Prantar Chakrabarti

Optimizing the Dose of Hydroxyurea Therapy for Patients with β-Thalassemia Intermedia (Hb E-β-thalassemia): A Single Center Study from Eastern India

Abstract Over the past 20 years, hydroxyurea (HU) has emerged as an important therapeutic agent to augment Hb F and thus total hemoglobin (Hb) in Hb E [β26(B8)Glu→Lys; HBB: c.79G>A]-β-thalassemia (Hb E-β-thal), albeit used in varying doses with little consensus on its optimal dose. We report the interim analysis findings of a broader study to assess the impact of Comprehensive Thalassemia Care, of which the present report was a part. Sixty-one Hb E-β-thal patients who were transfusion independent or requiring occasional transfusions [β-thal intermedia (β-TI)] were randomized to one of two groups; A (n = 32) and B (n = 29) to receive 10 and 20 mg/kg/day HU, respectively. The primary objective of the study was to assess the differences in responses to different doses of HU. Secondary end points were to see the tolerability and safety of HU in different doses. Good response (GR) was defined as a rise of Hb by >1.0 g/dL; intermediate response (IR) as a rise in Hb by 0.6–1.0 g/dL anytime during the study period. No response (NR): rise in Hb by <0.5 g/dL in 12 weeks or drop in Hb level from the previous value. Over a follow-up period of 24 weeks, we had 18 (56.2%) GRs, nine (28.2%) IRs and five (15.6%) NRs, while the number of GRs, IRs and NRs in group B were five (17.2%) 12 (41.4%) and 12 (41.4%), respectively. Adverse effects were more common in group B, making this dose (20 mg/kg/day) of HU more myelo-suppressive than Hb F inducing.

Development and validation of a noncontact spectroscopic device for hemoglobin estimation at point-of-care

Abstract. Anemia severely and adversely affects human health and socioeconomic development. Measuring hemoglobin with the minimal involvement of human and financial resources has always been challenging. We describe a translational spectroscopic technique for noncontact hemoglobin measurement at low-resource point-of-care settings in human subjects, independent of their skin color, age, and sex, by measuring the optical spectrum of the blood flowing in the vascular bed of the bulbar conjunctiva. We developed software on the LabVIEW platform for automatic data acquisition and interpretation by nonexperts. The device is calibrated by comparing the differential absorbance of light of wavelength 576 and 600 nm with the clinical hemoglobin level of the subject. Our proposed method is consistent with the results obtained using the current gold standard, the automated hematology analyzer. The proposed noncontact optical device for hemoglobin estimation is highly efficient, inexpensive, feasible, and extremely useful in low-resource point-of-care settings. The device output correlates with the different degrees of anemia with absolute and trending accuracy similar to those of widely used invasive methods. Moreover, the device can instantaneously transmit the generated report to a medical expert through e-mail, text messaging, or mobile apps.

Incidence of BCR-ABL transcript variants in patients with chronic myeloid leukemia: Their correlation with presenting features, risk scores and response to treatment with imatinib mesylate

Context: The exact role of the different transcript variants of BCR-ABL in the pathogenesis of chronic myeloid leukemia (CML) and their impact on prognosis is yet to be definitely enumerated. Aims: In this study, we have tried to correlate the presenting features, risk scores and treatment response with the BCR-ABL variants detected in our patients. Settings and Design: A cross-sectional unicentric hospital-based study on 80 patients diagnosed to have CML by bone marrow cytogenetics and confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Materials and Methods: RT-PCR for BCR-ABL was performed on consecutive patients with CML attending the CML clinic from January 2010 to December 2010. The medical charts of these patients were analyzed after a follow-up of 18 months in a retrospective manner. Statistical Analysis: Box plot and histogram was used to see the distribution of variables. t-test was performed to enumerate the difference between risk scores in two populations of patients carrying two different BCR-ABL transcript variants. Results: Nearly 56.25% of patients had b3a2 (e14a2) while 41.25% of patients showed b2a2 (e13a2) transcripts. The rest 2.5% (two patients) expressed the rare e19b2 variant. Patients with b2a2 presented with higher Sokal, Hasford and European Treatment and Outcomes Study score than their b3a2 counterpart. Different parameters such as the platelet count, leukocyte count, hemoglobin and splenomegaly showed a minor difference between the groups. More patients in the b2a2 group achieved complete hematologic response at 3 months, but it was not significant. Conclusions: Patients with b2a2 variant CML tend to present with higher risk score, but do not behave in a vastly different manner than their b3a2 counterparts.

A network map of thrombopoietin signaling

Thrombopoietin (THPO), also known as megakaryocyte growth and development factor (MGDF), is a cytokine involved in the production of platelets. THPO is a glycoprotein produced by liver and kidney. It regulates the production of platelets by stimulating the differentiation and maturation of megakaryocyte progenitors. It acts as a ligand for MPL receptor, a member of the hematopoietic cytokine receptor superfamily and is essential for megakaryocyte maturation. THPO binding induces homodimerization of the receptor which results in activation of JAKSTAT and MAPK signaling cascades that subsequently control cellular proliferation, differentiation and other signaling events. Despite the importance of THPO signaling in various diseases and biological processes, a detailed signaling network of THPO is not available in any publicly available database. Therefore, in this study, we present a resource of signaling events induced by THPO that was manually curated from published literature on THPO. Our manual curation of thrombopoietin pathway resulted in identification of 48 molecular associations, 66 catalytic reactions, 100 gene regulation events, 19 protein translocation events and 43 activation/inhibition reactions that occur upon activation of thrombopoietin receptor by THPO. THPO signaling pathway is made available on NetPath, a freely available human signaling pathway resource developed previously by our group. We believe this resource will provide a platform for scientific community to accelerate further research in this area on potential therapeutic interventions.

Vincristine Induced Reversible Vocal Cord Palsy in a Young Adult

Vincristine is a type of vinca alkaloid, with a well-known efficacy for the treatment of acute lymphoblastic leukaemia (ALL). Though vincristine is known for neurotoxicity, cranial nerve involvement is rare [1, 2]. Vincristine induced vocal cord palsy is a potentially reversible condition. The mainstay of therapy is withdrawal of the offending drug. However, there are no clear guidelines regarding the possibility of re-treatment with the causative agent. No more than 20 cases with vincristine induced vocal cord palsy have been reported. The Stollery Children’s Hospital, Canada on retrospectively reviewing the 293 cases involving vincristine therapy at their institution from 2002 to 2007, identified 4 children with vincristine induced vocal cord palsy, whereas only 10 paediatric patients are in the English-language literature since 1966, which probably means that this condition is under reported [2]. A 17-year-old male with B cell ALL was being treated with BFM-90 (Berlin-Frankfurt-Münster) protocol. Ten days after receiving the fourth dose of vincristine (1.5 mg/ m), he developed hoarseness of voice. There were neither any previous clinical symptoms of neuropathy nor any history for inherited neuropathies. A contrast enhanced computed tomographic (CT) scan of neckand also the magnetic resonance images (MRI) of brain were normal. Flexible fibreoptic endoscopy showed both vocal cords in intermediate position with loss of movement of both vocal cords. There was loss of deep tendon reflexes also. The nerve conduction velocity studies showed generalised sensorimotor axonal peripheral neuropathy. His subsequent doses of vincristine were stopped. Then gradually his hoarseness of voice started resolving after 15 days and resolved completely 30 days after the onset of palsy. Subsequent laryngoscopy and flexible fibre opticendoscope were not done. He completed his consolidation and reinduction phase uneventfully. Since more than 6 month she is in maintenance phase and is doing fine. Vincristine related vocal cord paralysis has been reported infrequently in the literature. Vincristine neurotoxicity is more severe when more than the recommended dose is given, if the patient is hypersensitive to this drug, if there is pre-existing liver dysfunction or a hereditary neuropathy, and if other drugs such as allopurinol, erythromycin, isoniazid, mitomycin C, phenytoin, and itraconazole are concomitantly used [3]. Hoarseness, secondary to upper airway infection, such as laryngotracheobronchitis, should be excludedby clinical and radiographic examination [4]. Visualization of the airway confirms the diagnosis and rules out treatable causes of stridor in the febrile, immunocompromised patient. Involvement of vocal cords may be unilateral or bilateral but it is the left side which is predominantly involved [2]. Paralysis appeared in most cases during induction phase only implying that even small doses of vincristine is toxic to the nerves. The first case series in paediatric patients by Annino et al. [4] reported that by reducing the dose of Vincristine from then used 0.05 mg/kg to 1.5 mg/m reduced the incidence of vocal cord palsy. The neurotoxicity has a varied presentation. Few children have generalized neurotoxicity like hypotonia, decreased & Prakas Kumar Mandal prakas70@gmail.com

Membrane perturbation through novel cell-penetrating peptides influences intracellular accumulation of imatinib mesylate in CML cells

Chronic myeloid leukemia is a stem cell disease with the presence of Philadelphia chromosome generated through reciprocal translocation of chromosome 9 and 22. The use of first- and second-generation tyrosine kinase inhibitors has been successful to an extent. However, resistance against such drugs is an emerging problem. Apart from several drug-resistant mechanisms, drug influx/efflux ratio appears to be one of the key determinants of therapeutic outcomes. In addition, intracellular accumulation of drug critically depends on cell membrane fluidity and lipid raft dynamics. Previously, we reported two novel cell-penetrating peptides (CPPs), namely, cationic IR15 and anionic SR11 present in tryptic digest of Abrus agglutinin. Here, the potential of IR15 and SR11 to influence intracellular concentration of imatinib has been evaluated. Fluorescent correlation spectroscopy and lifetime imaging were employed to map membrane fluidity and lipid raft distribution following peptide-drug co-administration. Results show that IR15 and SR11 are the two CPPs which can modulate membrane fluidity and lipid raft distribution in K562 cells. Both IR15 and SR11 significantly reduce the viability of CML cells in the presence of imatinib by increasing the intracellular accumulation of the drug.

Pancreatitis in acute promyelocytic leukemia: Drug-induced or differentiation syndrome?

Acute promyelocytic leukemia (APL) constitutes about 15% of all acute myeloid leukemia patients and can now be treated even without any chemotherapy, with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Acute pancreatitis (AP) is a rare adverse event in APL, which is primarily reported to be secondary to hypertriglyceridemia. Here, we have reported AP developed in a patient of APL, during induction with ATRA and ATO, but it was not associated with hypertriglyceridemia. Rather, it was associated with respiratory distress and weight gain, coincidental leukocytosis, bilateral pleural effusion, and edematous pancreatitis without any necrosis. Hence, AP in this case is diagnosed to be a manifestation of differentiation syndrome, and it responded to steroid.

VTD in newly diagnosed myeloma: an institutional experience

Background Myeloma management has evolved over the years with logarithmic expansion of available treatment options. The treatment algorithms are also changing because of the better responses obtained with newer agents. Bortezomib, thalidomide and dexamathasone (also known as VTD) is one such therapy that has shown improved long term outcomes. Materials and methods We conducted a single-center, retrospective analysis of all myeloma patients treated with VTD chemotherapy. Results An overall response achieved was 85.7% with 40% CR. Conclusion We conclude VTD is an effective chemotherapy regimen in newly-diagnosed myeloma patients.

Genotoxicity Study with Special Reference to Comet Test in the Blood Cells of Workers Exposed to Sewage Water

Awareness among sewage workers to occupational exposure is growing slowly in many developing countries. Lead (Pb) and cadmium (Cd) are present in sewage water and workers are exposed to these metals as a result of unprotected handling. These heavy metals exposures are responsible for DNA damage and lowering blood total iron (Fe) concentration. Zinc (Zn) is an element for promoting metallothionine expression and binds the free Cd. The total suspended solids (TSS), total dissolved solids (TDS), Pb, and Cd were estimated in sewage water. The whole blood Zn and Fe concentration and Pd and Cd were also estimated. Genotoxicity as indicated by DNA damage was studied by comet assay. It was observed that there were significant differences () of Pb and Cd concentration in blood for the sewage workers when compared with control population. DNA damage was also observed to be significantly () higher in the exposed groups but their blood Fe concentration was significantly lower, which may be the reason for their tendency for retention of blood Cd and make them more susceptible. This study also indicated that aged workers had higher blood Zn concentrations as compared to the younger (working 20 years).