation of the coagulation pathway, and dyslipidemia are important factors in the pathogenesis and progression of ischemic heart disease, and patients generally need to use an antiplatelet agent. Lipid-lowering cerivastatin, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was administered to 20 patients with primary mixed hyperlipidemia for the assessment of the effect of cerivastatin on lipid levels, plasma fibrinogen concentration, factor VII, VIII, and X levels, plasminogen and antiplasmin concentrations, platelet count, and aggregation (adenosine diphosphate [ADP], collagen, and epinephrine induced). Assessments were made immediately after 2 months of a standard lipid-lowering diet, 4 weeks of placebo administration, and 4 weeks of cerivastatin treatment. Cerivastatin achieved significant reductions in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels. The significant improvement of the lipid profile was associated with platelet aggregation reduction in vitro stimulated by ADP, collagen, and epinephrine (P > .05,P = .05,P > .005, respectively). Significantly lower levels of factor VII and fibrinogen were observed (P = .001,P > .0001) immediately after cerivastatin treatment. No significant differences were detected in factor VIII level, plasminogen and antiplasmin concentrations, and platelet count after cerivastatin treatment. It was concluded that cerivastatin in mixed hyperlipidemia can exert beneficial changes on specific hemostatic variables and platelet aggregation in addition to its positive effects on plasma lipid values.

Erythema annulare centrifugum as the presenting sign of CD 30 positive anaplastic large cell lymphoma--association with disease activity.

Erythema annulare centrifugum is a figurate erythema that has been associated with many different entities. A case of erythema annulare centrifugum related to non-Hodgkins lymphoma in a 38-year-old woman is described in this case report. Response of the lymphoma to a combination chemotherapy was accompanied by disappearance of skin lesions. When therapy was discontinued, both disorders recurred, and both responded to reinstitution of a different chemotherapy regimen. To our knowledge, this case is the first reported association of erythema annulare centrifugum and non-Hodgkins lymphoma in the medical literature.

Thrombocytopenia following intravenous iopamidol

Key words Thrombocytopenia AE IopamidolDear sir,We have recently seen a patient who was admitted to thehaematology clinic for evaluation of a 24-h history ofpetechial and purpuric lesions. Her past and familyhistory of bleeding disorders and the rest of her physicalexamination were unremarkable.On questioning the patient it was learned that for thepast 9 months she had su•ered from a headache. Noabnormalities were noticed in her complete blood countand routine laboratory tests during that time. There wasno drug administration history for the last month of the9-month period, except for the use of 100 ml of intra-venous iopamidol in computed tomography of the brainfor the evaluation of chronic headache. She reportedpetechial and purpuric lesions on her legs and abdomen,and gingival bleeding within 24 h following contrastmedium (CM).Her initial laboratory examination, done 48 h aftercontrastmedium,revealed ahaemoglobinof12 gAEdl

Prothrombin Gene 20210 G→A and Factor V Arg 506 to Gln Mutation in a Patient with Buerger's Disease A Case Report

Thromboangiitis obliterans, or Buergers disease, is a segmental occlusive inflammatory disorder of the arteries and veins most commonly affecting the lower extremities of young male cigarette smokers. The etiopathogenesis of the thromboangiitis obliterans is still obscure. The authors have identified heterozygosity for the recently described prothrombin gene 20210 G→A variation and Factor V Arg 506 to Gln (Factor V Leiden) mutation in a patient with Buergers disease. Both mutations confer a high risk of throm bosis. This coincidental observation may serve as further evidence that a thrombotic mechanism is involved in Buergers disease.

Chronic myelomonocytic leukemia developed 2 years after the onset of immune thrombocytopenic purpura like syndrome.

An 80-year old man was diagnosed as having immune thrombocytopenic purpura based on epistaxis, purpura and by the platelet count 8 x 10(9)/l. Prednisolone and gamma globulin were administered and the platelet count had been kept around 50 x 10(9)/l during his follow up. Two years from the onset of immune thrombocytopenic purpura he was admitted because of leukocytosis (79 x 10(9)/l with 79% monocytes), anemia and thrombocytopenia. Hypercellular bone marrow with dysplasia of three lineages was observed. In the bone marrow cytogenic analysis, a -6, clonal cytogenic abnormality was observed. 45XY, der(6), t(6;6)(q16;q23). He was diagnosed as having chronic myelomonocytic leukemia. This is a difficult case in which it was diagnosed as refractory thrombocytopenia as a subgroup of myelodysplastic syndrome, rather than immune thrombocytopenic purpura. which might have preceded the development of chronic myelomonocytic leukemia.

Changes in immunological recovery in patients who received post-transplant G-CSF or GM-CSF after autologous peripheral blood stem cell transplantation (PBSCT)

In this prospective study, the effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on immunological reconstitution after autologous peripheral blood stem cell transplantation (PBSCT) were investigated for 6 months. Thirty-five patients received G-CSF 5 microg/kg per day and 26 patients received GM-CSF SC 5 microg/kg per day from day 1 to leukocyte engraftment (>1000 per mm3). Peripheral blood samples were obtained on 14, 28, 100, and 180 days after transplantation for immunological evaluation. CD3+, CD4+, CD8+, CD19+, and CD56+ cells were analysed by flow cytometry. Immunoglobulin levels (IgG, IgA, and IgM) and complement levels (C3c and C4) were measured by nephelometry. Both G-CSF and GM-CSF groups were comparable with respect to age, sex, the period from diagnosis to transplantation, total nucleated cells infused, the number of CD34+ cells, conditioning regimens (TBI and non-TBI), and post-transplant infection. CD3+ and CD8+ cells on day 14 following autologous PBSCT + G-CSF were significantly higher than following autologous PBSCT + GM-CSF (p = 0.008 and p = 0.021, respectively). The number of CD4 cells and the CD4/CD8 ratio were not different at several time points between the two groups. CD19+, CD56+ cells and immunoglobulin levels showed a faster recovery pattern in the autologous PBSCT + G-CSF group. The effect of G-CSF on immune reconstitution after autologous PBSCT is more prominent than that of GM-CSF. The possible role of haematopoietic growth factor on immune recovery and its clinical importance should be investigated in further studies.

Mononeuropathy multiplex in the course of idiopathic thrombocytopenic purpura a case report

We report the simultaneous occurrence of idiopathic thrombocytopenic purpura and mononeuropathy multiplex in a 21-year-old man. Electromyographic study revealed various axonal degenerative alterations in the right and left peroneal and right tibial nerves.