Endemic pediatric fungal infections in India: clues to diagnosis.

This review is intended to familiarize readers with an emerging group of fungal infections that mostly manifest in immunocompetent individuals. This group was initially considered endemic to the tropics, but increasing worldwide prevalence has been reported. The organisms have been divided into dominant non-invasive forms and dominant invasive forms for ease of understanding. The non-invasive organisms include the group Entomophthoromycota, under which two genera Basidiobolus and Conidiobolus, have been identified as human pathogens. They present with plaques in the extremities and rhinofacial region, respectively. The invasive organisms are dematiaceous fungi (phaeohypomycosis), which includes Cladophialophora and Exophiala among others. They cause invasion of deep tissues, with the central nervous system being the most common target. The mycology, epidemiology, diagnosis, and treatment options have been summarized in brief. The clinical presentation, imaging manifestations, differentiation from other common infections and malignancies that show similar features have been detailed.

Wnt/ß-Catenin Signaling Pathway in Pediatric Tumors: Implications for Diagnosis and Treatment.

The evolutionarily conserved Wnt signaling has a significant and diverse role in maintaining cell homeostasis and tissue maintenance. It is necessary in the regulation of crucial biological functions such as embryonal development, proliferation, differentiation, cell fate, and stem cell pluripotency. The deregulation of Wnt/ß-catenin signaling often leads to various diseases, including cancer and non-cancer diseases. The role of Wnt/ß-catenin signaling in adult tumors has been extensively studied in literature. Although the Wnt signaling pathway has been well explored and recognized to play a role in the initiation and progression of cancer, there is still a lack of understanding on how it affects pediatric tumors. This review discusses the recent developments of this signaling pathway in pediatric tumors. We also focus on understanding how different types of variations in Wnt signaling pathway contribute to cancer development and provide an insight of tissue specific mutations that lead to clinical progression of these tumors.

Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Including Matched Sibling and Alternate Donor Transplants - Adaptations and Outcomes From a Tertiary Care Government Institute in India.

OBJECTIVE: To report the outcomes of pediatric patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) in single rooms without high-efficiency particulate air (HEPA) filters, laminar air flow or positive pressure at our centre and discuss the adaptations of a high-volume government centre. METHODS: Data of the first 20 children who underwent allogeneic HSCT between May 2019 and July 2023 in adaptive settings were reviewed retrospectively. All patients were managed in in single rooms without HEPA filters, positive pressure or laminar air flow. Supportive care in the form of antimicrobial prophylaxis, veno-occlusive disease prophylaxis, anti-epileptics (with busulfan) and irradiated blood products were provided. Trained manpower including multi-specialty consultations were readily available. All complications including infections were managed as per standard guidelines. RESULTS: The median (range) of children included was 6 (1-20) years. For eight patients we used alternate donors. The mean (SD) time to neutrophil and platelet engraftment were 17.0 (8.07) days and 18.8 (10.1) days, respectively. The mean (SD) time to discharge from the hospital was 30.9 (10.04) days. There were no deaths within 30 days. Six children each developed acute and chronic graft-versus-host disease (GVHD). The overall survival at a median follow-up of 292 days was 70% (n = 14). CONCLUSION: With certain adaptations in the existing infrastructure in resource-limited settings, allogeneic HSCT can be performed with good outcomes, provided experienced, dedicated and adequate personnel, comprehensive supportive care, multidisciplinary consultative support and isolation are provided.

Hematopoietic Stem Cell Transplantation for Storage Disorders: Present Status.

Storage disorders are a group of inborn errors of metabolism caused by the defective activity of lysosomal enzymes or transporters. All of these disorders have multisystem involvement with variable degrees of neurological features. Neurological manifestations are one of the most difficult aspects of treatment concerning these diseases. The available treatment modalities for some of these disorders include enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation (HSCT) and the upcoming gene therapies. As a one-time intervention, the economic feasibility of HSCT makes it an attractive option for treating these disorders, especially in lower and middle-income countries. Further, improvements in peri-transplantation medical care, better conditioning regimens and better supportive care have improved the outcomes of patients undergoing HSCT. In this review, we discuss the current evidence for HSCT in various storage disorders and its suitability as a mode of therapy for the developing world.

Autologous hematopoietic stem cell transplant at a tertiary care centre in India: achieving comparable outcomes with adaptations.

Autologous stem cell transplantation (ASCT) is the standard treatment for many high-risk solid tumors. Patients undergoing ASCT should be managed in a dedicated hematopoietic stem cell transplantation (HSCT) unit with isolation rooms, high-efficiency particulate air (HEPA) filters, and positive pressure. We report the outcomes of the first 20 pediatric patients who underwent ASCT in isolation rooms with no HEPA filters or positive pressure. Moreover, the isolation rooms were not part of a dedicated HSCT unit. Data from 20 patients were analyzed. All patients included in the study underwent ASCT after harvest and cryopreservation of the hematopoietic stem cells (HSC). Furthermore, all patients also underwent myeloablative conditioning. The most common indications for ASCT included high-risk neuroblastoma (HR-NB) (n=9) and refractory/relapsed Hodgkin's lymphoma (HL) (n=6). The median CD-34 positive HSC administered was 4.5 (0.8-21.9) million per kg. The median time to neutrophil and platelet engraftment was 16.5 (10-35) and 19 (10-87) days, respectively. Additionally, only one transplant-related mortality was observed and the mean time to discharge from the hospital was 27.6+8.3 days. The overall survival for all our patients was 75% at a median follow-up of 33.2 months (15 out of 20 patients survived), and the disease-free survival was 60% (median follow-up, 28.4 months). The overall survival for the patients with HL was 85.7% at a median of 45.3 months and for the HR-NB was 66.7% at a median of 34.9 months. This study provides evidence that ASCT can be safely performed in isolation rooms without HEPA filters and positive pressure if expertise and supportive care are available. In settings with limited resources, such a model could help establish low-cost HSCT units.

Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10-colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity.

INTRODUCTION: Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing. MATERIALS AND METHODS: Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single-cell sequencing of the whole transcriptome was also done in a bone marrow sample. RESULTS: LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34- LSCs (n = 41), no difference was observed between the groups. More than one sub-population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods. CONCLUSION: A single tube-10-colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter- and intra-sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression.

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights.

T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 patients with T-ALL to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) protein-coding genes-BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) epigenetic modifiers-DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long noncoding RNAs (lncRNAs)-XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 patients with T-ALL. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression was correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1 demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several hitherto unreported associations of gene expression patterns with clinicopathologic features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide prognostic markers.

Unusual case of 'scorbutic proptosis'.

Proptosis is a frequent presenting symptom/sign of many paediatric malignancies. Acute-onset proptosis is an ophthalmic emergency that can endanger vision if not treated promptly. Appropriate treatment must be instituted only after investigating for the underlying aetiology. Here, we report a developmentally delayed boy in middle childhood who presented with recent onset bilateral proptosis. Clinical examination followed by radiological evaluation suggested scurvy to be the underlying cause and vitamin C supplementation led to prompt reversal of proptosis. The relevant literature has been reviewed and presented here to apprise the paediatric oncologists about this rare but easily treatable cause of proptosis.

The 5th Edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors: What's New in Pediatrics?

The World Health Organization (WHO) has revised the classification of hematolymphoid tumors (WHO-HAEM5) in August 2022 to incorporate certain recent changes in understanding of disease biology. This article highlights the important changes, with particular reference to those most relevant to children.

Serum Adipokines as Biomarkers for Surveillance of Metabolic Syndrome in Childhood Acute Lymphoblastic Leukemia Survivors in Low Middle-Income Countries.

BACKGROUND: Serum adipokines (leptin and adiponectin) are dysregulated before the onset of metabolic syndrome and hence may be useful biomarkers for screening of cardiometabolic late effects in childhood Acute Lymphoblastic Leukemia (cALL) survivors. METHODS: We compared serum adipokine levels between 40 cALL survivors (aged 10-18 years, >2 years from treatment completion) with similar controls. A multivariable logistic regression analysis was then done to assess the association of metabolic syndrome in cALL survivors with variables including adipokines and other metabolic parameters, demographic and treatment details, and Dual-energy X-ray absorptiometry scan-derived variables. RESULTS: Compared to controls, cALL survivors had a higher prevalence of metabolic syndrome (8/40 vs. 2/40, P = .044) and central obesity (11/40 vs. 4/40, P = 0.042). Median Serum Leptin (7.39 vs. 4.23 ng/ml, P = 0.207) levels and derived Leptin-Adiponectin Ratio (1.44 vs. 0.80, P = 0.598), were higher but not statistically different in our survivors compared to controls; Adiponectin levels were similar (6.07 vs. 5.01 µg/ml, P = 0.283). In the cALL survivors, overweight/obesity (odds ratio [OR] 21.9, P = 0.020) or higher Leptin levels (OR 1.11, P = 0.047), were independently associated with metabolic syndrome. CONCLUSIONS: Serum Leptin, independently predictive of metabolic syndrome in our cALL survivors, may be tested in larger studies to assess its utility in surveillance and initiation of early preventive measures.

Efficacy and safety of plerixafor in pediatric cancer patients undergoing peripheral blood stem cell harvest for autologous hematopoietic stem cell transplant.

Plerixafor for peripheral blood hematopoietic stem cell (PB HSC) mobilization in children undergoing autologous hematopoietic stem cell transplantation is primarily used following failure of the initial mobilization attempt. Data on plerixafor use in pediatric patients are limited. This retrospective study conducted at a single tertiary care center in India, details the efficacy and safety of plerixafor for 10 children with relapsed/refractory solid tumors or lymphomas. High risk neuroblastomas (HR NB) underwent autologous HSCT as part of consolidation. Plerixafor was administered at a dose of 240 µg/kg body weight of the recipient, subcutaneously, approximately 11-12 h prior to harvest. Ten patients (eight males, two females), with a median age of 8 years (range 2-18 years), received plerixafor prior to PB HSC harvest. All patients were administered granulocyte colony stimulating factor (GCSF) before the administration of plerixafor. The median CD 34 count for all patients pre-plerixafor was 29/µL, nine patients exhibited higher CD 34 post plerixafor (median of 148/µL). In nine patients, the values of the CD 34 count and total leukocyte count (TLC) of the harvested product were available, and in all cases, we achieved a good yield. All patients in this study were heavily chemotherapy pre-treated, and the use of plerixafor resulted in a satisfactory yield of peripheral blood stem cells. No side effects were observed.

Clinico-Hematological Profile of Acute Myeloid Leukemia: Experience From a Tertiary Care Cancer Center in North India.

INTRODUCTION: Complete diagnosis of acute myeloid leukemia (AML) requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping, karyotyping, and molecular genetic testing. The study intends to evaluate the demographic profile, clinical workup, and investigation, including flow cytometric immunophenotyping, in adult and pediatric age groups of AML. MATERIALS AND METHODS: This is a retrospective study of AML patients treated between January 2017 and December 2021. Clinical and demographic characteristics and investigation findings were recorded from case files and the hematology database. RESULT: A total of 896 cases of AML were registered during the given period, of which 819 cases were de-novo AML. Among those 819 cases, more than two-thirds of cases, i.e., 78.9% (N = 646), received induction chemotherapy. A significantly higher male-to-female ratio was observed (1.5:1). The median age was 22 years. The median time for diagnosis was three days and the median time for treatment intervention was four days. There were significant differences in the Eastern Cooperative Oncology Group (ECOG) performance status scores between pediatric and adult AML patients. Pediatric AML patients presented with better ECOG performance scores (ECOG performance scores 0 and 1) than adult patients (74.76% vs. 43.14%, p < 0.001). Further comparing adult vs. pediatric AML patients, normal karyotype (60.56% vs. 31.93%, p < 0.001) and NPM1 (22.25% vs. 6.72%, p < 0.001) and FLT3-ITD mutations (20.28% vs. 7.98%, p<0.001) were more common in the adult group, whereas AML-ETO (40.76% vs. 16.34%, p < 0.001) was more common in the pediatric group. CONCLUSION: The study highlights the presenting age is lower than global figures. The median time for initial diagnosis and the start of treatment is within the acceptable norms. Normal karyotype and NPM1 and FLT3 mutations were common in adult AML patients, whereas AML-ETO was more common in the pediatric cohort. These findings will help plan prospective studies and see the correlation with treatment outcomes. The laboratory workup practice currently complies with the standard guidelines at our center.