Publications by authors named "Mohamed A Samra"

13 Publications

  • Page 1 of 1

Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation.

Clin Lymphoma Myeloma Leuk 2020 07 6;20(7):459-467. Epub 2020 Mar 6.

Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.

Background: Core binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome.

Patients And Methods: We performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received "3 + 7" induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study.

Results: The median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04).

Conclusion: CBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.
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http://dx.doi.org/10.1016/j.clml.2020.02.002DOI Listing
July 2020

Prognostic and Therapeutic Value of Day 14 Bone Marrow Aspiration in Adult Acute Myeloid Leukemia Patients.

Clin Lymphoma Myeloma Leuk 2019 07 1;19(7):e406-e413. Epub 2019 Apr 1.

Department of Medical Oncology, National Cancer Institute, Cairo, Egypt.

Background: Early blast clearance to induction chemotherapy in acute myeloid leukemia (AML) is an important prognostic indicator of treatment outcome in addition to genetics and molecular genetics. We evaluated the prognostic value of bone marrow aspiration (BMA) at day 14 (D14) and impact on outcome to asses the timing of a second induction.

Patients And Methods: This retrospective study included 303 adult AML patients managed at the National Cancer Institute, Cairo University, from the beginning of 2010 to the end of 2014.

Results: Median age was 34 years (range, 18-67 years). Sixty-six percent had early blast clearance with < 5% blasts and 34% had ≥ 5% blasts at BMA D14; 38 patients died early during or shortly after induction. Initial blast load (bone marrow and peripheral blood) and initial platelet count were significantly higher in those with disease that did not respond to therapy compared to those whose disease did respond to therapy at D14 (P < .001, .035, and .006, respectively). The median disease-free survival for early blast clearance at D14 was 18.5 months, versus 18.7 months for those with late response to therapy (day 28), and was only 1.3 months for patients who received immediate second-line therapy on the basis of BMA D14 (P < .001). The median overall survival for early blast clearance was 13.6 months, versus 7.2 months for those with late response to therapy, and only 1.3 months for patients who received immediate second-line therapy on the basis of BMA D14 (P < .001).

Conclusion: BMA D14 has a significant prognostic impact on the therapeutic outcome of AML patients (complete remission, disease-free survival, and overall survival); however, a second induction in patients with BMA D14 blasts > 5% should be delayed until neutrophil recovery to minimize death in aplasia.
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http://dx.doi.org/10.1016/j.clml.2019.03.024DOI Listing
July 2019

MPN10 score and survival of molecularly annotated myeloproliferative neoplasm patients.

Leuk Lymphoma 2018 04 22;59(4):844-854. Epub 2017 Aug 22.

b Faculty of Medicine, Cairo University , Cairo , Egypt.

JAK2, CALR, MPL and triple-negative mutational status has a direct impact on symptom severity and disease burden assessed by MPN10 score in myeloproliferative neoplasms (MPNs). Among 93 patients; median MPN10 score was 48 (5-76) in JAK2 mutants versus 25 (4-80) in JAK2 negative (p < .001); 22.5 (4-65) in CALR mutants versus 35 (5-80) in CALR negative (p < .050) and 21 (10-48) in triple negative versus 40 (4-80) in JAK2/CALR/MPL mutants (p < .001). At three years, progression free and overall survival of JAK2-positive versus JAK2-negative patients were 62% versus 100% (p < .001); 85% versus 100% (p = .011) and were 100% versus 78% (p = .067); 100% versus 92% (p = .197) in CALR-positive versus CALR-negative patients and 100% versus 75% (p = .004); 100% versus 90% (p = .015) in triple negative versus mutant patients, respectively. MPN10 score in association with driver gene mutations can be used as a predictor of survival in MPN patients.
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http://dx.doi.org/10.1080/10428194.2017.1365852DOI Listing
April 2018

Hematologic malignancies during pregnancy: A review.

J Adv Res 2016 Jul 8;7(4):589-96. Epub 2016 Feb 8.

Department of Hematology and BMT, Nasser Institute for Research and Treatment, Ministry of Health, Egypt.

Malignancy is the second most common cause of mortality in the reproductive period and it complicates up to one out of every 1000 pregnancies. When cancer is diagnosed during pregnancy, the management approach must take into consideration both the mother and her fetus. Hematologic cancers diagnosed in pregnancy are not common, resulting in paucity of randomized controlled trials. Diagnosis of such malignancies may be missed or delayed, as their symptoms are similar to those encountered during normal pregnancy. Also, many imaging studies may be hazardous during pregnancy. Management of these malignancies during pregnancy induces many treatment-related risks for mother and baby and should consider patient's preferences for pregnancy continuation. In this article, hematologic malignancies diagnosed in pregnant patients including acute leukemias, chronic myeloid leukemia, lymphomas, multiple myeloma and myeloproliferative neoplasms, will be reviewed, including diagnostic and management strategies and their impact on the pregnant patient and the developing fetus.
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http://dx.doi.org/10.1016/j.jare.2016.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921778PMC
July 2016

Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders.

J Adv Res 2015 May 7;6(3):449-58. Epub 2014 Nov 7.

Department of Hematology and BMT, Nasser Institute for Research and Treatment, Ministry of Health, Egypt.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a geno-identical matched sibling (MSD) is one of the most successful therapies in patients with non-malignant hematological disorders. This study included 273 patients with severe aplastic anemia (SAA), 152 patients with B-Thalassemia major (BTM), 31 patients with Fanconi's anemia (FA), 20 patients with congenital immunodeficiency diseases (ID), and 13 patients with inherited metabolic disorders (IMD) allografted from a MSD. In SAA, the 8-year overall survival (OS) of the whole group patients was 74%. OS was significantly better in patients conditioned with fludarabine and cyclophosphamide (Flu/Cy) than in those who received cyclophosphamide and antithymocyte globulin (Cy/ATG) (p = 0.021). Acute graft-versus-host disease (aGVHD) grade II-IV occurred in 15% while chronic GVHD (cGVHD) occurred in 28%. In BTM, the 12-year disease-free survival (DFS) of the whole group of BTM patients was 72.4%. DFS was 74% for peripheral blood stem cell (PBSC) group compared to 64% in the BM stem cell group. The incidence of graft rejection was significantly lower in patients who received PBSC than in those who received BM (9% vs 25%) (p = 0.036). AGVHD grade II-IV and cGVHD occurred in 15% and 12% of the whole group of BTM patients respectively. In FA, the 5-year OS was 64.5%. Graft rejection occurred in 10% of patients. Grade II-IV aGVHD occurred in 16% while cGVHD occurred in 4%. In ID, the 5-year OS was 62%. Graft rejection occurred in two (10%) patients. Three patients (15%) developed grade II-IV aGVHD, 2 of them progressed to secondary cGVHD. In IMD, OS was 46% at 5 years. Graft rejection occurred in 8% of patients. AGVHD grade II-IV occurred in 15% while cGVHD occurred in 14%. In conclusion, Allo-HSCT provides a higher DFS rate over conventional therapies for patients with non-malignant hematological disorders with prolonged survival.
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http://dx.doi.org/10.1016/j.jare.2014.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522586PMC
May 2015

CTLA-4 polymorphism and clinical outcome post allogeneic hematopoietic stem cell transplantation.

Hum Immunol 2013 Dec 22;74(12):1643-8. Epub 2013 Aug 22.

Bone Marrow Transplantation Laboratory Unit, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address:

CTLA-4 inhibitory molecule plays an important role in regulating T cell activation. It is considered a crucial element in keeping the immune balance and has been implicated in cancer, autoimmunity and transplantation immunology. Inconsistent observations are reported regarding its association with hematopoietic stem cell transplantation (HSCT). Genotyping of CTLA-4 was performed in recipients and their HLA-matched donors for +49A/G and CT60 polymorphisms (80 and 94 pairs, respectively) using PCR-RFLP. No association was encountered between both polymorphisms in patients and donors and acute or chronic graft versus host disease. Significant association was observed between recipient +49A/G G allele and lower disease-free survival and overall survival compared to AA genotype (HR: 2.17, p = 0.03, 95% CI: 1.05-4.48 and HR: 2.54, p = 0.01, 95% CI: 1.16-5.54), respectively. Our results suggest that CTLA-4 genotyping may predict outcome in patients post HSCT. To validate our results, further studies on a larger cohort are needed.
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http://dx.doi.org/10.1016/j.humimm.2013.08.002DOI Listing
December 2013

The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia.

J Egypt Natl Canc Inst 2013 Sep 29;25(3):135-42. Epub 2013 Jun 29.

Department of Medical Oncology, NCI, Cairo University, Egypt.

Background: Minimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse.

Objectives: We aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients.

Patients And Methods: Bone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS).

Results: Study included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18-49). DFS showed no significant difference with age, gender and initial TLC (p=0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017).

Conclusion: MRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients.
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http://dx.doi.org/10.1016/j.jnci.2013.05.004DOI Listing
September 2013

Primary gastrointestinal lymphoma in an Egyptian district: a study using a population-based cancer registry.

J Egypt Natl Canc Inst 2013 Jun 28;25(2):95-101. Epub 2013 Apr 28.

Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt.

Introduction: Gastrointestinal lymphoma (GIL) is the most common extranodal form of non-Hodgkin's lymphoma (NHL) with geographical and age variation of its various subtypes.

Aim: To study GIL in Gharbiah, Egypt and to recognize the treatments employed and their outcomes including survival.

Methods: This is a retrospective study. Between 2000 and 2002, 40 adult patients with GIL were identified in the Gharbiah population based cancer registry (GPBCR); 26 cases of whom were treated at Tanta Cancer Center (TCC).

Results: GIL in Gharbiah, Egypt represented 6.2% of all GIT cancers. The median age was 47 years with slight male predominance. The commonest primary site was the stomach followed by the colon/rectum then the small intestine (67.5%, 25% and 7.5%, respectively). The commonest histological subtypes were the diffuse large B-cell (41.5%) followed by marginal zone B-cell (39%). The commonest symptoms were abdominal pains followed by vomiting. Only 18% of GILs were surgically resected. Most patients (77%) received chemotherapy with a 60% complete response (CR) rate. Once in CR, relapses are occasional. The median overall survival (OS) and progression free survival (PFS) were 31 and 14 months (95% CI, 13.2-48.7 and 6.4-21.6 months, respectively). Gastric primary site and diffuse large B cell subtype carry a non-significant worse OS and PFS than those of other sites and subtypes.

Conclusions: GILs in Gharbiah, Egypt are characterized by predominance of male gender, gastric site and marginal zone histology. Survival is worse for gastric and diffuse large B-cell GILs compared to other sites and histologies.
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http://dx.doi.org/10.1016/j.jnci.2013.03.006DOI Listing
June 2013

Predictive Value of Pretreatment BCR-ABL(IS) Transcript level on Response to Imatinib Therapy in Egyptian Patients with Chronic Phase Chronic Myeloid Leukemia (CPCML).

Int J Biomed Sci 2013 Mar;9(1):48-53

Clinical Oncology Center, School of Medicine, Cairo University, Egypt;

Background: A wide range of responses of patients with CPCML to IM has been reported. Several factors were proposed to predict response including molecular response at 3 and 6 months.

Purpose: To study the impact of pretreatment BCR-ABL transcript level on molecular response to IM, and to assess the value of the milestone ; ≤10% transcript at 3 months on PFS and OS.

Patients And Methods: Fifty five adult CP-CML patients receiving daily dose of 400 mg IM were subjected to molecular and cytogenetic analysis at diagnosis and at regular time intervals. Median follow up period was 36 months (15-48). Hematologic, cytogenetic, and molecular responses were rated according to ELN.

Results: Two Patient groups were distinguished regarding response to IM therapy. A group of 22/55 patients (40%) having pretreatment BCR-ABL(IS) level ≤200% and a second patient group 33/55 (60%) having transcript level >200%. The ≤10% milestone was achieved by 15/22 patients (68%) versus 7/33 patients (21%), p=0.04 in favor of the first group. Optimal responders in first group were 14/22 (64%) compared to 13/33 (39%) in second group, p=0.02. Achievement of 10% transcript level significantly correlated with longer PFS. The median BCR-ABL(IS) transcripts levels in optimal responders at 3, 6 and 18 months was 10%, 2% and 0.1%, respectively compared to 100%, 65% and 10%, in suboptimal/resistant patients p=0.001. Resistance in 11 patients was correlated with identifiable ABL Kinase mutations.

Conclusions: The Pretreatment 200% cutoff and the 3 month BCR-ABL(IS) ≤10% transcript levels proved strong predictors of response to IM and significantly correlated with probability of CCyR, MMR and PFS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644415PMC
March 2013

Cost and outcome of treatment of adults with acute myeloid leukemia at the National Cancer Institute-Egypt.

J Egypt Natl Canc Inst 2007 Jun;19(2):106-13

The Department of Medical Oncology, National Cancer Institute, Cairo University.

Background: Despite important advances in the therapy of acute myeloid leukemia (AML), the majority of patients die of their disease, unless bone marrow transplantation (BMT) is done. Infection and hemorrhage are still the major causes of mortality in AML patients. Progress in therapy and supportive care has led to gradual improvement in the overall results, but further improvements are still needed.

Patients And Methods: The aim of this study is to identify the outcome and costs of adult AML patients treated with conventional chemotherapy (CCT) at the National Cancer Institute (NCI), Cairo University during the time period from April 1999 to January 2002. Clinical, laboratory characteristics were all recorded. Data regarding different types of therapies given for these patients including response, outcome and costs were also collected.

Results: The median age of 82 identified AML patients was 34 years. The complete remission (CR) rate after induction with CCT was 52% (42/82 patients) with a median CR duration of 9 months. Twenty-eight percent of patients who achieved CR subsequently relapsed. By January 2003, fifty-eight patients were dead (70.7%). Infections were the major mortality cause, followed by disease progression then bleeding (65% , 28% and 7% respectively). The median treatment cost per patient was 33158 Egyptian Pounds (LE). It was higher for patients who achieved CR compared to those who relapsed and/or died. Drugs contributed by 78 % to the total treatment cost, while hospitalization, investigations and blood-component therapy contributed by 6%, 7% and 8% respectively.

Conclusions: Outcome of patients with AML treated at NCI- Cairo University can be enhanced by improvement of supportive therapy; mainly infection control and expanding BMT programs to accommodate all eligible patients.
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June 2007

Glutathione S-transferase GSTM1 and GSTT1 polymorphisms in adult acute myeloid leukemia; its impact on toxicity and response to chemotherapy.

J Egypt Natl Canc Inst 2006 Sep;18(3):264-73

Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.

Background And Purpose: Heterogeneity in patient' s response to chemotherapy is consistently observed across populations. Pharmacogenomics, the study of inherited differences in drug disposition and effects, is emerging as a tool to predict efficacy and toxicity of drugs. Glutathione S-transferases (GST) are involved in the metabolism and detoxification of environmental carcinogens and some classes of chemotherapeutics. Polymorphism of GSTM1 and GSTT1, in the form of homozygous deletion, is encountered in varying frequencies in normal population. It has been associated with altered response and toxicity from cytotoxic chemotherapy. In this study, we investigated the impact of these polymorphisms on response and side effects of chemotherapy in adult acute myeloid leukaemia (AML) patients. Correlations between these genetic polymorphisms and other prognostic factors were also investigated.

Patients And Methods: We genotyped GSTM1 and GSTT1 in 98 adult AML patients using multiplex PCR. Induction therapy included Doxorubicin and Cytosine arabinoside (3+7) regimen. Treatment outcomes were compared in those with or without GSTM1 and GSTT1 genes.

Results: The frequencies of GSTM1 null and GSTT1 null genotypes were 56% and 14%, respectively. Six percent (6%) were double null. The rate of toxic death during induction was 3/7 (43%) and 17/56 (30%) in GSTT1 null and GSTT1 present patients, respectively, p=0.67. This constituted 75% and 42% of total deaths in each group, respectively, p=0.31. Differences were not statistically significant. On the other hand, the rate of complete remission (CR) in patients with GSTM1 present compared to those with GSTM1 null genotype was 12/27 (48%) versus 23/36 (64%), p=0.21. GSTT1 null genotype was significantly associated with lymphoid marker (mainly CD7) expression (p=0.03), known with its adverse effect on prognosis. Overall survival and disease-free survival were similar in patients with and without the genes. No significant associations were encountered between GST genotypes and treatment outcomes.

Conclusion: Our data suggest possible association, though not significant, between GSTT1 null genotype and toxic death during induction and between GSTM1 present genotype and lower rate of CR. Studies on larger numbers are needed focusing on selection of anticancer agents to avoid adverse reactions and therapeutic failure, with special emphasis on drug toxicity and dose adjustment.
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September 2006

Presence of simian virus 40 DNA sequences in egyptian patients with lymphoproliferative disorders.

Int J Health Sci (Qassim) 2007 Jan;1(1):11-6

Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Fom El-Khalig, Cairo 11796, Egypt.

Background: Although no definite risk factors have emerged for the different hematological malignancies, a viral cause has been postulated. Several studies have detected SV40 DNA sequences in tumor tissues obtained from non-Hodgkin's lymphoma patients. A link between SV40 and NHL is biologically plausible because SV40 causes hematological malignancies in laboratory rodents.

Methods: We investigated 266 Egyptian cases of different hematological malignancies, for the presence of SV40 DNA using multiplex nested PCR technique. These cases consisted of 158 non-Hodgkin's lymphoma (NHL), 54 Hodgkin's disease(HD), 26 acute lymphocytic leukemia (ALL), 13 acute myeloid leukemia (AML), 8 chronic lymphoblastic leukemia (CLL), 7 chronic myeloid leukemia (CML), in addition to 34 subjects of control group.

Results: Our results have shown that SV40 DNA sequences were found in 53.8% of non-Hodgkin lymphoma patients, 29.6% of Hodgkin's disease patients, and 40.7% of different types of leukemia cases. Frequency of SV40 DNA sequences was higher in NHL patients compared to the other tumor cases. Also, frequency of SV40 DNA sequences was significantly higher (p<0.05) in NHL patients than in the control group. Regarding the different histological types of non-Hodgkin's lymphoma, SV40 DNA sequences were detected frequently in diffuse large B-cell lymphoma and in follicular lymphoma.

Conclusions: The present study suggests that SV40 DNA virus is significantly associated with non-Hodgkin's lymphoma and might have a role in the development of these hematological malignancies. Polyomavirus SV40 may act as a cofactor in the pathogenesis of these tumors and this could lead to new diagnostic, therapeutic, and preventive approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068659PMC
January 2007

Risk factors for cytomegalovirus, hepatitis B and C virus reactivation after bone marrow transplantation.

Transpl Immunol 2004 Dec;13(4):305-11

Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Fom El-Khalig, Cairo 11796, Egypt.

To derive guidelines for a safer bone marrow transplantation (BMT) policy, we have to study pre-BMT risk factors that may be associated with an increased post-BMT death. Among those factors, the importance of pre-BMT viral hepatitis markers in BMT donors and recipients remains unsettled. In the present study, we have determined the effect of prior donor and recipient cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV) exposure on the incidence of those viral infections after bone marrow transplantation (BMT). The study included 63 patients presented to the BMT unit; 28 of them underwent transplantation and 35 were not transplanted. All serum markers of CMV, HBV, and HCV infections were monitored using ELISA technique, as well as PCR-DNA for CMV, HBV and HCV RT-PCR techniques for HCV. The incidence of active CMV and HCV was 11/28 (39%) and 6/28 (21%) in post-BMT recipients compared to 2/35 (6%) and 2/35 (6%) in the 35 untransplanted patients (P=0.00003 and P=0.05). Whereas active HBV infection was non significantly (P=0.13) higher 3/28 (11%) in the BMT patients in comparison to 1/35 (3%) in untransplanted patients. Ten out of the 19 (53%) of the CMV-seropositive recipients developed CMV reactivation compared to 1/9 (11%) of the CMV-seronegative recipients who developed CMV seroconversion. In addition, 3/8 (38%) of the HBV-seropositive recipients developed HBV reactivation in comparison to 0/20 of the HBV-seronegative recipients. Moreover, 5/13 (39%) of the HCV-seropositive recipients developed HCV reactivation in comparison to 1/16 (6%) of the HCV-seronegative recipients who developed HCV seroconversion. In conclusion, previous exposure to CMV, HBV, and HCV infections in the recipients of BMT patients were found to influence the risk of developing those viral infections.
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http://dx.doi.org/10.1016/j.trim.2004.10.001DOI Listing
December 2004