Low dose prophylaxis in Tunisian children with haemophilia.

INTRODUCTION: Low dose prophylaxis could be recommended in countries with limited resources. AIM: We report our single centre experience in children with haemophilia. PATIENTS: Fifty-five children were included in our study with a weekly median dose of 30 UI kg-1 given once, twice or thrice a week. Age of initiation of prophylaxis is 5.32 years (0.64-11.44). Outcome assessment used were number of bleeding before and after initiating prophylaxis, haemophilia joint health score (HJHS), functional independence score in haemophilia (FISH) and quality of life with the Haemo-QoL. RESULTS: Reduction of number of bleeding was clear in all patients; HJHS, FISH and Haemo-QOL were satisfactory. CONCLUSION: Low dose prophylaxis is effective and better than on-demand therapy. It should be the starting point for prophylaxis in countries with limited resources.

Real-life evidence in evaluating effectiveness of treatment in Haemophilia A with a recombinant FVIII concentrate: a non-interventional study in emerging countries.

Some progress has been made regarding availability of recombinant factor VIII concentrates and prophylaxis for haemophilia A in emerging countries, where plasma-derived concentrates were used in the vast majority. Clinical studies to document their introduction and effectiveness are so far not widely available in literature. This non-interventional study evaluates the real-life effectiveness and safety of prophylactic and on-demand treatment with recombinant factor VIII formulated with sucrose (rFVIII-FS) for bleed control and preservation of joints in emerging countries from Eastern Europe, North Africa and Middle East area. One hundred and eighty-six patients from 11 countries were enrolled, mean ± SD age 12.8 ± 12.7 years. At enrolment, majority (79.6%) had severe haemophilia A (<2% IU mL(-1) ), 47.8% had a target joint, 15% had an inhibitor history and one patient was on immune tolerance induction. During the 24-month observation period, 58.1% of the patients were prescribed prophylaxis at every visit, 31.7% were on an on-demand regimen. Patients with severe haemophilia A on prophylaxis (n = 82) had a mean annual rate of treated bleeds of 2.8 ± 4.4, whereas it was 19.1 ± 32.0 for the on-demand group (n = 31), and a mean total Gilbert Score of 9.9 ± 10.3 at baseline and 4.1 ± 6.7 at study end; vs. 15.2 ± 17.3 and 13.7 ± 17.1 for on-demand respectively. The majority of the bleeds (91.1%) were treated with one or two infusions. Four patients without inhibitor history had a first positive inhibitor test during the study. This study demonstrates the effective use of rFVIII-FS in emerging countries and adds to the established safety profile of rFVIII-FS.

Molecular cytogenetic aberrations in Tunisian patients with multiple myeloma identified by cIg-FISH in fixed bone marrow cells.

Cytogenetic studies in multiple myeloma (MM) are hampered by the hypo-proliferative nature of plasma cells. In order to circumvent this problem, we have used a combination of immunolabeling of cytoplasmic Ig light chains (λ or κ) and FISH (cIg-FISH), which allowed a comprehensive detection of the most common and/or recurrent molecular cytogenetic aberrations on fixed bone marrow cells of 70 Tunisian patients. Translocations involving the chromosome 14q32 region were observed in 32 cases (45.7%), including 18 cases with a t(11;14), 8 cases with a t(4;14), and 2 cases with a t(14;16). Deletions of the 13q14 region (D13S319/RB1) were detected in 18.6%, and deletions of the 17p13 region (TP53) in 5.7% of the cases, respectively. Of all patients with a D13S319/RB1 deletion, 61.5% also carried a 14q32 translocation, whereas TP53 deletions were associated with a t(11;14) in 2 cases (50%) and a D13S319 deletion in 1 case (25%). Our results suggest that there is a correlation between the presence of 14q32 translocations and chromosome 13q14 deletions in MM patients and that cIg-FISH is more sensitive as compared to conventional karyotyping in detecting molecular cytogenetic abnormalities in this disease.

Molecular analysis in two Tunisian families with combined factor V and factor VIII deficiency.

SUMMARY: Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2-LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state.

Transfusion-related acute lung injury (TRALI) during remission induction course of acute myeloid leukemia: a possible role for all-transretinoic-acid (ATRA)?

Transfusion-related acute lung injury (TRALI) is a clinical syndrome characterized by sudden onset of respiratory distress due to pulmonary edema during or following transfusion. Two proposed pathophysiologic mechanisms for TRALI were proposed: the antibody hypothesis and the two-event hypothesis. The two-event hypothesis postulates that a pathway to neutrophil activation and aggregation can occur without leukocyte antibodies. We report a case of TRALI occurring during remission induction course of acute myeloid leukemia in a 27-year-old woman who received All-transretinoic-acid (ATRA). We postulate that ATRA may have played a role in this life-threatening complication by priming neutrophil and enhancing their adherence and their activation in the pulmonary endothelium. TRALI improved with non-invasive ventilation support and use of high dose corticosteroids.

Quantitative detection of bcr-abl transcripts in chronic myeloid leukemia.

The optimal management of malignant haematological disorders depend on the degree of tumor load reduction after therapy. Chronic myeloid leukemia constitutes a clinical model for molecular detection and therapy surveillance of malignant disease since this entity was the first leukemia shown to be associated with a specific bcr-abl fusion gene in the patient's leukemia cells. Molecular monitoring of bcr-abl transcript levels by real-time quantitative PCR is increasingly used to assess treatment response in patients with chronic myeloid leukemia (CML). This has become particularly relevant in the era of imatinib therapy when residual levels of leukaemia usually fall below the level of detection by bone marrow cytogenetic analysis. We monitored bcr-abl transcript levels by quantitative real time PCR in 50 tunisian patients treated with imatinib for chronic myeloid leukemia in chronic phase for a median of 29 months (3-60) after they started imatinib.

[Clinical spectrum of cobalamin deficiency in Tunisia]. / Le spectre clinique des déficits en cobalamines en Tunisie.

PURPOSE: the aim of this study was to determine the prevalence of cobalamin (vitamin B12) deficiency in different populations of patients with clinical manifestations associated or secondary to cobalamin or folates deficiency and to analyse the demographic, clinical, paraclinical investigations in cobalamin deficient patients in Tunisia. METHODS: it was a prospective (1999-2001) multicenter study of 604 patients divided into four groups. The first group is composed of 478 consecutive patients with anaemia and/or macrocytosis with megaloblastic haemopoiesis on bone marrow examination without myelodyslasic or malignancy signs. The second group is made up of 34 patients with unexplained neurological symptoms without the presence of anaemia. The third group was composed of 82 invidious with isolated psychiatric disorders and the 10 patients with Hashimoto thyroïditis constituted the last group. RESULTS: serum cobalamin level was low in 98 %, 23%, 14% of cases, respectively, in the first three groups. Only one case of patients with Hashimoto thyroiditis has serum cobalamin deficiency. Pernicious anaemia (Biermer's disease) was established by dual isotope schilling examination in 103 patients among a sample of 120 serum cobalamin deficient patients (86%). The median age at presentation was 45.5 years. Severe chronic atrophic gastritis was diagnosed in 97.5% of patients with Biermer's disease. Serum antibodies against intrinsic factor and gastric parietal cells were detected in (42.5%) and (60.6%) patients, respectively; (25.5%) patients had the both types of antibodies. 23.4% patients were positive for antithyroid antibodies. Anti-nuclear antibodies were detected in 3% patients. CONCLUSION: an interesting finding of our study was the high frequency of cobalamin deficiency in Tunisia, particularly in relative young patients. Our patients had classic features of florid cobalamin deficiency (severe haematological manifestations and neuro-psychiatric disorders). The main underlying causes of such deficiencies were Biermer's disease. Subtle clinical manifestations should be recognized and investigated even in young patients at risk.

[Epidemiological features and complications of central venous catheters in pediatric oncology: prospective study about 125 cases]. / Profil épidémiologique et complications des voies veineuses centrales en oncologie pédiatrique: à propos de 125 cas.

OBJECTIVE: To report the indications and early and late catheter-related complications in a Tunisian unit of paediatric oncology. PATIENTS AND METHODS: This prospective study has been performed in a paediatric oncology unit of the Salah Azaïz Institute between 1989 and 2005. It concerns 58 girls and 57 boys with a median age of 7.9 years(4 months to 18 years) treated for cancer disease predominantly lymphoma (22%), sarcoma (23.2%) or leukaemia (8.5%) proposed for insertion of a central venous catheter (CVC). RESULTS: Excluding 2 insertion failures (1.6%), we placed 123 CVC (double for 10 patients), 43 (35%) exteriorised (EC) and 80 (65%) connected to an implantable site (IS). Catheters were placed in the subclavian vein in 59.2% of cases vs 32% for internal jugular vein and 8.8% for femoral vein. Early complications included 15 cases of multiple punctures (12%), 4 cases of pneumothorax (3.2%) and 6 of arterial punctures (4.8%) originating a cervical subcutaneous haematoma in 1 patient (0.8%). Late complications were represented by infection in 7 cases (5.7%). We observed 2 cases of intracardiac catheter migration due to catheter disconnection from the IS (1.6%) and 2 cases of thrombosis (1.8%). The mean life of CVC was longer for IS (305.2 days) than for EC (64.4 days). CONCLUSION: Implantable sites are effective progress for venous access in children with cancer. They improved the quality of care in pediatric oncology.

[RT-PCR use for the diagnostic of chronic myeloid leukaemia]. / Contribution de la RT-PCR au diagnostic de la leucémie myéloïde chronique.

The molecular analysis of chromosomal abnormalities associated with hematological malignancies allowed the identification of genes involved in theses rearrangements as well as of some recurrent mechanisms. Polymerase chain reaction (PCR) tools are now available to detect these rearrangements, allowing a better follow-up of these diseases. Chronic myeloid leukemia is a myeloproliferative disorder characterized by a reciprocal translocation t(9;22)(q34;q11) which results in a bcr-abl fusion gene. Retro-transcription polymerase chain reaction (RT-PCR) is used to detect bcr-abl to establish diagnosis and to monitor patients. We report here the results of 30 patients samples tested in the hematology laboratory at Pasteur Institute, diagnosed as chronic myeloid leukemia and monitored with RT-PCR. Our results highlight the interest of molecular tools to diagnose and monitor patients mainly when cytogenetic techniques are irrelevant such as cases with complex chromosomal rearrangements or when patients achieve Philadelphia negativity after treatment.

[Cytology and immunophenotyping of acute promyelocytary leukaemia]. / Cytologie et immunophénotypage des leucémies aiguës promyélocytaires.

Acute promyelocytic leukaemia (AML3) is characterized by particular clinical and biological features. We report the cytology and the immunophenotype of 14 AML3 from which 3 were AML3v. A double negativity of HLA-DR and CD34 is found in 12 cases and aberrant expression of CD2 in 2AML3v. Aberrant expression of CD56 and CD22 was shown in, respectively, one case, CD15, CD65 and CD117 expressions were variable. Cytological diagnosis is often evident, although in some cases, it is not typical and immunophenotype will contribute to the diagnosis.

Leukemia in Patients with Klinefelter Syndrome: A Report of Two Cases.

Klinefelter syndrome (KS) is a chromosome abnormality characterized by a 47, XXY karyotype associated with hypogonadism and infertility. We present two cases of leukemia in patients with KS. The first patient presented with acute promyelocytic leukemia. He relapsed after the end of treatment. The second patient was diagnosed with chronic myeloid leukemia. Treatment with imatinib failed and the patient presented with myeloid blast crisis.

Solid tumors after chronic lymphocytic leukemia patients: Report of six cases and review of the literature.

INTRODUCTION: Malignancies have been reported to occur with increased frequency in chronic lymphocytic Leukemia (CLL) patients. The aim of this study was to describe which second malignancies occur in patients with CLL, whether these malignancies are related to CLL, its treatment, or both. We also attempt to study factors predicting the development of other malignancies. PATIENTS AND METHODS: Between 1995 and 2009, six cases of CLL associated with solid tumor were diagnosed in Hematology Department of Military Hospital of Tunis. The diagnosis of CLL was made by immunophenotyping of peripheral blood circulating B cells, and the diagnosis of solid tumors was made by biopsy with anatomopathological exam and immunohistochemical study. RESULTS: The mean age of patients was 71 years. Five patients were male. The CLL was classified Stage A in one case, Stage B in three cases and Stage C in two cases. Two patients had abnormal karyotype. Three patients have not received specific treatment for their CLL. Solid tumors were represented by skin cancer in three cases, lung cancer in two cases and breast cancer in one case. The median time between diagnosis of CLL and that of solid tumor was 53 months. CONCLUSION: Patients with CLL have an increased risk of developing a second cancer. Awareness of risk factors could permit early detection.

The clinical impact of early gram-positive bacteremia and the use of vancomycin after allogeneic bone marrow transplantation.

BACKGROUND: Gram-positive bacteremia (GPB) is an increasing infection after allogeneic bone marrow transplantation (BMT). Our purpose was to identify risk factors for GPB, to evaluate its impact on early mortality and morbidity, and to compare prophylactic with empirical intravenous vancomycin. METHODS AND RESULTS: We studied 89 consecutive BMTs in adult patients. Early GPB occurred in 29% of posttransplantation episodes. T-cell depletion (odds ratio [OR]: 0.18) and vancomycin-prophylaxis (OR: 0.28) reduced the risk of GPB. Mortality at 6 weeks was not significantly different in patients with GPB (15% vs. 9.5%, P = 0.669). GPB was associated with the development of major complications, the use of amphotericin B, and prolonged neutropenia. Vancomycin prophylaxis led to an increased risk of early renal dysfunction (OR: 18.7). CONCLUSION: GPB contributes to overall morbidity during the early post-BMT episode but has no impact on mortality. Vancomycin prophylaxis is effective to reduce GPB but has a negative effect on renal function.

[Results of a prospective protocol for the treatment of adult Hodgkin's disease]. / Resultats d'un protocole prospectif de traitement de la maladie de Hodgkin de l'adulte.

To report the results of an adapted protocol of treatment of Hodgkin disease in Tunisian patients. 70 patients (47 males and 23 females, sex-ratio = 2.04) with a mean age of 38.5 years (15 to 75) are enrolled in a therapeutic protocol to the prognostic factors and based on chemotherapy with MOPP/ABV or hybrid associated to radiotherapy. We perform an evaluation of response to chemotherapy after the 4th cycle, after the 6th cycle and then at the end of the protocol. Our population is characterized by the frequency of young patients(34% between 30 and 40 years), histologic types 2 and 3 (45 and 48%) and advanced disease with 60% of stages III and IV. After the 4th cycle, 32 patients(45%) are in complete response and 31(44%) in partial response, while 6 patients(9%) progress under chemotherapy. After 6 cycles, we observe 44 in complete response(72%) including 46% of the bad responders after 4 cycles. At the end of the protocol and on the 58 evaluable patients, 50 remain in complete response(86%). We observe 5 deaths occurred in 3 progressing patients and in 2 patients by infection after chemotherapy. 5-year actuarial and disease-free survival is 60% and 56% and median survival is 83 months. In the univariate analysis, response to chemotherapy represent the unic significant prognostic factor.

[The 5q(-) syndrome. Report of 2 cases]. / Le syndrome 5q(-). A propos de 2 cas.

A rare and primitive myelodysplastic syndrome 5q(-) is characterised first, by the persistence of the cytogenetic anomaly 5q(-), and second, by its feminine predominance. Among 13 cases of myelodysplastic syndromes, the subject of a substantial and systematic cytogenetic medullar study (1996-1998), this paper is a case study of 2 syndromes 5q(-) diagnosed in two male patients, respectively, aged 41 and 68. The following diagnosis was made on the basis of an aregenerative macrocytic anaemia, a high platelet count, and a megakaryocytic hyperplasia, along with dysmegakaryocytopoiesis. The diagnosis of the 5q(-) syndrome was verified by cytogenetic analysis showing in one of the patients a deletion 5q(-)(q13, q33) and 5q(-)(q14, q34) with trisomy in the second one. Treatment was only limited to a blood transfusion. Subsequently one of the patients developed an advanced case of leukaemia. This paper suggests that a systematic medullar cytogenetic study must be conducted in the case of any refractory anaemia in order to identify the syndrome 5q(-) in individual cases.

[Hairy cell leukemia: report of 8 cases]. / Leucémie à tricholeucocytes à propos de 8 cas.

Hairy cell leukemia haemopathy is a rare lymphoïd haemopathy type B. 8 cases are reported and diagnosed at Hôpital Aziza Othmana over a period of 20 years between 1979 and 1999, 7 men and one women. The mean age of the patients is 51 years, with externe ages from 42 to 81 years. 4 patients consulted for an infections and, or anaemia syndrome. The disease was revealed due to the presence of an isolated splenomegaly in other cases. At the clinical examination, the spleen is hypertrophied in 7 patients out of 8. Pancytopenia is observed in 50% of the patients. Only one patient has presented a moderated hyperleukocytosis at 11,000/mm3 related to the presence of moving on tricholeukocytes. The myelogramme is pocr. It allowed to mention the diagnosis in 6 cases out of 8. Bone Marrow biopsy revealed a diffuse infiltration by TCL with a reticulinic fibrosis in all patients. 4 patients out of 8 have been splenectomized. Cytopenies have been corrected in all patients. Only one patient has been treated by alpha Interferon for 3 years with a partial hematological response. A relapse was observed once the Interferon was stopped. With the introduction of new drugs such purine analogues. The HCL treatment has been revolutionarized thanks to the improvement of the rate of complete response (from 10% to 80% of CR). If splenectomy is still observed in HCL for splenomegalic and or severe cytopenia, our findings could be improved thanks to new purine analogues.

[Long-term survival and prognostic factors in multiple myeloma treated with conventional chemotherapy. Report of 109 cases]. / Survie a long terme et facteurs pronostiques du myelome multiple traite par chimiotherapie conventionnelle. A propos de 109 cas.

Our study is retrospective. We report the results of conventional chemotherapy ins previosly untreated patients with myeloma. Survival and prognostic factors were analysed in 109 patients diagnosed from 1983 to 1992. The median age was 65 years, 87 patients (80%) were including in the stage III according the Durie Salmon staging system. The median survival time was 27 months and 10 years survival rate is 3.66%. In the univariate analysis, two prognostic variables were retained namely the hemoglobin and creatinine level. The study suggest that conventional therapy is a good treatment for old patients. However, patients younger than 55 years, must benefit from intensive chemotherapy supported by autologous bone marrow, pheripheral blood stem cells, or allogenic bone marrow transplantation. A considerable encrace in duration of remission and survival is possible.