Polyneuropathy and myopathy in beta-thalassemia major patients.

The thalassemias are the most common single gene disorder in the world. Nowadays, the average life expectancy of patients in developed countries has increased significantly, while, there was an increase of complications. We aimed to investigate peripheral neuropathy and myopathy in this patient group using a neurophysiological study. We performed nerve conduction studies and electromyography of upper and lower extremities on 36 beta-thalassemia major (ß-thal) patients. The electrophysiological findings were correlated with demographic data and laboratory parameters of the disease. Patients with ß-thal present polyneuropathy or myopathy at (50%). Polyneuropathy was detected in (38.9%) and myopathy in (27.8%), while polyneuropathy and myopathy were present at (16.7%) with an overlap of the diseases in 1/3 of the patients. There was not a statistically significant correlation of polyneuropathy and myopathy with age, sex, splenectomy, nor with respect to laboratory parameters, hemoglobin, and ferritin. However, there was a statistically significant correlation of polyneuropathy and myopathy with iron overload, as recorded by the magnetic resonance imaging (MRI) of the heart and the liver. Our findings suggest that iron overload plays a key role in the pathogenesis of polyneuropathy and myopathy in ß-thal patients, and performing heart and liver MRI for the prediction of such lesions in an annual basis is warranted.

Hypercalcemia and multiple osteolytic lesions in an adult patient with relapsed pre-B acute lymphoblastic leukemia: a case report.

BACKGROUND: Hypercalcemia and severe osteolytic lesions are rare complications of acute lymphoblastic leukemia (ALL) in childhood, and those cases share similar clinical features. Similarly, hypercalcemia is a rare feature in adult ALL. Here, we report an uncommon case of an adult patient with relapsed precursor B ALL (pre-B ALL) who developed multiple osteolytic lesions and hypercalcemia. CASE DESCRIPTION: A 24-year-old male patient, diagnosed with pre-B ALL, was admitted in our hospital due to severe lumbar pain. After reviewing laboratory, radiological and clinical findings, the patient was diagnosed as having relapse of a mixed phenotype acute leukemia, according to bone marrow aspiration (9% blasts) and cytogenetic analysis, with multiple osteolytic lesions in all lumbar vertebrae, sacrum and ilium and severe hypercalcemia (13.3 mg/dL). Thus, FLAG-IDA rescue therapy and hydration plus furosemide, corticoids and bisphosphonates were administered. Despite initial amelioration, his hematological condition deteriorated and he died due to severe sepsis as a result of severe immunosuppression. CONCLUSION: Two possible mechanisms have been suggested for hypercalcemia in hematological malignancy, either the leukemic infiltration or the paraneoplastic production of a variety of humoral factors and proinflammatory cytokines. However, hypercalcemia and severe osteolytic lesions are rare features in ALL adult patients and their combination may be indicator of poor prognosis. Hippokratia 2015, 19 (1): 78-81.

Neurological complications of beta-thalassemia.

The thalassemias are the most common single gene disorder in the world. Over the last years, several reports have demonstrated neurological complications in beta-thalassemia patients. In most cases, these complications remained subclinical and were detected only during neuropsychological, neurophysiological, or neuroimaging evaluation. Cognitive impairment, abnormal findings on evoked potentials, complications due to extramedullary hematopoiesis, cerebrovascular disease, and peripheral neuropathy comprise the broad spectrum of neurological involvement. Chronic hypoxia, iron overload, desferrioxamine neurotoxicity, and bone marrow expansion are implicated, but sufficient explanatory evidence is lacking and development of biomarkers is needed. This review summarizes current knowledge of the neurological complications. As life expectancy for beta-thalassemia patients increases, we support the use of neurophysiological, neuropsychological, or neuroimaging monitoring, enabling the evaluation of neural pathway impairment, to achieve appropriate management and as a result a better quality of life for this patient group.

Functional hyposplenism.

Functional hyposplenism is a condition accompanying many diseases such as sickle cell disease, celiac disease, alcoholic liver disease, hepatic cirrhosis, lymphomas and autoimmune disorders. It is characterised mostly by defective immune responses against infectious agents, especially encapsulated organisms, since the spleen is thought to play an important role in the production and maturation of B-memory lymphocytes and other substances like opsonins, both of which are considered crucial elements of the immune system for fighting infections. It is also associated with thrombocytosis, which might lead to thromboembolic events. Functional hyposplenism is diagnosed by the presence of Howell-Jolly bodies and pitted erythrocytes in the peripheral blood smear, and by nuclear imaging modalities such as spleen scintigraphy with the use of Technetium-99m and/or spleen scintigraphy with the use of heat-damaged Technetium-99m labeled erythrocytes. Severe infections accompanying functional hyposplenism can lead to the overwhelming post infection syndrome, which can often be fatal. Identifying patients with functional hyposplenism is important because simple measures such as vaccination against common infective microorganisms (e.g. Streptococcus pneumonia, Neisseria meningitides and Haemophilous influenzae) and antibiotic therapy when needed are considered beneficial in diminishing the frequency and gravity of the infections accompanying the syndrome.

Simultaneous manifestation of pleural effusion and acute renal failure associated with dasatinib: a case report.

WHAT IS KNOWN AND OBJECTIVE: Dasatinib is a novel second-generation inhibitor of multiple tyrosine kinases, indicated for the treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. Although dasatinib is a potent, efficacious and generally well-tolerated drug, patients are also subject to various adverse effects. The most common pulmonary-related side effect is pleural effusion (PE). Renal failure has been reported rarely as a side effect of dasatinib treatment. We report the first case of a patient with imatinib-resistant CML who developed PE and acute renal failure (ARF) simultaneously, after being placed on dasatinib therapy. CASE SUMMARY: We report a 58-year-old female dasatinib-treated patient with Ph+ chronic phase CML who was admitted to our hospital due to persisted dyspnoea and fever. After reviewing the laboratory and clinical findings, we determined our patient as having simultaneously ARF and PE related to dasatinib therapy. Dasatinib was discontinued, and after 10 days of treatment with ampicillin-sulbactam, allopurinol, amlodipine, furosemide and methylprednisolone, she was discharged home effusion free and with ameliorated renal function. WHAT IS NEW AND CONCLUSION: PE is the most common extra-haematological toxicity observed during dasatinib treatment whose pathogenesis is still unclear. A possible role of cytokines, such as platelet-derived growth factor receptor (PDGFR)-ß and vascular endothelial growth factor (VEGF), in causing endothelial permeability has been suggested. The aetiology of renal failure is also unclear in these patients, but two different possible mechanisms have been suggested such as tumour lysis syndrome and toxic tubular damage. In conclusion, here we describe the first case of simultaneous manifestation of PE and ARF associated with dasatinib. Thus, in patients treated with tyrosine kinase inhibitors, especially those with predisposing nephrological or haematological factors, serum creatinine levels should be monitored routinely.

Cyclosporine therapy during pregnancy in a patient with ß-thalassemia major and autoimmune haemolytic anemia: a case report and review of the literature.

Recent advances in the management of hemoglobinopathies offer an improved potential for safe pregnancy with favourable outcome in patients with ß-thalassemia major. Autoimmune diseases that are common in women at reproductive age might be fulminant and hardly manageable in pregnant women with thalassemia. Thus immunosuppressant drugs like cyclosporine A could be necessary in order to maintain good maternal and foetal health. We present a case report of a 35-year-old woman with ß-thalassemia major, splenectomy, autoimmune hemolytic anemia and insulin treated diabetes mellitus who was treated with cyclosporine A during her pregnancy, and delivered a healthy male infant. First line therapy with steroids was ineffective, due to deregulation of diabetes mellitus.

Absence of JAK2V617F mutation in patients with beta-thalassemia major and thrombocytosis due to splenectomy.

The report of Janus Kinase 2 (JAK2) mutations in myeloid malignancies with high frequency in myeloproliferative neoplasms has been well known since 2005. By monitoring allele burden, it is found that the expression of JAK2V617F mutation is increasing significantly from essential thrombocytosis to polycythemia vera. Furthermore, JAK2 abnormalities are reported in the majority of unexplained thrombotic episodes. Thalassemic syndromes are characterized by ineffective erythropoiesis and thrombocytosis, mainly due to splenectomy. The high incidence of thromboembolic events has led to the identification of a prothrombotic state in these patients. The contribution of JAK2 mutations to the hypercoagulable state of thalassemic patients is still unknown. Furthermore, the potential role of Janus Kinase mutations in hepcidin expression and consequently in ineffective erythropoiesis is still under investigation. This study was scheduled to determine whether the presence of JAK2V617F mutation in thalassemic patients is associated with thrombocytosis. We studied 20 patients DNA with beta-thalassemia for JAK2V617F mutation by using RG-PCR method. None of the patients were positive for this particular mutation. More studies are needed to prove the role of JAK2 in ineffective erythropoiesis, iron metabolism and thrombocytosis and to determine if using JAK2 inhibitors in thalassemic patients can be a potential therapeutic option.

Multiple myeloma and bone disease: pathogenesis and current therapeutic approaches.

Multiple myeloma is a haematologic malignancy caused by clonal expansion of malignant plasma cells and associated with bone disease and hypercalcaemia. Myeloma cells are in close proximity to sites of active bone resorption and the interactions between those cells, osteoblasts and osteoclasts, are crucial not only for the bone distraction but for the proliferation of bone marrow cells as well. Recent studies have revealed that numerous regulating factors of osteoblast and osteoclast activity interfere with the pathogenesis of multiple myeloma's bone disease and that the understanding of the pathophysiological pathways involved is the first step towards discovering novel potential therapeutic approaches.

Persistent effect of zoledronic acid in Paget's disease.

Paget's bone disease is a disorder in which bone regions with high turnover are replaced by new, vascular, but disorganized and immature bone with excessive fibrosis, high tendency of deformity and diminished mechanical resistance. Treatment aims at the suppression of osteoclast activity and is achieved with bisphosphonates, which represent the treatment of choice for Paget's disease. Zoledronic acid, a relatively new member of this class, normalizes alkaline phosphatase in the majority of patients and has a favorable safety profile. We report the case of an asymptomatic patient who was diagnosed with Paget's disease based on typical biochemical, radiological and histological findings and was treated with a single intravenous infusion of 4 mg of zoledronic acid. No side effects were observed. Alkaline phosphatase levels normalized within four months. At the last follow up examination, three years after treatment, the patient remains asymptomatic, without significant changes in radiology imaging, and alkaline phosphatase levels are still within the normal range. In conclusion, zoledronic acid, apart from being safe and effective in Paget's disease, also appears to be able to achieve significantly prolonged remissions.

Management of acute bleeding in a patient with congenital afibrinogenaemia.

Congenital afibrinogenaemia is a rare bleeding disorder characterized by absence of fibrinogen and varying bleeding tendency. Treatment with fibrinogen concentrates is considered to be the best choice for afibrinogenaemic patients who experience bleeding. We report the case of a 22-year-old Greek patient who presented with large muscular haematomas and was treated with fibrinogen concentrates. The efficacy of this treatment and the problems that arose during his hospitalization are being discussed.

A patient with Klinefelter's syndrome and thalassemia intermedia.

Klinefelter's syndrome (KS) is associated with a wide spectrum of clinical features, such as tall stature, eunuchoid proportions, testes disproportionately small for the level of pubertal development, gynecomastia and behavioral problems. The association of KS with thalassemia intermedia has not been previously reported. A male patient with thalassemia intermedia was diagnosed with KS at the age of 14 years when endocrine evaluation for delayed puberty showed hypergonadotrophic hypogonadism. Thyroid function was normal; however, basal and GnRH-stimulated gonadotropin concentrations were raised while serum testosterone was low. Karyotype analysis revealed KS (47,XXY). Testosterone replacement therapy started soon after diagnosis and now at the age of 20 years the patient's height is 178.3 cm, the U/L ratio is 0.91. Testicular volume is 12 ml (Prader orchidometer) and his pubic hair is stage 4. To our knowledge this is the first case of a patient suffering from KS and thalassemia intermedia reported in the literature.

Long term audiological evaluation of beta-thalassemic patients.

OBJECTIVE: The objective of this study was to identify the incidence and to monitor the progression of hearing loss in children and young adults with beta-thalassemia major. METHODS: One hundred and four (104) patients aged 6-35 years (mean 17,2 years) participated in the study. All patients were on a regular transfusion-chelation program maintaining a mean hemoglobin level of 9.5 gr/dl. Subjects were receiving desferrioxamine (DFO) chelation treatment with a mean daily dose of 50-60 mg/kg, 5-6 days a week during the first six years of the study, which was then reduced to 40-50 mg/kg for the following eight years. Patients were followed for 8-14 years. RESULTS: Overall, 21 out of 104 patients (20.2%) presented with high frequency sensorineural hearing loss (SNHL), either unilateral or bilateral. No ototoxic factor, other than DFO, was present in any of the patients. Patients with SNHL presented with relatively lower serum ferritin levels than those with normal hearing, however, no statistically significant difference was observed. Subjects with SNHL were submitted to DFO reduction or temporary withdrawal. Following intervention, 7 out of 21 affected patients recovered, 10 remained stable and 4 demonstrated aggravation. CONCLUSION: The findings are indicative of DFO's contributing role in the development of hearing impairment. Regular audiologic evaluation is imperative in all thalassemic patients so that early changes may be recognized and treatment may be judiciously adjusted in order to prevent or reverse hearing impairment.

Urine biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia.

Renal dysfunction in thalassemia patients can be attributed to chronic anemia, and iron overload as well as to desferioxamine (DFO) toxicity. We analyzed the urine of 91 well-maintained homozygous beta-thalassemia patients, with no evidence of renal disease, for early evidence of kidney dysfunction by means of electrophoresis and quantitative biochemical tests. Measurement of liver magnetic resonance imaging (MRI) T2 values and serum ferritin concentration was used to estimate iron overload. In 55 of the 91 patients, urine analysis indicated signs of tubular dysfunction. The urine concentration of albumin and beta 2-microglobulin, as well as the activity of N-acetyl-beta-D-glucosaminidase (NAG), correlated positively with serum ferritin concentration and liver iron deposition, as detected by MRI T2 values. This suggested that the cause of renal dysfunction in homozygous beta-thalassemia is iron overload. On the other hand, the same urine markers did not correlate with age, indicating that chronic anemia or desferrioxamine (DFO) treatment are not related to renal dysfunction in thalassemia.