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Thalassaemias are the most common inherited autosomal recessive single gene disorders characterised by chronic hereditary haemolytic anaemia due to absence or reduced synthesis of one or more of the globin chains. Haemoglobin E (HbE)-β-thalassaemia is the genotype responsible for approximately one-half of all cases of severe β-thalassaemia worldwide. This study proposes to evaluate response of hydroxyurea in reducing transfusion requirements of severe HbE-β-thalassaemia patients, and its correlation with foetal haemoglobin (HbF) level and α-mutation. Hydroxyurea was started at a baseline dose in 82 transfusion-dependent HbE-β-thalassaemia patients. HbF levels and %F-cells were measured. β-Thalassaemia mutations and α-globin gene deletions and triplications were detected by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) and Gap-PCR, respectively. Patients were categorised as good (41.5%), moderate (31.7%), and poor responders (26.8%) based on their decrease in transfusion requirements. Nine patients were excellent responders who became transfusion independent. The mean increase in HbF levels and %F-cells after therapy was correlated with decrease in transfusion requirements. Patients having a deletion of the α-globin gene were better responders. The response was proportional to the number of α-globin gene deletions. We conclude that hydroxyurea treatment decreases transfusion requirements, and the response correlates with α-globin gene deletions., (© 2019 S. Karger AG, Basel.)

Microparticles (MPs) are present in healthy subjects and their concentration increases in patients at high risk of thrombosis. We evaluated 10 patients with sickle cell anemia (SCA) treated with hydroxyurea (HU) and 13 SCA patients without this treatment. MP concentrations were determined by flow cytometry. Coagulation was evaluated using the thrombin-antithrombin complex (TAT) and D-dimers. Total MP concentrations were increased in the HU-treated group (265 × 10(6)/ml vs. 67.45 × 10(6)/ml; p = 0.0026), as well as MPs derived from RBC (67.83 × 10(6)/ml vs. 26.31 × 10(6)/ml; p = 0.05), monocytes (51.31 × 10(6)/ml vs. 9.03 × 10(6)/ml; p = 0.0084), monocytes with tissue factor (TF) expression (2.27 × 10(6)/ml vs. 0.27 × 10(6)/ml; p = 0.0058), endothelium (49.42 × 10(6)/ml vs. 7.23 × 10(6)/ml; p = 0.007) and endothelium with TF (1.42 × 10(6)/ml vs. 0.26 × 10(6)/ml; p = 0.0043). Furthermore, the concentrations of TAT (7.56 vs. 10.98 µg/l; p = 0.014) and D-dimers (0.65 vs. 1.29 µg/ml; p = 0.007) were reduced with HU. The MP elevation may suggest a direct cytotoxic effect of HU. Another explanation is a cell surface increase secondary to a megaloblastic process, resulting in increased vesicle release. In our opinion, the known benefits of HU on SCA patients, along with the reduction in coagulation activation, surpass its potential detrimental effect on MPs. Future studies should elucidate the role of MPs and demonstrate their significance in different contexts.

Objective: This study was designed to compare the oxidative stress parameters of patients with polycythemia vera (PV) to those of healthy volunteers and to investigate the probable relationship between vascular events and parameters of oxidative status such as total oxidative status (TOS), total antioxidant status, oxidative stress index (OSI) and malondialdehyde (MDA) in PV patients., Material and Methods: Thirty-five PV patients (20 males and 15 females) and 20 healthy volunteers (11 males and 9 females) were enrolled. The oxidative status parameters of the patients were measured by spectrophotometric analyses at the time of diagnosis and at 6 months after treatment which consisted of phlebotomy and 100 mg/day acetyl salicylic acid with or without hydroxyurea for the high- and low-risk disease group, respectively. These parameters were compared both to healthy controls and to each other, in order to obtain the values before and after treatment. In addition, during diagnosis, the oxidative status parameters of patients with PV and a history of a vascular event were compared with those of patients with no history of a vascular event., Results: The TOS, OSI and MDA values were significantly higher in the patients than in the control group at the time of diagnosis. At 6 months after phlebotomy and 100 mg/day acetyl salicylic acid therapy, the TOS, OSI and MDA values were significantly lower in the patients when compared to the pretreatment values. The TOS and OSI levels were notably higher in the patients with a vascular-event history than in those without this history., Conclusion: Oxidative stress parameters were increased in PV patients., (© 2014 S. Karger AG, Basel.)

Background: Chronic myeloid leukemia (CML) is characterized by the formation of the BCR/ABL fusion gene, as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. This study was to investigate the incidence and prognostic significance of derivative chromosome 9 (der(9)) deletions in CML patients who received hydroxyurea treatment in the chronic phase., Patients and Methods: Fluorescence in situ hybridization (FISH) analysis was used to assess the der(9) deletion status of 48 CML patients in blast crisis (CMLBC)., Results: Among the 48 CML patients, 8 (16.7%) showed der(9) deletions, and the deletions were also existent at diagnosis. The median duration of the chronic phase for patients with der(9) deletions was 18 (range 4-38) months compared to 48 (range 0-204) months for patients without deletions (p < 0.001). Der(9) deletions were not associated with increased karyotypic instability. There was no difference in the probability of the der(9) deletions between the cases having progressed to myeloid or lymphoid blast crisis., Conclusion: The results indicated that the FISH technique could effectively detect der(9) deletions. CML patients with der(9) deletions show more rapid progression and poorer prognosis, and the deletion status is a powerful prognostic factor.

Hypereosinophilic syndromes (HES) and systemic mastocytosis (SMCD) are heterogeneous disorders with clinical symptoms from local and remote effects of excessive proliferation of eosinophils and mast cells, respectively. Interferon alpha (IFN-alpha), alone or in combination with other medications, can be a useful, and at times life-saving, treatment for patients with HES. Receptors for IFN-alpha are present on eosinophils, and clinical benefits are due to its effect on eosinophil proliferation, migration, activation, and survival. These effects are likely mediated through multiple pathways including, but not limited to, inhibition of eosinophil colony-forming cells, upregulation of IFN-gamma synthesis, and inhibition of production of eosinophil-active cytokines by T cells, mast cells, and mononuclear cells. IFN-alpha has been life-saving for patients with intractable HES that were resistant to prednisone, hydroxyurea, and other agents. Resistance to the eosinopenic effect of IFN-alpha does not develop and the dose of IFN-alpha necessary to maintain control of eosinophilia often decreases with time. The combination of IFN-alpha and hydroxyurea is very useful and allows dosage reduction of IFN-alpha and better control of hypereosinophilia than with either agent alone. The efficacy of IFN-alpha for treatment of SMCD has been more difficult to establish, with both favorable and unfavorable results reported. The disparate results may have resulted from the small number of patients with SMCD treated with IFN-alpha, the use of various criteria for a "successful" treatment outcome, short duration of treatment and follow-up, and the use of modest dosages. In reported series, side effects from IFN-alpha have frequently been dose-limiting. IFN-alpha improves many of the clinical symptoms of SMCD including dermatological, hematological, gastrointestinal, and systemic symptoms associated with histamine release. IFN-alpha has a beneficial effect on skeletal symptoms because of its ability to increase bone density and reduce painful episodes from vertebral fractures. No consistent improvement in bone marrow infiltration by mast cells has been demonstrated except in a recent study employing high dosages of IFN-alpha. A beneficial effect from the combination of IFN-alpha and prednisone has been reported for several patients, suggesting that combined use of these two medications may provide synergism in treatment outcomes., (Copyright (c) 2005 S. Karger AG, Basel.)

In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1-3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1-3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. approximately 60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Zileuton, a 5-lipoxygenase inhibitor, reduces the number of inflammatory lesions in moderate acne and inhibits the synthesis of sebaceous lipids., Objective: To detect whether zileuton directly reduces sebum synthesis., Methods: A 40-year-old female with mild disseminated sebaceous gland hyperplasia and seborrhea was treated with zileuton 4 x 600 mg/day over 2 weeks, was followed-up for 6 weeks after discontinuation of zileuton and was re-treated with low-dose isotretinoin 10 mg/2nd day over 5 weeks. Casual skin surface lipids and sebum synthesis were determined., Results: Under treatment with zileuton increased casual skin surface lipids were normalized and synthesis of facial sebum was decreased. Six weeks after discontinuation of treatment casual skin surface lipids were increased again and synthesis of sebum returned to baseline. Subsequent low-dose isotretinoin treatment led to similar changes of casual skin surface lipids and sebum synthesis with zileuton already after 2 weeks., Conclusion: Zileuton directly inhibits sebum synthesis in a transient manner with a potency similar to low-dose isotretinoin at least in our patient.

It has been reported that trisomy 14 is associated with myeloid malignancies, but a case with increased platelet count has also been reported. However, the clinical significance of trisomy 14 is still uncertain. We report a patient with trisomy 14 with thrombocytosis and a gradual increase in monocytosis. He was treated with hydroxyurea, cytarabine and aclarubicin in low doses and his quality of life was maintained for a period of about 1 year from blastic crisis. Hydroxyurea, cytarabine or aclarubicin in low doses may be the treatment of choice for trisomy 14 patients with respect to the patients' quality of life., (Copyright 2000 S. Karger AG, Basel)

We report on a patient with essential thrombocythemia treated with hydroxyurea who became febrile 3 weeks after the treatment was started. After drug withdrawal, the fever resolved but after rechallenge there was recurrence of the fever. Although hydroxyurea-induced fever is rare, this drug must be added to the list of drugs that produce fever and the physicians should be aware of this possibility., (Copyright 2000 S. Karger AG, Basel)

In an in vitro study, rabbit subconjunctival fibroblasts were cultured and the effects of an antineoplastic drug, hydroxyurea (HU), on fibroblast proliferation and fibroblast attachment was investigated. The effects of HU were compared with those of mitomycin C (MMC). Different concentrations of HU and MMC were added to culture medium. The HU doses which led to 50% of inhibition (ID(50)) and the dose which led to about 90% of inhibition (subtoxic high dose, STHD) were determined to be 8 and 1,000 microg/ml, respectively. ID(50) of MMC and its STHD which led to about 100% inhibition were found to be 0.01 and 1 microg/ml, respectively. Reversibility studies revealed that inhibition disappeared depending on the dose and incubation period of both HU and MMC. In an in vivo study, glaucoma filtration surgery (GFS) was performed in rabbits which were treated with HU (treatment group) and distilled water (control group). Tissue samples were taken from the subconjunctival area treated at 1 h, 1 day, 5 days and 30 days postoperatively. The biopsy specimens were then placed in tissue culture media. Fibroblast outgrowth rates detected in the HU group were found to be significantly lower than those in the control group in the specimens taken at the end of the first hour. The difference was significant on culture days 9-15 in the biopsy specimens taken on day 1 while it was not significant in those taken on days 5 and 30.

We have treated 9 patients with sickle cell anemia (SS) with hydroxyurea (HU). All 9 patients carried 4 alpha-globin genes and the beta s-globin haplotypes 19/19 (Benin/Benin), except for 1 who had haplotype 19 together with type 3 (Benin/Senegal). Six patients received HU for 10 months and were again treated with the drug for 5 months after an interval of 1 year. One patient was given HU for 22 consecutive months. A record was kept of hematological and biochemical data, Hb F and G gamma levels, as well as possible clinical complications. Our data show that HU generally improves the hematological and biochemical values and the level of Hb F, and reduces painful crises in some patients. However, although the clinical symptoms improved in some patients during HU therapy, the older patients did not observe any changes in their general condition; the same is the case for the patient with haplotype 19/3. One patient also experienced life-threatening liver sequestration during treatment. We conclude that the selection of patients who may benefit from HU therapy needs further evaluation.

Chronic myelogenous leukemia (CML) is a clonal disorder starting with a chronic phase and progressing to an acute blastic phase. Philadelphia (Ph) chromosome formation results in the relocation of the ABL oncogene from the chromosome 9q34 to BCR region on 22q11, forming the BCR/ABL fusion gene. The Ph chromosome once detected rarely disappears, except as a result of therapy. We present an unusual Ph-positive CML case, which developed lymphoid blast crisis in complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. Sequential cytogenetic investigations were carried out on bone marrow. After a standard Ph translocation seen at diagnosis, from the 8th month of therapy all metaphases showed a normal diploid karyotype. Fluorescence in situ hybridization detected residual BCR/ABL-positive interphase cells during the 12th month of therapy. In the 14th month, the patient showed 27% blasts in marrow though normal cytogenetics was maintained. Present findings suggest blastic transformation occurred in a Ph-negative lymphoid clone. This supports the hypothesis that an actual leukemogenic event occurs in a multipotent stem cell prior to the acquisition of Ph translocation.

Inferferon alfa-2b (IFN) plays a major role in the current management of previously untreated patients with chronic myelogenous leukemia (CML) as well as patients with CML who have relapsed after bone marrow transplantation. Hydroxyurea (HU) is the best conventional drug for treatment of CML in the chronic phase. Ten patients, six men and four women, 40-70 years of age, were treated during the accelerated phase of CML with a combination of IFN and HU. Patients had received only HU during the chronic phase of the disease. All patients were positive for the Philadelphia chromosome and had an excess number of blasts in peripheral blood smears (more than 10%), as well as increased numbers of basophils and eosinophils but a low leukocyte level of alkaline phosphatase. Eight of them had splenomegaly. Five patients (50%) survived for 1-3 years, achieving complete hematological remission. Three patients had a partial hematological response and died within 1-2 years. Two patients with aggressive disease died within 3 months of the blastic crisis. It appears that combination therapy with IFN and HU might be a useful alternative for patients in the accelerated phase of CML who have failed to respond to HU alone.

A 60-year-old woman who presented with weakness, night sweats, bone pain, easy bruising and weight loss was found to have ecchymoses and hepatosplenomegaly. Blood counts showed persistent neutrophilia of mature cell type with Döhle bodies and toxic granulation. Coexistence of chronic neutrophilic leukemia and multiple myeloma of kappa light chain type was documented by bone marrow examination and immunofixation.

We report an unusual case of a 44-year-old female patient with 'malignant' ascites caused by ectopic foci of extramedullary hematopoiesis in the course of agnogenic myeloid metaplasia. The patient had suffered also from severe Coombs-positive acquired hemolytic anemia and had been splenectomized. Two years after splenectomy, ascites caused by peritoneal implants of hematopoietic tissue appeared. The ascites responded promptly to treatment with busulfan and hydroxyurea. The clinical picture, treatment and a review of the literature concerning the mechanisms of this uncommon evolution are discussed.

In this study 21 adults with severe form of sickle cell disease (SCD; sickle cell anaemia, n = 15; Hb S/beta degree-thal, n = 6) were treated with hydroxyurea (HU) to assess the effectiveness of the drug in managing SCD. The individual dose was selected for each patient. The dose selection was based on the HU clearance study. Thereafter, the patients received daily doses of 15-20 mg/kg body weight. An evaluation data form was filled out at the monthly visit. The severity index (SI) of the disease was determined and haematological parameters including red cell indices, platelet counts, reticulocyte counts, irreversibly sickled cells, red cell deformability, Hb F, Hb F cells, total and direct bilirubin levels were measured prior to treatment, at follow-up intervals during treatment and after cessation of treatment. The trial period lasted 3 months. Statistically significant improvement was observed in the clinical presentation, haematological and biochemical parameters. Hb F level and F cells showed a significant increase in most patients, but to a variable degree. A major resultant effect was an increase in mean cell volume. Our experience shows that HU can be used for the treatment of severe forms of SCD with no major side effects, provided that the doses are monitored and that laboratory investigations are regularly undertaken.

In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon alpha instead of busulfan prolongs the chronic phase of Philadelphia-positive CML. Additional goals are the examination, whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By September 5, 1990, 593 CML-patients had been randomized, 221 for busulfan, 228 for hydroxyurea and 144 for interferon alpha. The average age is about 51 years. By April 30, 1990, 106 patients had reached the end of the chronic phase, 126 had died. The median survival of Philadelphia-positive patients was 3.95 years, that of all patients 3.75 years. The median observation time of all patients was 1.34 years (mean 1.60 years). At present, no significant difference in survival is recognizable between the three treatment arms, although fewer adverse effects have been observed in the hydroxyurea arm.

A randomized trial comparing chemoimmunotherapy (bacillus Calmette-Guérin + chemotherapy) and immunotherapy (bacillus Calmette-Guérin alone) was carried out in high-risk stage I and II malignant melanoma patients. Eight-two evaluable patients were included. The follow-up median duration was 11 years. Recurrent melanoma developed in 28 patients (34%). The overall survival rate was 76% at 5 years and 65% at 10 years. There were no statistical differences in survival probability or disease-free survival (DFS) probability between the two treatment groups. Survival and DFS were also analyzed in relation to various prognostic factors. Statistically significant differences were only seen in a subset of 33 patients with lower limb malignant melanoma, the prognosis being better for the chemoimmunotherapy group in this location. Because of the small number of patients in each group, a week positive effect of either of these two treatments cannot be ruled out. Chemoimmunotherapy only seems to improve the prognosis of stage I or II malignant melanoma of the legs.

The clinical course of 196 patients with chronic myelocytic leukemia (CML) was studied. Prognostic factors were analyzed using a standard prognostic model. From a univariate analysis of patients with nonblastic Philadelphia chromosome-positive CML, splenomegaly, bone marrow fibrosis, percentage of blasts and promyelocytes in the peripheral blood and LDH activity were shown to be factors with a significant negative influence on survival. However, age and the platelet count did not influence survival. The standard prognostic model, generated with the 4 variables (1) percentage of blasts and promyelocytes, (2) spleen size, (3) platelet count and (4) age did not provide a useful representation of risk status in this heterogenous patient population. However, the addition of further variables (LDH, additional chromosomal aberrations, percentage of basophiles/eosinophiles and percentage of bone marrow blasts) to the standard model allowed a separation into 2 patient groups: one with low and the other with intermediate to high risk. Our data support the general validity of the prognostic model; however, the applicability of the model may be compromised in hematologic centers with a heterogenous CML population due to the selection of high-risk patients. In this situation additional risk factors may have to be added to the prognostic formula.

The intensity of modern protocols for remission induction of acute nonlymphocytic leukemia presents a major problem in elderly patients because of toxicity. Most studies concerning this question indicate that in higher age groups (greater than 60 yrs.) remission incidence worsens and the death rate increases. Therefore, the purpose of this multicenter study is to prospectively compare survival and quality of life of two different therapeutic strategies: immediate intensive remission induction using Daunomycin and Cytosine Arabinoside (branch I) versus supportive care, "wait and see" policy, and palliative cytoreduction (branch II) with Hydroxyurea and Ara C when necessary. During the first 8 months after activating this study, 27 patients entered, 13 were randomized to branch I and 14 to branch II. It is too early to report meaningful results.

Twenty-five institutions are participating in the AML-6-trial designed to improve remission incidence and to delay the time of relapse. Therefore, an intensive cyclic therapy is employed early after achievement of remission using either the same drugs of the induction regimen or rotating combinations of alternative drugs, e.g. AMSA, 5-AZA and HD-araC. So far, 266 patients entered the trial. The overall C.R. rate is 71%. 58 patients are randomized to 'maintenance' arm I, 54 to arm II, 79/112 patients are still being studied. Toxicity was in 7% and 3% respectively a reason to interrupt the study during induction or 'maintenance'. Since the intensity of modern protocols for remission induction of AML presents a major problem in elderly patients due to toxicity, and since most studies indicate low remission rates with an increasing death rate in this age group, the AML-7-study was initiated to prospectively compare survival and quality of life of two different therapeutic strategies: immediate intensive remission induction versus supportive care, 'wait and see' policy, and palliative cytoreduction with hydroxyurea and ara C when necessary. During the first 8 months after activating this study, 27 patients entered, 13 were randomized to branch I, and 14 to branch II.

Donor rats of the Hebrew University strain were administered a single intraperitoneal injection of hydroxyurea (400 mg/kg body weight). 1--3 h following the administration of the drug, a suspension of spleen cells, the majority of which consisted of lymphocytes, was prepared. Spleen cells were placed in diffusion chambers and these were implanted in the peritoneal cavity of preirradiated mice. 5--8 days following implantation, erythroid and granulocytic colonies developed in 30.3% of the diffusion chambers studied. However, in most chambers, macrophages were observed. In control experiments with implantation of spleen cells of normal rats, granulocytic colonies did not grow and in only 3.1% of the chambers erythroid colonies were noted. Macrophage colonies, however, developed in all 32 control cultures. Our previous studies showed that administration of a single dose of hydroxyurea strips the rat bone marrow of approximately 50% of replicating cells within 9--10 h. The results of the present study indicate that such a severe depletion of rat marrow cells results in early committment of spleen stem cells to various blood cell lines.

19 patients with metastatic gastrointestinal malignancy were treated with a regimen of 5-fluorouracil (FU) 500 mg/m2 intravenously and hydroxyurea (HU) 80 MG/KG orally administered on consecutive days weekly. Antitumor responses were not observed and an unusually high incidence of neurotoxicity (21%) was noted related to dose. It is suggested that the lack of therapeutic effect and the observed toxicity may be related to the biochemical interaction of FU and HU resulting in an inability to convert FU to the active metabolite and an accumulation of catabolic products with neurotoxic effects.

42 consecutive patients with head and neck squamous cell carcinoma were entered into a multi-agent chemotherapy protocol including: bleomycin and Cis-platinum (in continuous infusion), sequenced with methotrexate and Vinblastine (by bolus infusion). Hydroxyurea was substituted for bleomycin when the accumulative dose of bleomycin reached 400 units. 9 of 11 patients with untreated disease responded to chemotherapy, with 36.4% showing complete response following the second cycle. After completion of all therapy, complete response had occurred in 10 patients and partial response in 1. At a median follow-up of 1 year, 9 patients are disease-free, and the median duration of response has not yet been reached. For recurrent disease, the overall regression rate is 45.1% (14/31). The median duration of response is 6.5 months, with responding patients showing a median survival of 8.7 months and non-responders, 5.4 months. The data for response and survival are comparable to previous studies and suggest that toxic manifestations may be mitigated by careful attention to nutrition and production of an anabolic state prior to therapy.