Mohamed A. Yassin

Diabetes and Glucose Metabolism in Thalassemia Major: An Update

ABSTRACT In patients with TM, uncontrolled iron overload has serious clinical consequences with considerable morbidity and mortality. Complications include liver damage, cardiac disease and endocrine dysfunction. Diabetes is an important complication of TM. The mechanisms of abnormal glucose homeostasis are complex and multifactorial. This review updates the current knowledge about glycemic abnormalities in TM patients and directs the attention to an early diagnosis and proper management

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

BackgroundProtein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients.MethodsTPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry.ResultsCo-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells.ConclusionsThe availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.

Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar

Background Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients’ treatments fail. Aim This study investigates the correlation between patient adherence and failure of TKIs’ treatment in a follow-up study. Methods This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European LeukemiaNet 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. Results A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P < 0.0001). The rate of poor adherence was as high as 39% using MEMS, which correlates with 37% treatment failure rate. The survey results show that 97% of patients increased the IM dose by themselves when they felt unwell and 31% of them took the missing IM dose when they remembered. Other factors known to influence adherence show that half of patients developed one or more side effects, 65% of patients experienced lack of funds, 13% of patients declared unavailability of the drug in the NCCCR pharmacy, and 72% of patients believed that IM would cure the disease. The MPR results reveal that 16% of patients had poor access to treatment through the hospital pharmacy. Discussion and Conclusion This is the first prospective study to evaluate CML patients’ adherence and response to IM in Qatar. The high rate of treatment failure observed in Qatar is explained by poor adherence. An economic factor (unaffordable drug prices) is one of the main causes of nonadherence and efforts should be made locally to improve access to medication for cancer diseases. Other risk factors associated with poor adherence could be improved by close monitoring and dose adjustment. Monitoring risk factors for poor adherence and patient education that include direct communication between the health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients’ response to treatment may be directly linked to patients’ adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort.

Congenital methemoglobinemia misdiagnosed as polycythemia vera: Case report and review of literature

Methemoglobinemia is a rare overlooked differential diagnosis in patients presented with cyanosis and dyspnea unrelated to cardiopulmonary causes. Our patient is 29 year old Indian non-smoker male, his story started 6 months prior to presentation to our center when he had generalized fatigue and discoloration of hands. He presented with persistent polycythemia with elevated hemoglobin level. The patient was misdiagnosed in another center as polycythemia and treated with Imatinib. The diagnosis of PV was revisited and ruled out in view of negative JAK2, normal erythropoietin level and absence of features of panmyelosis. Clinical cyanosis and lowoxygen saturation in the presence of normal arterial oxygen tension was highly suggestive of methemoglobinemia. Arterial blood gas revealed a methemoglobin level of 38% (normal: 0-1.5%). Cytochrome B5 reductase (Methemoglobin reductase B) was deficient at level of <2.6 U/g Hb) (normal: 6.6-13.3), consistent with methemoglobin reductase (cytochrome b5) deficiency and hence the diagnosis of congenital methemoglobinemia was established. The role of Imatinib in provoking methemoglobinemia is questionable and association between Imatinib and methemoglobinemia never described before. In our case, there were no other offending drugs in aggravating the patients’ symptoms and cyanosis. The patient started on Vitamin C 500 mg once daily for which he responded well with less cyanosis and significant reduction of methemoglobin level. Congenital methemoglobinemia is a rare underreported hemoglobin disease and often clinically missed. Upon extensive review of English literature for cases of congenital methemoglobinemia due to deficiency of cytochrome b5 reductase, we found 23 cases diagnosed as type I (including the case reported here). 17 cases (~74%) of type I and 6 cases (27%) of type II. There is male predominance 73% versus 26% in females. Almost half of reported cases 12 cases (52%) are Indian, 2 Japanese, 3 English, 2 Arabic, one case Spanish and one case Italian. For type I, the median calculated age is 31 years with cyanosis and shortness of breath being the most common sign and symptoms. For type II: Six cases were reported in English literature, all in pediatric age group with median calculated age at presentation is 6 years with neurologic manifestations and mental retardation are the most common type II associated symptoms. Due to lack of systematic epidemiological studies, congenital methemoglobinemia is under diagnosed as it is under investigated and usually overlooked especially when presenting in adulthood and in absence of obvious acquired agents.

Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment

Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (β-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with β-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD β-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function. (www.actabiomedica.it)

De Novo Precursor B-Lymphoblastic Leukemia/Lymphoma With Double-Hit Gene Rearrangements ( MYC/BCL-2 ) Presented With Spinal Cord Compression and Acquired Factor XIII Deficiency

Double-hit lymphomas (DHLs) are aggressive mature B-cell neoplasms associated with rearrangements involving MYC and B-cell lymphoma-2 (BCL-2). Such DH events are extremely rare in B-cell precursor acute lymphoblastic leukemia (B-ALL), especially in young adults. A 29-year-old male patient initially presented to emergency department with right mandibular mass of 2 months duration associated with intermittent fever. Laboratory workup revealed very high lactate dehydrogenase at 2,026.0 U/L. Peripheral blood revealed pancytopenia with many circulating blasts (about 77%). Bone marrow (BM) aspirate revealed infiltration with many small sized blasts of very high nucleocytoplasmic ratio, finely dispersed nuclear chromatin and prominent nucleoli. The BM biopsy reflected marked hypercellularity with diffuse replacement by sheets of blasts, positive for TdT, PAX-5, CD10, cMYC, BCL-2 and CD20 with Ki-67 > 90%. Flow cytometry on BM revealed a precursor B-immunophenotype (CD45 (dim), CD19, CD10, Tdt and CD20). The blasts are negative for cytoplasmic and surface IgM. Cytogenetics revealed complex karyotype: 46,XY,del(6)(q21q23),t(8;22)(q24.1;q11.2),t(14;18)(q32;q21)(20). A diagnosis of B-lymphoblastic leukemia/lymphoma with t(8;22)(q24.1;q11.2) and t(14;18)(q32;q21) was made. Fluorescent in situ hybridization (FISH) analysis revealed an abnormal hybridization signal pattern for CDKN2A probe, indicating biallelic (homozygous) deletion of the short arm of chromosome 9 (9p) in 94% of the cells analyzed. The patient had severe life-threatening bleeding despite of normal prothrombin time (PT) and activated partial thromboplastin time (APTT) due to acquired factor XIII deficiency, an overlooked rare coagulopathy disorder. In addition, the patient developed acute sudden onset paraplegia, and magnetic resonance imaging (MRI) of spine showed acute cord compression which necessitated emergency radiotherapy after which chemotherapy was started on hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone) protocol. MRI showed dramatic resolution of the mass. Very few cases of B-ALL with DH rearrangement with true precursor B-cell phenotype (positivity for TdT with negativity for surface light chain) have been reported. Many of these had frequent central nervous system (CNS) involvement, with complex karyotypes, highly aggressive course, with short survival of less than 1 year. This case however showed very good response to treatment. In contrary to DHL, de novo B-ALL with double-hit rearrangements is more prevalent in pediatrics and young adults. Although most of reported cases represent transformation of follicular lymphoma, our patient’s young age, acute onset and absent lymphadenopathies all support de novo ALL.

Spinal Abscess Caused by Salmonella Bacteremia in a Patient with Primary Myelofibrosis

Patient: Male, 50 Final Diagnosis: Spinal cord compression associated with spinal abscess Symptoms: Diarrhea • fever • low back pain Medication: — Clinical Procedure: Laminectomy Specialty: Hematology Objective: Rare co-existance of disease or Background: In Primary Myelofibrosis (PMF; a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells) patients, spinal cord compression (SCC) is a common complication or even a presentation symptom due to extramedullary hematopoiesis (EMH). However, a case of SCC caused by a spinal abscess is unusual. To the best of our knowledge, this is the first case report of this rare condition. Case Report: We are reporting the case of a 50-year-old male with primary myelofibrosis and long-standing splenomegaly with back pain as a presenting symptom who was found to have spinal cord compression. An MRI was performed, as EMH was suspected. The blood cultures revealed an infection with Salmonella, so the patient was placed on ceftriaxone, with no response. The patient demonstrated substantial clinical improvement after 2 weeks of neurosurgical intervention and pain management. Conclusions: In PMF patients, back pain with fever or mild neurological symptoms needs to be investigated urgently because of the high risk of irreversible spinal cord damage leading to partial or complete loss of functional independence and shortened survival. The compression could be related to EMH or infections due to an immunodeficiency.