Search

Objectives LPS-responsive beige-like anchor protein (LRBA) deficiency abolishes LRBA protein expression due to biallelic mutations in the LRBA gene that lead to autoimmune manifestations, inflammatory bowel disease, hypogammaglobulinemia in early stages, and variable clinical manifestations.Materials and methods Mutational analysis of the LRBA gene was performed in Indian patients using targeted Next Generation Sequencing (t-NGS) and confirmed by Sanger sequencing using specific primers of exons 53. Then, bioinformatics analysis and protein modeling for the novel founded mutations were also performed. The genotype, phenotype correlation was done according to the molecular findings and clinical features.Results We report an unusual case of a female patient born of a consanguineous marriage, presented with severe anaemia and jaundice with a history of multiple blood transfusions of unknown cause up to the age of 5 yrs. She had hepatosplenomegaly with recurrent viral and bacterial infections. Tests for hemoglobinopathies, enzymopathies, and hereditary spherocytosis were within the normal limits. The t-NGS revealed a novel homozygous missense variation in exon 53 of the LRBA gene (chr4:151231464C > T; c.7799G > A) (p.C2600Y), and the parents were heterozygous. The further immunological analysis is suggestive of hypogammaglobulinaemia and autoimmune haemolytic anaemia. The bioinformatics tools are suggestive of deleterious and disease-causing variants.Conclusion This study concludes the importance of a timely decision of targeted exome sequencing for the molecular diagnostic tool of unexplained haemolytic anaemia with heterogeneous clinical phenotypes.

Introduction: Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). Aim: This study assessed the economic evaluation of emicizumab treatment for non‐inhibitor severe haemophilia A (HA) patients in India. Methods: A Markov model evaluated the cost‐effectiveness of emicizumab prophylaxis compared to on‐demand therapy (ODT), low‐dose prophylaxis (LDP; 1565 IU/kg/year), intermediate‐dose prophylaxis (IDP; 3915 IU/kg/year) and high‐dose prophylaxis (HDP; 7125 IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN‐1 and HAVEN‐3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. Results: In the base‐case analysis, emicizumab was cost‐effective compared to HDP, with an incremental cost‐effectiveness ratio (ICER) per quality‐adjusted life‐years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost‐effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One‐way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost‐effective at willingness‐to‐pay (WTP) thresholds of three and two‐times per capita GDP. Conclusion: Emicizumab prophylaxis is cost‐effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non‐inhibitor PwHA in India. Its long‐term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource‐constrained settings. [ABSTRACT FROM AUTHOR]

Context: Chromosomal abnormalities play an important role in diagnosis and prognosis of hematological diseases. Aims: The aim of the present study was to study the pattern and frequency of chromosomal aberrations in acute myeloid leukemia (AML) subgroups from western India. Settings and Design: A retrospective study was conducted through evaluating laboratory proforma which were filled during 2005 to 2014 for diagnosis and treatment of AML subjects. Methods and Material: We have studied chromosomal aberrations in 282 subjects with AML from western India. AML patients were sub‑grouped according to FAB classification. Cytogenetic study using conventional cytogenetics (GTG‑banding) and Fluorescence in situ hybridization (FISH) was carried out using FISH probes (AML1/ETO, PML/RARA, CBFB). Statistical analysis: Student’s t test for continuous variables and Pearson’s Chi‑squared test for categorical variables were used to identify the relationship between variables. Results: Cytomorphological study revealed AML‑ M3 as most frequent (32.3%) group followed by AML‑M2 (25.2%) and AML‑M4 (19.9%). Chromosomal abnormalities were identified in 145 (51.42%) of the total AML cases. A high frequency (38.6%) of chromosomal abnormalities was identified in AML‑M3 subgroup as compared to AML‑M2 (31%) and AML‑M4 (20.6%). Conclusions: Cytogenetic study is important for the diagnosis and management of the AML patients. Our study identified chromosomal abnormalities in AML subgroups with varied frequencies. It is important in diagnosis and monitoring of the disease. As younger AML patients were more affected in our study, etiological factors such as environmental factors need to be studied. Combination of conventional cytogenetics and FISH has an advantage of identifying high frequency of chromosomal aberrations in AML patients. [ABSTRACT FROM AUTHOR]

Dyskeratosis congenita (DC) is an inherited, progressive bone marrow failure (BMF) and cancer predisposition syndrome with a prevalence of one in 1,000,000 people. In this report, we present a case of a young male patient harboring a novel mutation in the I DKC1 i gene and manifesting the classical clinical triad of DC and BMF. Dyskeratosis congenita is an inherited multisystem bone marrow failure syndrome associated with very high risk of developing aplastic anemia, MDS, leukemia, and solid tumors. In summary, the novel variant identified herein, the DKC1 gene, provides scientific evidence for the genotype-phenotype correlation of DC and has important implications for the clinical and molecular characterization of the disease. [Extracted from the article]

The article discusses the cell signaling in putative leukemic stem cells and blast population in acute myeloid leukemia (AML). Observations include constitutive activation of signaling molecules, cytokine-mediated signal transduction, and activation through growth factor irrespective of receptor expression. The study concludes the crucial role of abnormal signal transduction pathways in AML.

Acute myeloid leukemia is often called as stem cell disease that presents with treatment failure and poor disease outcome. Leukemic stem cells in acute myeloid leukemia ( AML) are enriched in Lineage-/ CD38−/ CD34+ compartment of CD34−positive AML. Many markers important for stem cell biology have been reported for their association with leukemic stem cell population, but what remains clinically most important is a rapid identification of prognostic information. In this study, we evaluated four signal transduction pathways and thirteen markers on Lin−/ CD38−/ CD34+ population in AML. Expressions were compared in different AML subtypes, survival, and treatment outcome groups. We observed that markers important in homing, cell quiescence, and signal propagation such as CD44, CD96, CD90, WT-1, CD123 and CD25 were most significantly differentially expressed on Lin-/ CD38−/ CD34+ population in AML from their normal counterparts ( P < 0.05, Mann-Whitney). Constitutive activation of phospho ERK, AKT, and STAT5 in these cells was associated with poor outcome. Also, an increased frequency of putative leukemic stem cell population shows negative impact on treatment outcome and overall survival, suggesting that initial evaluation of AML samples for pLSC frequency and constitutively activated signaling pathway can provide prognostic and therapeutic information at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the biodistribution and dosimetry of lutetium-177-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (177Lu-DOTA)-rituximab in CD20+ non-Hodgkin's lymphoma and other hematological malignancies treated with rituximab., Methods: The standard dosimetry protocol was used, with cold rituximab infusion, then a diagnostic activity of 177Lu-DOTA-rituximab. Planar images were acquired at multiple time points. Normal organs and tumor dosimetry were performed by using organ and tumor-specific regions of interest and whole-body counts were obtained serially after pixel matched, background, scatter, and attenuation correction. The mean radiation absorbed doses were obtained from OLINDA/EXM v2.1.1 and ORIGIN software., Results: A total of 22 patients were included in this study. Prolonged blood pool clearance of 177Lu-DOTA-rituximab with long residence time in the blood pool and normal organs were observed. The whole body effective half-life was 104.5 ± 22 h. The mean total body radiation absorbed dose was 0.208 ± 0.03 mGy/MBq and the mean total body effective dose was 0.196 ± 0.05 mGy/MBq of 177Lu-DOTA-rituximab. The mean radiation absorbed doses of 0.613 ± 0.21, 1.68 ± 2, 1.01 ± 0.42, and 0.136 ± 0.02mGy/MBq were seen for the liver, spleen, kidneys, and bone marrow, respectively. Tumor lesion uptake was noticed in two patients with tumor radiation absorbed doses were 0.842 mGy/MBq in one and 9.9 mGy/MBq in the other patient. A strong correlation was obtained between the cumulative activities of radiation-absorbed doses derived from ORIGIN and OLINDA software methods at a significant P value less than 0.001., Conclusion: The results of our study demonstrated favorable biodistribution and dosimetry of indigenously produced 177Lu-DOTA-rituximab in patients with CD20+ lymphoma. These results can be used for future studies of radioimmunotherapy employing 177Lu-DOTA-rituximab., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenia, marrow dysplasia and has a propensity to develop into acute myeloid leukemia (AML). The disease progression is majorly affected by genetic defects. However, about 40% - 50% of patients with MDS present with a normal karyotype and develop different courses of disease. Hence there remains a room to advance the biological understanding and to find molecular prognostic markers for cytogenetically normal (CN) MDS., Methods: We performed a high-resolution CGH + SNP array along with NGS of 77 primary diagnosed MDS patients and also they were clinically followed up., Results: Our study revealed 82 clinically significant genomic lesions (losses/gains) in 49% of MDS patients. CGH + SNP array reduced the proportion of normal karyotype by 30%. SNP array in combination with NGS confirmed the biallelic loss of function of the TP53 gene (2/6), which is a clinically relevant biomarker and new genetic-based MDS entity i.e. MDS-biTP53 as per the new WHO classification 2022. Genomic region 2p22.3 presented with frequent lesions and also with a more hazard ratio (2.7, 95% CI 0.37 - 21) when analyzed by Kaplan Meier survival analysis., Conclusion: CGH + SNP array changed the cytogenetic and IPSS-R risk group in 18% and 13% of patients respectively with an improved prediction of prognosis. This study emphasizes the cytogenetic heterogeneity of MDS and highlights that abnormality with chromosome 2 may have a diagnostic and prognostic impact., (S. Karger AG, Basel.)