Publications by authors named "Halima El-Omri"

31 Publications

Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.

Leukemia 2021 Feb 17. Epub 2021 Feb 17.

Área de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, IDISNA, Pamplona, Spain.

Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
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http://dx.doi.org/10.1038/s41375-021-01147-yDOI Listing
February 2021

Downregulation of Lymphoid enhancer-binding factor 1 (LEF-1) expression (by immunohistochemistry and/ flow cytometry) in chronic Lymphocytic Leukemia with atypical immunophenotypic and cytologic features.

Int J Lab Hematol 2020 Dec 12. Epub 2020 Dec 12.

Department of Laboratory Medicine and Pathology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Introduction: Lymphoid enhancer-binding factor 1 (LEF-1) overexpression has been recently remarkably reported in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has shown utility in distinguishing CLL/SLL from other B-cell lymphomas. CLL has a well-defined immunophenotype, yet, some cases of CLL demonstrate atypical morphology/ phenotype reflected by low Matutes score (atypical CLL). Till date, LEF1 expression has not been systematically studied in cases of CLL with atypical features.

Methods: In this study, LEF-1 expression was assessed by two different techniques, (immunohistochemistry and flow cytometry), to investigate the expression profile of LEF-1 in cases of CLL/SLL, in comparison with other low-grade B-lymphomas and CLL with atypical features, including atypical immunophenotype and CLL with increased prolymphocytes or morphologically atypical cells.

Results: We found that LEF-1 expression is downregulated in CLL with atypical immunophenotype/features compared to classic CLL; Chi-Square P < .0001. The ratio for LEF-1 expression in malignant B-cells/NK (by flow cytometry) in CLL/SLL with classic immunophenotype was higher than atypical CLL and is significantly higher in other small B-cell lymphomas (P < .01). Absence of LEF-1 expression in CLL/SLL is correlated (P < .05) with downregulation of CD5, CD23, CD200, expression of FMC7, brighter expression of CD79b, brighter expression of surface light chain, increased prolymphocytes and lower Matutes score.

Conclusion: As downregulation of LEF-1 expression is well correlated with atypical CLL, we suggest adding LEF-1 to Matutes score as a beneficial marker to differentiate classic from atypical CLL LEF-1 could also serve as a potential prognostic indicator for CLL clinical course.
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http://dx.doi.org/10.1111/ijlh.13420DOI Listing
December 2020

Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma.

Genome Res 2020 Sep 20;30(9):1217-1227. Epub 2020 Aug 20.

Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, 28029 Madrid, Spain.

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (), a major regulator of cellular redox status and, in addition, identified as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
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http://dx.doi.org/10.1101/gr.265520.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545147PMC
September 2020

Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma.

Int J Mol Sci 2020 Jul 15;21(14). Epub 2020 Jul 15.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host's immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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http://dx.doi.org/10.3390/ijms21145002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403981PMC
July 2020

Characterization of circulating myeloma tumor cells by next generation flowcytometry in scleromyxedema patient: a case report.

Medicine (Baltimore) 2020 Jul;99(27):e20726

Hamad Medical Corporation, Hematology and Medical Oncology Department.

Introduction: Scleromyxedema (rare cutaneous mucinosis), is characterized by the formation of lichenoid papules and presence of Serum monoclonal IgG in most cases, or all; after repeated testing.

Patient Concerns: The patient is a 51-year-old male presented with thick, disfiguring elephant-like erythematous skin folds over the forehead, papular shiny eruptions over ears and trunk and waxy erythematous papules over arms and hands without dysphagia or respiratory or neurologic symptoms DIAGNOSIS: : Skin biopsy from right arm was consistent with scleromyxedema. Serum cryoglobulin was reported negative. Complete blood count and routine blood biochemistry were normal. Thyroid function tests were normal. Serum protein electrophoresis and immunofixation showed monoclonal band of 14.5 g/L typed as IgG lambda.

Interventions: Our patient was refractory to lenalidomide however improved clinically on immunoglobulins infusions on monthly basis without change in the MGUS level.

Outcomes: NGF analysis revealed approximately 0.25% Lambda monotypic plasma cells in the bone marrow expressing CD38, CD138, and CD27 with aberrant expression of CD56 and were negative for CD45, CD19, CD117, and CD81. We also detected 0.002% circulating plasma cells (PCs) in peripheral blood.

Conclusion: The immunophenotype of circulating tumor cells (CTCs) remain close to the malignant PCs phenotype in the BM. Hence, we report NGF approach as a novel diagnostic tool for highly sensitive MRD detection in plasma cell dyscrasias including scleromyxedema.
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http://dx.doi.org/10.1097/MD.0000000000020726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337479PMC
July 2020

Acute Myeloid Leukemia in Qatar (2010-2016): Clinical, Biological, and Prognostic Factors and Treatment Outcomes.

Front Genet 2020 17;11:553. Epub 2020 Jun 17.

Center of Excellence in Bionanoscience Research and Genomics and Biotechnology Section and Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.

The current study retrospectively evaluated cytogenetic profiles, various prognostic factors, and survival outcomes in 128 acute myeloid leukemia (AML) patients (14 ≤ age ≤ 70 years) admitted to the National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar, between January 2010 and December 2016. The median age at diagnosis was 43 years, and 80% were less than 60 years old; 75% of patients were male. Cytogenetic analysis was integrated into the World Health Organization 2008 classification and showed that the percentages of normal and abnormal karyotypes were similar, accounting for 48.4% of each group of patients. The AML risk stratification based on cytogenetic analysis resulted in the following distribution: 18% in the favorable risk group, 57% in the intermediate-risk group, 24% in the unfavorable risk group, and 1% unknown. Only 88 patients received therapy with curative intent; 67% achieved complete remission, increasing to 81% after inductions 1 and 2. The median overall survival (OS) and disease-free survival (DFS) in AML patients were 26.6 and 19.5 months, respectively. The 3-year OS and DFS were 40 and 36%, respectively. Prognostic factors including age, gender, white blood cell count, and risk stratification were not significantly associated with treatment outcomes, whereas response to treatment vs. failure was significantly associated with the outcome ( = 0.01). The current study supports the importance of cytogenetics as a useful tool in diagnosis, prognosis, and risk assessment in AML treatment.
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http://dx.doi.org/10.3389/fgene.2020.00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313235PMC
June 2020

Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma.

Leukemia 2020 11 1;34(11):3007-3018. Epub 2020 Jun 1.

Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), Navarra, Spain.

Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.
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http://dx.doi.org/10.1038/s41375-020-0883-0DOI Listing
November 2020

Concomitant BRAF Mutation in Hairy Cell Leukemia and Papillary Thyroid Cancer: Case Report.

Case Rep Oncol 2019 Sep-Dec;12(3):922-927. Epub 2019 Dec 17.

Hematology Department, National Center for Cancer Research (NCCCR), Hamad Medical Corporation (HMC), Doha, Qatar.

Hairy cell leukemia (HCL) is rare type of leukemia. This neoplasm is well-known to present with pancytopenia and splenomegaly. HCL is associated with BRAF mutation in 100% of cases. It is also associated with hematological and oncological malignancies such as melanoma and papillary thyroid cancer. Although the association of both cancers (HCL and papillary thyroid cancer) with BRAF mutation is well established in the literature, as far as we know it has not been reported before in the same patient. Here we report 48-year-old male diagnosed with HCL and papillary thyroid cancer and who is BRAF positive in both diagnostic tissues.
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http://dx.doi.org/10.1159/000504929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036560PMC
December 2019

Highly Aggressive CD4-Positive Mast Cell Leukaemia (Leukaemic Variant) Associated with Isolated Trisomy 19 and Hemophagocytosis by Neoplastic Mast Cells: A Case Report with Challenging Experience and Review.

Case Rep Hematol 2019 27;2019:1805270. Epub 2019 Oct 27.

Department of Hematology and Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Background: Mast cell leukaemia is a unique disease among hematopoietic neoplasms, being one of the rarest leukaemia subtypes. In addition, its prompt diagnosis is usually challenging. This is due to its heterogeneity in clinical presentations and cytomorphological and immunophenotypical features together with potential associations with other hematologic neoplasms which can complicate the condition and delay accurate diagnosis. To the best of our knowledge, this is the first case report of CD4-positive mast cell leukaemia.

Case Presentation: A 39-year-old male presented with acute onset of fever, abdominal pain, and generalized body aches of two-week duration. Peripheral blood smear showed circulating blasts (13%) with coarsely basophilic granulation. Bone marrow (BM) aspirate showed extensive infiltration with immature mast cells of blast-like morphology with trilineage dysplasia and evident hemophagocytic activity exhibited by histiocytes and neoplastic mast cells. BM biopsy was diffusely infiltrated with many atypical mast cells positive for CD45, CD117, mast cell tryptase, CD25, and CD4 with partial positivity for CD7 and CD30. Cytogenetics showed an abnormal karyotype: 47, XY, +1947, XY, +19[13]/46, XY[9]. Molecular analysis revealed a D816V mutation consistent with a diagnosis of systemic mastocytosis, mast cell leukaemia.

Conclusion: The expression of T-cell associated markers by abnormal mast cells is well documented; however, CD4 and CD7 expression have not previously been described in association with mast cell leukaemia. Coexpression of CD2, CD4, CD7, and CD30 by the mast cells particularly in skin lesions may provoke misinterpretation as a cutaneous T-cell neoplasm. To the best of our knowledge, this is the first report of CD4-positive mast cell leukaemia. Moreover, hemophagocytic mast cell leukaemia is a very rare morphologic variant, and possible correlation between this finding and expression of CD4 by neoplastic mast cells is a topic for further investigation.
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http://dx.doi.org/10.1155/2019/1805270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854920PMC
October 2019

Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination.

Leukemia 2020 02 8;34(2):589-603. Epub 2019 Oct 8.

Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369 and CB16/12/00489, Pamplona, Spain.

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.
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http://dx.doi.org/10.1038/s41375-019-0588-4DOI Listing
February 2020

Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling.

Front Oncol 2019 17;9:285. Epub 2019 Apr 17.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.
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http://dx.doi.org/10.3389/fonc.2019.00285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478801PMC
April 2019

Sanguinarine suppresses growth and induces apoptosis in childhood acute lymphoblastic leukemia.

Leuk Lymphoma 2019 03 6;60(3):782-794. Epub 2018 Sep 6.

a Translational Research Institute , Academic Health System, Hamad Medical Corporation , Doha , Qatar.

Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS4;11, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.
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http://dx.doi.org/10.1080/10428194.2018.1494270DOI Listing
March 2019

Current Opinions on Chemoresistance: An Overview.

Bioinformation 2018 28;14(2):80-85. Epub 2018 Feb 28.

Medical Oncology Department, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Sub population of cancer cells, referred to as Cancer stem cells (CSCs) or tumor initiating cells, have enhanced metastatic potential that drives tumor progression. CSCs have been found to hold intrinsic resistance to present chemotherapeutic strategies. This resistance is attributed to DNA reparability, slower cell cycle and high levels of detoxifying enzymes. Hence, CSCs pose an obstacle against chemotherapy. The increasing prevalence of drug resistant cancers necessitates further research and treatment development. The current review presents the essential mechanisms that impart chemoresistance in CSCs as well as the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies.
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http://dx.doi.org/10.6026/97320630014080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879949PMC
February 2018

Acute Myeloid Leukemia With Inv(16)(p13q22) Associated With Hidden Systemic Mastocytosis: Case Report and Review of Literature.

Clin Med Insights Blood Disord 2017 30;10:1179545X17700858. Epub 2017 Mar 30.

Department of Hematology/Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Systemic mastocytosis (SM) is a condition associated with clonal neoplastic proliferation of mast cells. In up to 40% of systemic mastocytosis cases, an associated clonal hematological disease of non-mast cell lineage, such as acute myeloid leukemia (AML), is diagnosed before, simultaneously with, or after the diagnosis of SM. Herein, we report a case of a 30-year-old man diagnosed with AML with inv(16) (p13;q22) CBFB:MYH11. Associated mastocytosis was not noted at diagnosis and was only detected in the bone marrow at time of remission after successful chemotherapy. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mast cell infiltrate in the marrow biopsy with aberrant immunophenotype, with coexpression of tryptase, CD117, and CD25. The mast cells showed atypical morphology mostly with irregular nuclear contour, bilobed or multilobed nuclei with cytoplasmic hypogranulation or irregular metachromatic granule distribution, and some cells with eccentric nucleus or spindle shape. Reexamination of the pretherapeutic bone marrow with immunostain for tryptase and CD25 revealed that mastocytosis was present from the start but masked by extensive blast proliferation. This case indicates that mast cell infiltrates are sometimes underappreciated at the original diagnosis of AML with inv(16) and that the concurrent diagnosis of SM with AML requires a high index of suspicion supported with comprehensive morphologic and immunohistochemical evaluation for a neoplastic mast cell proliferation.
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http://dx.doi.org/10.1177/1179545X17700858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428180PMC
March 2017

Concomitant Classic Hodgkin Lymphoma of Lymph Node and cMYC-Positive Burkitt Leukemia/Lymphoma of the Bone Marrow Presented Concurrently at the Time of Presentation: A Rare Combination of Discordant Lymphomas.

Clin Med Insights Blood Disord 2016 3;9:23-8. Epub 2016 Aug 3.

Department of Hematology and Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Discordant lymphoma is rare condition in which different types of malignant lymphomas occurring in different anatomic sites. The two diseases may present clinically as concurrent or sequential disease (10). Herein we are reporting a Pakistani female in her 60s, a carrier of hepatitis B virus with multiple comorbidities presented with cervical lymphadenopathy, diagnosed as Hodgkin's lymphoma, mixed cellularity. During the staging workup, the patient was discovered to have extensive bone marrow (BM) involvement by Burkitt leukaemia/lymphoma (BL). Cytogenetic analysis revealed positivity for t(8;14)(q24;q32) confirmed by Fluorescence In Situ Hybridization (FISH) for IGH/MYC. Epstein-Barr virus (EBV) was demonstrated heavily in our case, with (EBV) DNA of 24,295,560 copies/ml by PCR at time of presentation, in addition, the neoplastic cells in both diagnostic tissues (cervical lymph node and BM) demonstrated positivity for EBV. A diagnosis of concomitant EBV related discordant lymphoma (classical Hodgkin lymphoma (cHL) and Burkitt lymphoma (BL) in leukemic phase was made. Among all reported cases, this case is highly exceptional because it is the first case of discordant/composite lymphoma, with this combination and concomitant presentation. Since we are dealing with a case with an exceptionally rare combination, we found it significant to elaborate more on its clinical features, contributing factors including EBV role, response to treatment, complications, and prognosis.
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http://dx.doi.org/10.4137/CMBD.S39908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973772PMC
August 2016

Aggressive Lymphoma "Sarcoma Mimicker" Originating in the Gluteus and Adductor Muscles: A Case Report and Literature Review.

Clin Med Insights Case Rep 2016 5;9:47-53. Epub 2016 Jul 5.

Hematology Consultant, Department of Hematology and BMT, National Center for Cancer Care and Research (NCCCR)-Hamad Medical Corporation (HMC), Doha, Qatar.

Extranodal lymphoma (ENL) occurs in approximately 30%-40% of all patients with non-Hodgkin lymphoma and has been described in almost all organs and tissues. However, diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin lymphoma, primarily arising in the retroperitoneal region. In this article, we report a rare case of an adult male diagnosed with primary diffuse large B-cell lymphoma of the gluteal and adductor muscles with aggressive bone involvement. All appropriate radiological and histopathological studies were done for diagnosis and staging. After discussion with the lymphoma multidisciplinary team, it was agreed to start on R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin®), and prednisone) as the standard of care, which was later changed to R-CODOX-M/R-IVAC protocol (rituximab, cyclophosphamide, vincristine (Oncovin®), doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine) due to inadequate response. Due to the refractory aggressive nature of the disease, subsequent decision of the multidisciplinary team was salvage chemotherapy and autologous stem cell transplant. The aim of this case report was to describe and evaluate the clinical presentation and important radiological features of extranodal lymphoma affecting the musculoskeletal system.
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http://dx.doi.org/10.4137/CCRep.S39052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934407PMC
July 2016

An Unusual Case of Hepatosplenic αβ T-Cell Lymphoma Presenting with Coombs'-Negative Hemolytic Anemia.

Clin Med Insights Oncol 2015 2;9:123-8. Epub 2015 Dec 2.

Department of Laboratory Medicine and Pathology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive extranodal T-cell lymphoma that comprises <5% of peripheral T-cell lymphomas. The majority of cases harbor the γδ T-cell receptor (TCR), but recently, a few cases have been shown to express the αβ TCR. Comparison of these two subtypes (αβ and γδ) shows similar clinicopathologic and cytogenetic features; however, due to the paucity of reported cases, it is not clear whether they are prognostically distinct entities. We report a case of αβ HSTCL with a rather unusual presentation of Coombs'-negative hemolytic anemia. Diagnosis proved challenging due to an unusual blastoid morphology with the absence of typical intrasinusoidal distribution of tumor cells in the bone marrow. This unique case adds to the growing list of this rare subtype of T-cell lymphomas, which warrant urgent attention due to the lack of effective treatment options and dismal prognosis.
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http://dx.doi.org/10.4137/CMO.S35120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668954PMC
December 2015

Mixed Phenotype Acute Leukemia with Two Immunophenotypically Distinct B and T Blasts Populations, Double Ph (+) Chromosome and Complex Karyotype: Report of an Unusual Case.

Clin Med Insights Blood Disord 2015 21;8:25-31. Epub 2015 Sep 21.

Department of Haematology and Medical Oncology, Hamad Medical Corporation, Doha, Qatar.

Mixed phenotype acute leukemia (MPAL) is considered as a rare type of leukemia with an incidence of less than 4% of all acute leukemia based on the most recent 2008 WHO classification. Common subtypes are the B/myeloid and T/myeloid; B/T and trilineage MPAL being extremely rare. We present a case of a male in his 20s, whose peripheral blood smears showed 34% blast cells and bone marrow with 70% blasts. Immunophenotyping by multiparametric flow cytometry showed two populations of blasts, the major one with B-lineage and the minor one with T-lineage. Conventional karyotyping revealed complex karyotype with the presence of double Philadelphia chromosome (Ph (+)). BCR/ABL1 rearrangement was confirmed by fluorescent in situ hybridization (FISH) analysis. The BCR/ABL1 ES probe on interphase cells indicated p190 minor m-BCR/ABL fusion in 46% and a second abnormal clone with double Ph (+) in 16% of the cells analyzed confirmed by reverse transcription-PCR (RT-PCR). The case was diagnosed as MPAL with double Philadelphia chromosome Ph (+). The patient was treated with dasatinib, four cycle hyper CVAD/methotrexate cytarabin protocol, and allogeneic transplant. He is still alive in complete hematological, cytogenetic, and molecular remission. Mixed phenotype B/T acute leukemia is an extremely rare disease, particularly those with double Philadelphia chromosomes and clinically presents challenges in diagnosis and treatment.
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http://dx.doi.org/10.4137/CMBD.S24631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578553PMC
October 2015

Tubercular Meningitis and Lymphadenitis Mimicking a Relapse of Burkitt's Lymphoma on (18)F-FDG-PET/CT: A Case Report.

Case Rep Oncol 2015 May-Aug;8(2):226-32. Epub 2015 May 7.

Department of PET/CT, National Center for Cancer Care & Research, Hamad Medical Corporation, Doha, Qatar.

Tuberculosis (TB) can present with various forms and can occasionally be mistaken for malignancy. Hereby, we report a 53-year-old man diagnosed and treated for Burkitt's lymphoma in 2009 who achieved a complete remission confirmed by a computed tomography (CT) scan. During the follow-up 2 years later, he complained of left hip pain that warranted investigation with magnetic resonance imaging and whole-body (18)F-fludeoxyglucose-positron emission tomography (FDG-PET)/CT which showed a benign lesion in the left hip associated with multiple lymph nodes in the chest and abdomen not amenable for biopsy. A follow-up PET/CT scan a few months later showed intense tracer uptake in the lymph nodes with size progression and appearance of new lymph nodes suspicious of lymphoma relapse. The patient was asymptomatic, and all investigations including viral and connective tissue disease studies were negative. Also the tuberculin skin test and QuantiFERON were negative. Lymph node biopsy was planned; however, the patient presented a few days earlier with fever, headache and photophobia. Cerebrospinal fluid (CSF) examination confirmed meningitis with lymphocytic pleocytosis and elevated protein. The CSF Gram stain, culture, viral and acid-fast bacilli were negative. CSF flow cytometry and cytopathology confirmed polyclonal lymphocytosis and suggested reactive causes. CSF TB culture grew Mycobacterium tuberculosis. Mediastinal lymph node biopsy also confirmed TB lymphadenitis. Four antituberculosis drugs were started. One year later, a PET/CT scan showed regression of all the involved lymph nodes. This case highlights the importance of excluding TB in patients with suspected malignancy, especially if they belong to endemic regions, and the increasing role of (18)F-FDG-PET/CT in the early detection of extrapulmonary TB.
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http://dx.doi.org/10.1159/000430768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464102PMC
June 2015

Efficacy and Safety of Rituximab for Refractory and Relapsing Thrombotic Thrombocytopenic Purpura: A Cohort of 10 Cases.

Clin Med Insights Blood Disord 2015 24;8:1-7. Epub 2015 May 24.

Medical Oncology Department, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Objective: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder mediated by autoantibodies directed against ADAMTS13. This provides a rationale for the use of rituximab in this disorder. We report our experience and the outcome of 10 cases of TTP (9 refractory and 1 relapsing) successfully treated with rituximab in combination with plasma exchange (PE) and other immunosuppressive treatments.

Methods: The diagnosis of TTP was based on clinical criteria and supported by severe deficiency of ADAMTS13 activity and presence of inhibitors in seven cases. Rituximab was started after a median of 18.6 sessions of PE (range: 5-35) at the dose of 375 mg/m(2)/week for 4-8 weeks.

Results: Complete remission was achieved in all patients after a median time of 14.4 days of the first dose (range: 6-30). After a median follow-up of 30 months (range: 8-78), eight patients were still in remission and two developed multiple relapses, treated again with the same therapy, and achieved complete responses; they are alive, and in complete remission after a follow-up of 12 and 16 months.

Conclusion: Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. However, longer follow-up is recommended to assess relapse and detect possible long-term side effects of this therapy.
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http://dx.doi.org/10.4137/CMBD.S25326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451552PMC
June 2015

Rare aggressive natural killer cell leukemia presented with bone marrow fibrosis - a diagnostic challenge.

Springerplus 2014 29;3:390. Epub 2014 Jul 29.

Department of Laboratory Medicine and pathology, Hamad Medical Corporation, Doha, Qatar.

Aggressive natural killer cell leukemia is an extraordinary rare aggressive malignant neoplasm of natural killer cells. Although its first recognition as a specific entity was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized as fewer than 200 cases have been reported in the literature and up to our knowledge, this is the first case report in Qatar. Reaching a diagnosis of aggressive natural killer leukemia was a challenging experience, because in addition to being a rare entity, the relative scarcity of circulating neoplastic cells, failure to obtain an adequate aspirate sample sufficient to perform flow cytometric analysis, together with the absence of applicable method to prove NK clonality (as it lack specific clonal marker); our case had atypical confusing presentation of striking increase in bone marrow fibrosis that was misleading and complicated the case further. The bone marrow fibrosis encountered may be related to the neoplastic natural killer cells' chemokine profile and it may raise the awareness for considering aggressive natural killer leukemia within the differential diagnosis of leukemia with heightened marrow fibrosis.
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http://dx.doi.org/10.1186/2193-1801-3-390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130965PMC
August 2014

Frequency of specific coagulation inhibitors and antiphospholipid antibodies in Tunisian haemophiliacs.

Ann Biol Clin (Paris) 2012 Nov-Dec;70(6):659-65

Laboratoire d'hématologie et Banque du sang, CHU Sahloul, Sousse, Tunisie.

Production of factor VIII or factor IX inhibitors is a major complication limiting the efficiency of substitutive therapy in haemophiliacs. Moreover, viral infections, the second serious complication of replacement therapy, may be associated to the occurrence of antiphospholipid antibodies which paradoxically lead to thrombosis. We investigated the prevalence of coagulation inhibitors (factor VIII and factor IX inhibitors, antiphospholipid antibodies) in Tunisian haemophiliacs, and we assessed concomitant coagulation factor deficiencies. Thirty-two previously treated haemophiliacs (20 haemophiliacs A; 12 haemophiliacs B) were screened for factor VIII and factor IX inhibitors by APTT mixing study, Bethesda test and modified Nijmegen method, and investigated for the presence of anticardiolipin, anti-β2 glycoprotein I, lupus anticoagulant and associated coagulation factors deficiencies. The frequency of factor VIII and factor IX inhibitors was low (5%) in contrast to the high prevalence of antiphospholipid antibodies (28.1%). Four and nine patients were positive for anticardiolipin and anti-β2 glycoprotein I, respectively. No lupus anticoagulant was detected. The prevalence of antiphospholipid antibodies was higher in patients with positive hepatitis C virus infection serology as compared to patients with negative serology (41.6% vs. 20%). Concomitant factor VII and/or factor V deficiency was found in 10 patients. In conclusion, the occurrence of factor VIII and factor IX inhibitors is rare among Tunisian haemophiliacs. The clinical relevance of antiphospholipid antibodies requires further investigations. We emphasize the importance of screening for concomitant deficiencies in haemophiliacs when the clinical presentation is suggestive.
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http://dx.doi.org/10.1684/abc.2012.0765DOI Listing
July 2013

Nasopharyngeal/nasal type NK/T lymphoma: analysis of 23 cases and current review of the literature.

Kulak Burun Bogaz Ihtis Derg 2012 Sep-Oct;22(5):275-83

Department of Clinical Hematology, Farhat Hached University Hospital, Sousse, Tunisia.

Objectives: This study aims to identify the presenting symptoms, treatment and outcome of patients with nasal natural killer T (NK/T)-cell lymphoma and to find possible differences in survival based on Ann-Arbor stage and international prognostic index (IPI).

Patients And Methods: Computed tomography and biopsy results of 23 patients (15 males, 8 females; mean age 41 years; range 22 to 72 years) with extranodal NK/T-cell lymphoma who were treated at the department of clinical hematology between 1995 and 2011 were retrospectively analyzed.

Results: The median time from onset of clinical symptoms to histological diagnosis was five months. Most patients presented with nasal obstruction (69%) and rhinism (52%). The site of extranodal NK/T-cell lymphoma primarily involved nasal cavity in 39%. Orbital extension was observed in 26%. Lymphomas were classified as stage IE in 30.4%, stage IIE in 47.8% and stage IVE in 21.7%. Nineteen patients received treatment: 10 received chemotherapy plus radiotherapy, nine received chemotherapy only. We used several regimens of chemotherapy including some protocols containing etoposid, L-asparaginase and others without this drugs. Univariate analysis showed that lower IPI score, low Ann-Arbor stage and responsiveness to treatment with both chemotherapy and radiotherapy were significant factors influencing both OS and PFS.

Conclusion: Nasal type NK/T-cell lymphoma showed a poor response to the conventional anthracycline-based chemotherapy, thereby an investigation for a novel therapy is urgently needed to improve survival.
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http://dx.doi.org/10.5606/kbbihtisas.2012.053DOI Listing
March 2015

Fatal Strongyloides stercoralis hyper-infection in a patient with multiple myeloma.

Braz J Infect Dis 2010 Sep-Oct;14(5):536-9

Hematology Department, Al-Amal Hospital, Doha, QATAR.

Strongyloides stercoralis (S.S.) is a human intestinal parasite, which may lead to complicated strongyloidiasis. We report a case of disseminated strongyloidiasis following the treatment of myeloma. The patient developed skin lesions, respiratory distress, aseptic meningitis and bacterial and fungal sepsis. The diagnosis of strongyloidiasis was established through endotracheal tube secretions. Despite the treatment with Ivermectin and Albendazole, the outcome was fatal. The value of screening for strongyloidiasis is unclear but may be of benefit in patients with hematological malignancies from high endemic areas.
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August 2011

Acquired pure megakaryocytic aplasia successfully treated with cyclosporine.

Turk J Haematol 2010 Dec;27(4):289-93

Department of Hematology and Bone Marrow Transplant Al Amal Hospital - Hamad Medical Corporation P.O. Box 3050 Doha, Qatar Phone: +974- 4397857 E-mail:

Acquired pure megakaryocytic aplasia is a rare hematological disorder characterized by thrombocytopenia with absent or markedly reduced megakaryocytes in the bone marrow. We report a case of a 25-year-old male diagnosed as acquired pure megakaryocytic aplasia. Treatment with prednisone and intravenous immunoglobulin failed, but he was successfully treated with cyclosporine, with complete remission after 90 days and normal platelet count maintained thereafter.
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http://dx.doi.org/10.5152/tjh.2010.51DOI Listing
December 2010

Two Ocular Infections during Conventional Chemotherapy in a Patient with Acute Lymphoblastic Leukemia: A Case Report.

Case Rep Oncol 2010 Jul 10;3(2):234-239. Epub 2010 Jul 10.

Department of Hematology and Medical Oncology, Al Amal Hospital, Hamad Medical Corporation, Doha, Qatar.

Viral retinitis due to cytomegalovirus (CMV) infection is rare in patients with acute leukemia who did not receive hematopoietic stem cell transplantation. We report a case of CMV retinitis that developed in a 49-year-old patient with acute lymphoblastic leukemia. The patient was treated with salvage chemotherapy using a hyper-CVAD regimen and did not receive hematopoietic stem cell transplantation. The incidence of CMV retinitis in this subgroup of patients is not described in literature. He had a very complicated course during chemotherapy but was successfully treated, with preservation of visual acuity, and to date he is in complete remission. Interestingly, prior to CMV retinitis, the patient had been diagnosed with and treated for candida retinitis. This case shows the importance of eye examination and care in patients diagnosed with hematological malignancies.
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http://dx.doi.org/10.1159/000318230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920006PMC
July 2010

Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.

Blood 2008 Feb 17;111(4):1805-10. Epub 2007 Sep 17.

Centre National de Greffe de Moelle Osseuse, Tunis, Tunisia.

From April 2003 to December 2006, 195 patients with de novo symptomatic myeloma and younger than 60 years of age were randomly assigned to receive either tandem transplantation up front (arm A, n = 97) or one autologous stem-cell transplantation followed by a maintenance therapy with thalidomide (day + 90, 100 mg per day during 6 months) (arm B, n = 98). Patients included in arm B received a second transplant at disease progression. In both arms, autologous stem-cell transplantation was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m(2)) and granulocyte colony stimulating factor. Data were analyzed on an intent-to-treat basis. With a median follow-up of 33 months (range, 6-46 months), the 3-year overall survival was 65% in arm A and 85% in arm B (P = .04). The 3-year progression-free survival was 57% in arm A and 85% in arm B (P = .02). Up-front single autologous transplantation followed by 6 months of maintenance therapy with thalidomide (with second transplant in reserve for relapse or progression) is an effective therapeutic strategy to treat multiple myeloma patients and appears superior to tandem transplant in this setting. This study was registered at www.ClinicalTrials.gov as (NCT 00207805).
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http://dx.doi.org/10.1182/blood-2007-07-101212DOI Listing
February 2008

Chemiluminescent detection of clonal immunoglobulin and T cell receptor gene rearrangements in Tunisian lymphoid malignancies, leukemias and lymphomas.

Leuk Lymphoma 2006 Jun;47(6):1129-37

Laboratoire de Biochimie, Faculté de Médecine, Sousse, Tunisia.

Clonal rearrangement of antigen receptor genes is commonly used to characterize the lymphoproliferative diseases. In order to perform molecular characterization in the diagnostics and monitoring of lymphoid malignancies, leukemias and lymphomas in Tunisia, we have introduced the use of chemiluminescent probes for immunoglobulin (IG) and T cell receptor (TR) gene rearrangement detection employing the Southern blot method. The chemiluminescent and radioactive detection methods tested with alkaline phosphatase and 32P labelled probes, respectively, were used for the IG and TR gene rearrangement characterization. Our results show the same pattern of rearrangement. Moreover, the chemiluminescent signal is detected faster and it is as sensitive as the radioactive one. We report the optimized conditions for using IGH, IGK, IGL, TRB and TRG probes in non radioactive detection. We have applied the chemiluminescent Southern blot method to analyze examples of Tunisian leukemias and lymphomas. The results allowed the assessment of clonality and the T or B cell lineage of these cases. The use of non radioactive probes makes chemiluminescent Southern blot detection reliable, safe and sensitive. As the use of radioactivity is not common in our laboratories and the licensing requirements needed for its use prohibitive, the chemiluminescent technique will be of great help for detection and characterization of molecular markers in lymphoid malignancies in Tunisia.
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http://dx.doi.org/10.1080/10428190600563250DOI Listing
June 2006

[Primary non-Hodgkin's lymphoma of the thyroid. A case report and review of the literature].

Tunis Med 2003 Feb;81(2):130-3

Service O.R.L., Hôpital Farhat Hached, Sousse.

The authors report an observation of a non-Hodgkinien primitive lymphoma of the thyroid, developed on Hashimoto's thyroiditis. The 61 years old woman was operated on a total thyroidectomy for a multinodular goiter with dysphagia. The non-Hodgkinien high-grade lymphoma infiltrated the perithyroidal tissues. The extension' assessment was negative and the lymphoma was classified stage IE. The treatment was supplemented by 6 cures of standard chemotherapy CEOP. Based on this observation and on a literature' review, we will discuss the clinical and therapeutic characteristics of this thyroid cancer.
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February 2003

[Primary renal non-Hodgkin lymphoma].

Tunis Med 2002 May;80(5):296-8

Service d'Hématologie Clinique, CHU Farhat Hached de Sousse, Tunisie.

Primary renal non Hodgkin lymphoma is rare and unusual because the renal parenchyma does not have lymphatics. We report a case of bilateral primary lymphoblastic T lymphoma presenting with renal insufficiency in a 14 year old girl. We discuss clinical, pathological particularity and prognosis.
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May 2002