Neelam Varma

Visceral leishmaniasis associated hemophagocytic lymphohistiocytosis – Case report and systematic review

BACKGROUND The clinical features of leishmaniasis overlap with that of hemophagocytic lymphohistiocytosis (HLH) and the diagnosis of visceral leishmaniasis (VL) related HLH can be challenging. OBJECTIVES To review information available on disease course, treatment, adjunctive therapy used and the outcomes of VL related HLH. METHODS We describe an illustrative case and review all reported cases of VL associated HLH in the English literature till March 2007. RESULTS VL associated HLH is rare, with 56 cases reported in the English literature. Clinical features lack discriminating value to recognize VL as the inciting etiology. Bone marrow aspiration (BMA) establishes the diagnosis in 78% of cases but is often negative at onset of the syndrome due to the pauci-microbial nature of the disease and patchy involvement. Repeated marrow aspiration, liver biopsy, blood cultures and serology may be required to establish the diagnosis. Liposomal amphotericin is the drug of choice. IVIG may be considered when there is an inadequate response to anti-leishmanial therapy in severe and refractory disease. CONCLUSIONS VL related HLH is often under-recognized because of overlapping clinical features and negative marrow evaluation at onset, leading to high mortality rates.

Potential tumor suppressive function of miR-196b in B-cell lineage acute lymphoblastic leukemia.

Keeping in view the fact that genes coding microRNAs (miRNAs) have been found to be localized in chromosomal regions susceptible to genetic translocations, this study was addressed to identify and characterize the miRNAs that are present near/within the regions involved in genetic translocations characteristic of B-cell acute lymphoblastic leukemia (B-cell ALL). Out of six such identified miRNAs miR-196b was not only found to be significantly down-regulated in both EB-3 cell line as well as B-cell ALL patients as compared to that found in the corresponding controls, but also had the inherent capacity to down-regulate the highly expressed c-myc gene, a consequence of genetic translocation characteristic of EB-3 cells at both transcriptional and translational level. This phenomenon was in conformity with the observed reciprocal relationship between the expressed genes coding for miR-196b and c-myc in B-cells derived from ALL patients as well as c-myc gene was found to be a putative target of miR-196b as predicted by bioinformatic algorithms. Also down-regulation of c-myc gene was accompanied by decreased expressions of c-myc effector genes coding for hTERT, Bcl-2, and AATF. Based upon these results, we propose for the first time that miR-196b has the inherent capacity to down-regulate the overamplified c-myc gene recognized as a common pathognomonic feature leading to cancer in general and B-cell ALL in particular. Hence miR-196b can be assigned with the tumor suppressor function and can be of therapeutic importance in paving the way toward the treatment of B-cell ALL.

Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF‐1 axis

The frontline treatment for chronic myeloid leukemia (CML) is tyrosine kinase inhibitor therapy. There is increasing evidence that imatinib results in growth failure in children; etiology is unclear.

Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias

Abstract Regulatory T-cells (Tregs) have been shown to be important for the balance of autoimmunity and oncogenesis. Tregs have a protective role in autoimmune diseases and conversely promote oncogenesis. Chronic lymphocytic leukemia (CLL) is unique in being at the cross-roads of oncogenesis and autoimmunity. We studied Tregs, defined as CD4+CD25highCD127lowFOXP3+, in 32 treatment-naive patients with CLL. Our study shows that patients with CLL had a higher absolute Treg count than the control group (p < 0.001). A progressive increase of Tregs was noted in advanced stages of the disease (p < 0.001). The increase in absolute Treg count is more significant than the increase in percentage Tregs. The absolute Treg count appears to be more important in disease pathogenesis. The absolute Treg count was significantly higher in those patients having autoimmune cytopenias. There was an inverse correlation between lymphocyte doubling time and absolute Treg count (p = 0.03). The absolute Treg count may be used as a prognostic marker in CLL.

Outcome of chronic idiopathic thrombocytopenic purpura in children

There is paucity of data on long‐term probability of remission in chronic idiopathic thrombocytopenic purpura (ITP). Aim was to study the course and factors influencing remission of chronic ITP. Chronic ITP was defined as thrombocytopenia persisting >6 months following initial diagnosis.

Functional genomics of tumor suppressor miR-196b in T-cell acute lymphoblastic leukemia

Huge data accumulated in last few years have shown that differential expression of candidate miRNAs in normal versus transformed cell provides important insights into the pathogenesis of cancer including leukemias. In our previous report, we have revealed that miR-196b was significantly down-regulated in both EB-3 cells as well as B-cell ALL (acute lymphoblastic leukemia) patients as compared to their respective controls. We have unambiguously proven that miR-196b restoration in EB-3 cells leads to significant down-regulation of c-myc and its effector genes, i.e., human telomerase reverse transcriptase (hTERT), B-cell lymphoma/leukemia-2 (Bcl-2), apoptosis antagonizing transcription factor (AATF), and qualifies for tumor suppressor function in B-cell ALL. Keeping in view these results, the present study was aimed at dissecting the role of miR-196b and other miRNAs present near/within the genomic regions involved in genetic translocations characteristic of ALL in T-cell ALL cell lines and patient samples. We have demonstrated significant down-regulation in the expression of miR-196b in MOLT-4 and T-cell ALL patients with respect to the respective control cells. Transfection experiments revealed that none of the six identified miRNAs were able to knock down the expression of c-myc gene. Interestingly, it was found that miR-196b loses its ability to down-regulate c-myc gene expression in T-cell ALL as a consequence of mutations in target 3′-untranslated region (3′-UTR) of the c-myc gene. Results of the present study revealed that miR-196b becomes non-functional in T-cell ALL as a consequence of mutations in 3′-UTR of c-myc gene in T-cell ALL cellular models.

Can fluorodeoxyglucose positron emission tomography/computed tomography avoid negative iliac crest biopsies in evaluation of marrow involvement by lymphoma at time of initial staging?

Abstract The assessment of bone marrow involvement (BMI) is important for accurate prognostication and deciding the appropriate therapy in patients with lymphoma. Conventional bilateral iliac crest biopsies (ILBMBs) have many limitations. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a useful investigative tool for detecting BMI. F-18 FDG PET/CT data for 97 patients with either non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) were analyzed. ILBMB was performed 7–10 days later. A final diagnosis of BMI was made in 38/97 patients on the basis of composite criteria derived from both FDG PET/CT and ILBMB results. ILBMB detected BMI in 29/38 patients, 2/5 patients with HL, 27/33 patients with NHL, 19/25 patients with aggressive NHL, and 8/8 patients with indolent NHL with a sensitivity of 76%, 40%, 82%, 76%, and 100%, respectively. FDG PET/CT was true positive for BMI in 5/5 patients with HL and 29/33 patients with NHL, comprising 25/25 patients with aggressive NHL and 4/8 patients with indolent NHL, with a sensitivity of 100%, 88%, 100%, and 50%, respectively. FDG PET/CT performed better than ILBMB in cases of HL and aggressive NHL, but its sensitivity was poor in cases of indolent lymphoma. In addition, FDG PET/CT had a very high negative predictive value approaching 100% in HL and aggressive NHL, which might help in avoiding negative ILBMBs.

Methylenetetrahydrofolate reductase gene polymorphisms: association with risk for pediatric acute lymphoblastic leukemia in north Indians.

Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with the development of acute leukemias and various malignancies. We conducted a case–control study in 95 north Indian children with acute lymphoblastic leukemia (ALL) and 255 controls, to investigate the role of MTHFR C677T and A1298C polymorphisms as risk factors in the development of ALL. PCR-RFLP on genomic DNA was carried out to determine C677T and A1298C genotypes. The frequency of MTHFR C677T for the T allele was found to be 23.2% among patients and 18.2% among controls. The frequency of the C allele in MTHFR A1298C was 44.2% among cases and 48.2% in controls. Patients showed a higher frequency of heterozygosity for the MTHFR C677T polymorphism as compared to controls (40% vs 27.8%; OR = 1.73, 95% CI 1.02–2.91, p = 0.02), and the A1298C polymorphism did not show any difference in genotype frequency between cases and controls. MTHFR 677CC/1298AC genotype frequencies showed a statistically significant difference between cases and controls (OR = 0.58, 95% CI 0.34–1.01, p = 0.04). In conclusion, our study in north Indian controls and patients with pediatric ALL showed increased frequency for MTHFR C677T in the heterozygous state and no significant difference in the frequency of A1298C genotype between the two groups.

Pediatric patients with bicytopenia/pancytopenia: Review of etiologies and clinico-hematological profile at a tertiary center

BACKGROUND The etiology of bicytopenia/pancytopenia varies widely in children, ranging from transient marrow viral suppression to marrow infiltration by fatal malignancy. Depending on the etiology, the clinical presentation can be with fever, pallor or infection. Knowing the exact etiology is important for specific treatment and prognostication. AIMS To evaluate the etiological and clinico-hematological profile in children with bicytopenia and pancytopenia. MATERIALS AND METHODS A review of bicytopenic and pancytopenic children referred for bone marrow examination from January 2007 to December 2008 was done. Detailed history, clinical examination and hematological parameters at presentation were recorded. RESULTS AND CONCLUSION During the study period, a total of 990 children were referred for bone marrow examination for different indications. Of these, 571 (57.7%) had either pancytopenia (17.7%) or bicytopenia (40%). Commonest form of bicytopenia was anemia and thrombocytopenia seen in 77.5% cases, followed by anemia and leukopenia in 17.3% and leukopenia and thrombocytopenia in 5.5% cases. Most common etiology was acute leukemia (66.9%) in bicytopenic children and aplastic anemia (33.8%) in pancytopenic children. Children with bicytopenia had a higher incidence of underlying malignancy (69.5% vs. 26.6%), splenomegaly (60.5% vs. 37.4%), lymphadenopathy (41.8% vs. 15.1%) and circulating blasts (64.6% vs. 20.1%) and a lower incidence of bleeding manifestations (12.1% vs. 26.6%) as compared to children with pancytopenia.

Co-expression of two FAB-specific chromosome changes, t(15;17) and t(8;21), in a case of acute promyelocytic leukemia

Abstract We describe a case of acute promyelocytic leukemia ANLL-M3 with association of t(15; 17) and t(8; 21) and various chromosomal aberrations. Clinically, immunologically, and morphologically, our patient fits the diagnosis of typical ANLL-M3. The co-existence of two specific FAB chromosomal translocations in a single leukemic clone is rare. The rarity of this association enhances the significance of this report.