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Deborah Rund
Leukemia & lymphoma 06/2011; 52(6):941-2. · 2.40 Impact Factor
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ABSTRACT: Traditionally, medication dosage was based on clinical and demographic parameters, but drug metabolism was recently recognized as an important factor for proper dosing and prediction of side effects. Metabolic considerations are crucial when administering drugs with a narrow therapeutic index, such as those of the thioguanides family (azathioprine and 6-MP). These can cause life-threatening myelosuppression due to low activity of a critical metabolic enzyme, thiopurine S-methyl transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies.
To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the thioguanide family due to enzymatic variants.
DNA analysis was performed using polymerase chain reaction methods. We tested TPMT allelic variants TPMT*3A (G460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpopulations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews.
The Druze (P = 0.0002) and Ethiopian Jewish (P = 0.015) subpopulations had a significantly unique distribution of allelic variants compared to the rest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote for TPMT*3A/ *3A was detected. Ethiopian Jews were found to carry mainly the TPMT*3C variant, also observed in other studies of African populations.
It is advisable that Druze patients be tested for the TPMT enzyme before starting treatment with 6-MP or azathioprine. Such testing may also be considered for other Israeli ethnic subgroups.
The Israel Medical Association journal: IMAJ 12/2010; 12(12):721-5. · 1.02 Impact Factor
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Deborah Rund
Leukemia & lymphoma 10/2010; 51(10):1771-2. · 2.40 Impact Factor
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ABSTRACT: The diagnosis of APL is based on clinical and morphological tests though the final diagnosis is at the molecular level. An accurate diagnosis is important as it mandates targeted therapy to improve survival. We report a case of APL without t(15;17) in conventional cytogenetic study and with initially negative fluorescence in situ hybridization (FISH) study on cells in interphase. Reverse transcription polymerase chain reaction (RT-PCR) for the promyelocytic/retinoic acid receptor alpha gene (PML/RARα) fusion oncogene proved the clinical diagnosis as well as FISH study on cells in metaphase. The cause was a cryptic translocation of the RARα gene into PML. We reviewed 36 additional cases of APL diagnosed in our hospital since 1992. This was the only case that failed to show t(15;17) in cytogenetics. However, three cases with t(15;17) in cytogenetics had negative RT-PCR for PML/RARα. Our case emphasizes that cytogenetics, FISH and RT-PCR studies are complementary studies for the molecular diagnosis of APL.
Hematology (Amsterdam, Netherlands) 10/2010; 15(5):332-7. · 1.33 Impact Factor
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ABSTRACT: Hypertriglyceridemia (hyperTG) is a common form of dyslipidemia and is frequently associated with premature coronary disease, and when severe, recurrent events of pancreatitis may occur. The management of hyperTG is generally medical (life style modification, medications). Plasma exchange (PE) has been reported to be useful in emergency situations particularly when acute pancreatitis results from extreme hyperTG. To our knowledge, there is only one report on long-term use of PE for hyperTG. We here report our results of long-term treatment of hyperTG in 6 patients with Frederickson Type V hyperlipidemia who had recurrent attacks of pancreatitis due to hyperTG refractory to medical therapy. PE was performed from one to eight times a month, mostly using a Cobe Spectra apparatus. In total, our center has performed a total of 1,593 PE sessions for hyperTG. There were no safety issues associated with PE for hyperTG other than occasional access problems (clotted fistula, IV access problems). Determination of plasma TG levels before and after PE demonstrated high efficiency of TG removal (42% to 58% reduction). There was marked clinical improvement in recurrent pancreatitis; patients had a major decrease in episodes (39% to 100%) while on regular PE, as long as they adhered to the treatment schedule. We conclude that long-term PE for hyperTG, while costly, is feasible and safe and may reduce recurrent attacks of pancreatitis.
Journal of Clinical Apheresis 11/2009; 24(6):254-8. · 1.93 Impact Factor
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Deborah Rund
Leukemia & lymphoma 08/2009; 50(7):1065-6. · 2.40 Impact Factor
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ABSTRACT: Hyperploidy is a rare finding in leukemias, with isolated cases of tetraploidy reported in acute myeloblastic and acute lymphblastic leukemias. We report the first case of acute myeloid leukemia with near-pentaploidy (5 n+/-) which was present in 100% of metaphases at diagnosis. By light microscopy, the leukemic blasts were exceptionally large and coarsely granulated. Following one cycle of induction chemotherapy, complete morphologic and cytogenetic remission was documented. Four weeks later relapse occured, at which time the karyotype was diploid and the morphological and immunophenotypic characteristics were those of a lym-phoid leukemia. However, the presence of three aberrant chromosomes (5q+, 6q+ and 20q+) confirmed that this was clonal evolution of the original myeloid leukemia. To the best of our knowledge, this case represents the first report of near-pentaloidy in de novo, pretreatment human leukemia.
06/2009; 25(5-6):585-590.
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PLoS Medicine 05/2009; 6(4):e1000053. · 16.27 Impact Factor
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Deborah Rund
Leukemia & lymphoma 05/2009; 50(4):521-2. · 2.40 Impact Factor
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ABSTRACT: Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.
Current Molecular Medicine 12/2008; 8(7):600-8. · 5.10 Impact Factor
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ABSTRACT: Drug metabolism/disposition and transporter genes may influence predisposition or prognosis of AML (acute myeloid leukemia) patients. We analyzed polymorphisms in 3 transporters and 4 drug metabolism genes in 293 Israeli individuals (112 AML patients and 181 controls). We analyzed: ABCC3 (MRP3) C-211T; ABCG2 (BCRP) C421A; CNT1 (SLC28A1) G565A and NAT1, NAT2, and GSTT1 and GSTM1 null alleles for influence on predisposition, as well as treatment response and survival. We found that the ABCC3 C-211T polymorphism and GSTM1 null genotype have adverse prognostic significance in AML. None of the other polymorphisms studied were found to influence either predisposition or prognosis in Israeli AML patients.
Leukemia Research 07/2008; 32(6):919-29. · 2.92 Impact Factor
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Deborah Rund
Leukemia and Lymphoma 01/2008; 48(12):2302-3. · 2.58 Impact Factor
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ABSTRACT: EBV associated hemophagocytic syndrome (HPS) is an aggressive and potentially life-threatening condition. So far, most EBV associated HPS has been characterized mainly in infants and children in Asian countries.
Here, we report six cases of EBV associated HPS occurring in previously healthy adults in a non-endemic area within a short period of 3 years. All patients presented with fever, hepatosplenomegaly and pancytopenia as well as disturbed liver function tests and coagulopathy. Half were diagnosed as having lymphoma. While EBV-specific serological assays were non-diagnostic in four of the six patients, the presence of EBV DNA in plasma allowed the diagnosis of EBV associated HPS in all patients.
EBV associated HPS may be more prevalent in non-Japanese adults than was previously considered. Screening for hemophagocytic syndrome, in adults as well as in children, should include real-time PCR for EBV.
Journal of Clinical Virology 11/2007; 40(2):156-9. · 3.97 Impact Factor
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Deborah Rund
Leukemia and Lymphoma 09/2007; 48(8):1470-1. · 2.58 Impact Factor
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ABSTRACT: Recent studies have examined the relationship between polymorphic alleles of the MDR1 gene and the course of HIV. Such polymorphisms may alter the metabolism of antiretroviral medications or influence susceptibility to HIV infectivity. We therefore studied a polymorphism in MDR1 (C3435T), and the CYP3A4*1B variant allele, the latter of which has not been previously studied in HIV. Ninety-six patients of either Ethiopian (57) or Caucasian (39) ethnicity and 276 controls were studied including serial CD4 counts, clinical course, and AIDS-defining illnesses. For both ethnic groups, the C allele of MDR1 C3435T was highly associated with being infected with HIV (p < 0.0001) compared to controls, but genotype did not influence change in CD4 counts over time in the patients, whether or not they were treated with antiretrovirals. CYP3A4*1B was also significantly associated with being infected with HIV (p < 0.0001) both in heterozygotes and in homozygotes for the polymorphism, but only for Ethiopians (p < 0.023 compared to Caucasians, p = 0.44). CYP3A4*1B did not influence CD4 count or AIDS defining illnesses. We conclude that in Israeli patients, polymorphisms in drug metabolism and disposition genes may influence infectivity of HIV but do not influence the course of the disease. Larger studies are needed to confirm these findings.
AIDS PATIENT CARE and STDs 09/2007; 21(9):653-8. · 2.41 Impact Factor
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Deborah Rund
Leukemia and Lymphoma 05/2007; 48(4):643-4. · 2.58 Impact Factor
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ABSTRACT: The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti-viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy-induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti-HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre-emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre-emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre-treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.
British Journal of Haematology 04/2007; 136(5):699-712. · 4.94 Impact Factor
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ABSTRACT: Lawsone (2-hydroxy-1,4-naphthoquinone) is the active ingredient of Lawsonia alba, whose crushed leaves are known as henna, used as a hair and skin dye in many parts of the world. Accidental or deliberate ingestion of Lawsone has a high mortality rate (up to 31%) owing to rhabdomyolysis and renal failure. The authors report the first successful use of plasmapheresis as an adjunct to the treatment of these symptoms in a 69-year-old man who suffered severe symptoms of Lawsone poisoning due to inadvertent ingestion. Although most cases reported in the literature have been treated using supportive techniques, including hemodialysis, the high mortality despite these measures suggests that prompt plasma exchange may be a lifesaving technique for this syndrome.
Journal of Clinical Apheresis 02/2007; 22(4):243-5. · 1.93 Impact Factor
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ABSTRACT: NAD(P)H:quinone oxidoreductase (NQO1) detoxifies quinones. The NQO1*2 variant enzyme (codon 609 C-->T, encoding a proline to serine substitution) with greatly reduced activity has been reported to predispose to acute myeloid leukemia (AML). Our aim was to examine the relationship between NQO1*2 and AML in Israeli patients. We analyzed for NQO1*2 in 262 adult Israeli patients with de novo AML and 688 controls of the same ethnic groups (Arabs, and Caucasian and Ethiopian Jews). Our analysis showed significant differences in the frequencies of NQO1*2 by ethnic group (p=0.000068). However, NQO1*2 frequencies did not differ between AML patients and controls. Karyotype was not found to be associated with NQO1*2. In Israeli patients, NQO1*2 does not predispose to de novo AML.
Haematologica 08/2006; 91(7):956-9. · 6.42 Impact Factor
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ABSTRACT: The incidence of infections among patients with thalassaemia and the role of risk factors for infection are uncertain. We studied the occurrence of infections necessitating hospitalisation in 92 homozygous beta-thalassaemia patients who had been followed longitudinally for decades, and investigated the role of potential risk factors for these infections. Pneumonia accounted for 26% of the infections and fever of unknown origin for 14%. Staphylococcus aureus was the major pathogen possibly related to injections associated with intensive chelation with deferoxamine. There was a significant increase in the rate of infection over time, notably after 15 years. Splenectomy correlated with the incidence of infection (P < 0.001) without being confounded by other variables and with highest frequencies of infections present after 10 years. A direct correlation between iron overload and infection was evident only before the initiation of iron-chelating treatment (P < 0.01). Following initiation of deferoxamine, paradoxically, the infection rate increased (P = 0.046). The combination of splenectomy and deferoxamine treatment was associated with the highest adjusted infection rate. Parathyroid dysfunction and glucose-6-phosphate dehydrogenase deficiency were significantly associated with infection (P = 0.02 and P = 0.04 respectively). The infection rate in thalassaemia is affected mainly by the duration of the disease and is increased by splenectomy and, in the long term, by treatment with deferoxamine.
British Journal of Haematology 07/2006; 133(6):667-74. · 4.94 Impact Factor
