Publications by authors named "Amita Trehan"

145 Publications

Next-Generation Sequencing Based Approach to Identify Underlying Genetic Defects of Glanzmann Thrombasthenia.

Indian J Hematol Blood Transfus 2021 Jul 24;37(3):414-421. Epub 2020 Oct 24.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012 India.

Glanzmann thrombasthenia (GT) is an autosomal recessive platelet function disorder characterized by mucocutaneous bleeding as the most common clinical phenotype. Patients with GT have normal platelet counts, platelet morphology but reduced platelet aggregation in response to various agonists. Homozygosity or compound heterozygosity for variants in the genes is the genetic basis for GT. Establishing a molecular diagnosis is definitive and is important for predictive testing. Using multi-gene panels is an accurate, faster, and cost-effective mode as compared to Sanger sequencing in large genes. We used a targeted resequencing based approach to identify pathogenic variants in eight cases in seven families. These variants were validated using Sanger sequencing in patients as well as family members and were predicted probably pathogenic using prediction tools. The variants include three missense (3/7 = 43%) (c.1028 T > C, c.1186G > A, c.1388G > C), two deletions (c.559delG, c.3092delT), one duplication (c.1424_1427dupAGGT) and nonsense variant (c.2578C > T, p.Gln860Ter). Except for one case which was compound heterozygous, the rest of the cases were homozygous. We found two novel variants that are reported for the first time in GT. The targeted resequencing based approach revealed varied genetic variants in North Indian patients, including two novels ones. The high yield of our panel indicates its suitability for usage in larger cohorts for the genetic diagnosis of GT patients. This approach is cost-effective and less cumbersome as compared to Sanger sequencing for these large size genes with multiple exons. The information so obtained is helpful in prenatal testing, carrier analysis, and genetic counseling.
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http://dx.doi.org/10.1007/s12288-020-01368-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239080PMC
July 2021

Pediatric oncology infrastructure and workforce training needs: A report from the Pediatric Oncology East and Mediterranean (POEM) Group.

Pediatr Blood Cancer 2021 Sep 1;68(9):e29190. Epub 2021 Jul 1.

Department of Oncology, Aga Khan University, Karachi, Pakistan.

Background: Inadequate numbers of trained health care providers (HCPs) contribute to poor pediatric oncology (PO) outcomes, particularly in low- and lower middle-income countries (L/LMICs). An understanding of the characteristics of the workforce challenges is vital for addressing these problems.

Methods: The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of North Africa, Middle East, Central Asia, and Indian subcontinent on infrastructure and workforce capacity, service availability, and training opportunities for HCPs. Participating centers were categorized by the World Bank income levels for their countries and correlated with services, workload and staffing characteristics, and training needs.

Results: Fifty of 82 member centers (61%) from 21 countries responded to the survey. Two hundred ninety-nine pediatric oncologists and 1176 nurses treated 12 496 new PO patients/year, with a 1451-bed utilization. The majority (71%) of new cases occurred in L/LMICs. The availability of HCPs correlated with country income level, as did pediatric subspecialty access, while availability of support services was unrelated. Twenty-five centers in 11 countries offered PO fellowship training for physicians, whereas 13 PO nurse training centers in nine countries had the capacity to train 273 nurses annually. The survey respondents indicated that, among their existing workforce, an average of 3.5 physicians and 14 nurses per institution would benefit from additional PO training opportunities.

Conclusions: The participating centers exhibited intraregional heterogeneity in financial resources, infrastructure, workload, workforce, and medical services. Our findings provide insight into the disparities and regional resources available to POEM, which can be mobilized to rectify specific deficiencies.
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http://dx.doi.org/10.1002/pbc.29190DOI Listing
September 2021

Hematological characteristics, cytogenetic features, and post-induction measurable residual disease in thymic stromal lymphopoietin receptor (TSLPR) overexpressed B-cell acute lymphoblastic leukemia in an Indian cohort.

Ann Hematol 2021 Aug 22;100(8):2031-2041. Epub 2021 Jun 22.

Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, 160012.

The overexpression of cytokine receptor-like factor-2 (CRLF2) identified by anti-thymic stromal lymphopoietin receptor/TSLPR flow cytometry (FCM) has been reported as a screening tool for the identification of BCR-ABL1-like B-cell acute lymphoblastic leukemia/B-ALL with CRLF2 re-arrangement. TSLPR expression was studied prospectively in consecutive 478 B-ALLs (≤ 12 years (n = 244); 13-25 years (n = 129); > 25 years (n = 105)) and correlated with various hematological parameters and end-of-induction measurable residual disease (day 29; MRD ≥ 0.01% by 10-color FCM). TSLPR positivity in ≥ 10% leukemic cells was detected in 14.6% (n = 70) of B-ALLs. CRLF2 re-arrangement was detected in eight cases (11.4%) including P2RY8-CRLF2 (n = 6), and IgH-CRLF2 (n = 2) with a median TSLPR positivity of 48.8% and 99% leukemic cells, respectively. Recurrent gene fusions/RGF (BCR-ABL1 (17.1%); ETV6-RUNX1 (4.2%), TCF3-PBX1 (1.4%)), other BCR-ABL1-like chimeric gene fusions/CGFs (PDGFRB-rearrangement (2.9%), IgH-EPOR (1.4%)), CRLF2 extra-copies/hyperdiploidy (17.1%), and IgH translocation without a known partner (10%) were also detected in TSLPR-positive patients. CD20 positivity (52.9% vs 38.5%; p = 0.02) as well as iAMP21 (4.3% vs 0.5%; p = 0.004) was significantly more frequent in TSLPR-positive cases. TSLPR-positive patients did not show a significantly higher MRD, compared to TSLPR-negative cases (37% vs 33%). Increasing the threshold cut-off (from ≥ 10 to > 50% or > 74%) increased the specificity to 88% and 100% respectively in identifying CRLF2 translocation. TSLPR expression is not exclusive for CRLF2 translocations and can be seen with various other RGFs, necessitating their testing before its application in diagnostic algorithms. In patients with high TSLPR positivity (> 50%), the testing may be restricted to CRLF2 aberrancies, while patients with 10-50% TSLPR positivity need to be tested for both CRLF2- and non-CRLF2 BCR-ABL1-like CGFs.
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http://dx.doi.org/10.1007/s00277-021-04574-0DOI Listing
August 2021

ALK-1-negative anaplastic large-cell lymphoma presenting as a dura-based mass in an infant.

Clin Neuropathol 2021 May 25. Epub 2021 May 25.

Introduction: Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system in the pediatric population.

Case Presentation: We describe a diagnostically challenging case of an 11-month-old infant presenting with cranial nerve palsies and peripheral eosinophilia. Imaging demonstrated meningeal thickening with enhancement and dura-based deposits, the biopsy of which revealed features of ALK-1 negative ALCL on histologic and immunophenotypic analysis. A thorough investigation excluded the possibility of any extra-cranial origin. Hence, a diagnosis of "primary" ALCL was rendered.

Conclusion: ALCL arising in the dura in an infant has not been described earlier, to the best of our knowledge.
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http://dx.doi.org/10.5414/NP301395DOI Listing
May 2021

Clinicopathological characteristics and outcomes in embryonal tumor with multilayered rosettes: A decade long experience from a tertiary care centre in North India.

Ann Diagn Pathol 2021 Aug 19;53:151745. Epub 2021 Apr 19.

Departments of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Background: Embryonal tumor with multilayered rosettes (ETMR) are a heterogenous group clinically, pathologically and topographically. Due to limited cases, data regarding its molecular genetics, pathology and prognostic factors is evolving. We retrospectively analysed our cohort of ETMR over last decade in order to study their clinicopathological characteristics and outcome.

Methods: Our cohort consisted of patients diagnosed with Embryonal tumor with abundant neuropil and true rosettes (ETANTR)/Ependymoblastoma (EBL)/ Medulloepithelioma (MEPL) over the past decade. Clinical details, including outcome and imaging data was retrieved. Histological analysis including immunohistochemical work-up was performed.

Results: Cohort included 15 patients with age range between 1 and 28 years and M:F ratio of 1.5:1. Supratentorial location predominated in comparison to tumors arising in posterior fossa. ETANTR and EBL patterns were equally distributed (40% each), followed by one case each of mixed pattern (EBL + ETANTR), MEPL and embryonal tumor, unclassified. All tumors readily expressed LIN 28A and INI-1 was retained. Recurrence with evidence of glial and rhabdoid differentiation was noted in a single patient 9 months following resection. Follow-up period ranged from 1 to 31 months, with overall median survival of 6.4 months. Eight patients were planned for adjuvant treatment following surgery, of which only four could complete it. All patients, except for one, succumbed to the disease.

Conclusions: ETMR have a heterogenous morphology and gathers ETANTR, EBL, MEPL within its spectrum. Following treatment, the recurrent tumor may feature glial/rhabdoid differentiation. LIN28A is expressed in all cases, however should be interpreted in context of histology. Prognosis of ETMR remains dismal despite multimodal therapy.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151745DOI Listing
August 2021

A case series highlighting structured hematological, biochemical and molecular approach to clinical oral iron refractoriness in children: A pressing need for a 3-tier system for classification of variants in TMPRSS6 gene.

Blood Cells Mol Dis 2021 07 16;89:102569. Epub 2021 Apr 16.

Pediatric Hematology-Oncology Unit, Department of Pediatrics, India. Electronic address:

In current study, we discuss clinical oral iron refractoriness cases and highlight need for a classification system to define TMPRSS6 gene variants. Out of 231 cases of microcytic hypochromic anemia screened (Sept 2019-Dec 2020), 17 cases (7.35%) with unexplained iron refractoriness (URIDA) phenotype were enrolled after ruling out secondary causes and compliance related issues. 11 (65%) had absent/negligible response (0-0.4 g/dl Hb rise) while 6 (35%) partial (0.5-0.9 g/dl Hb rise) response to initial iron trial at 4-8 weeks. Of these 17 cases, inappropriate hepcidin levels (normal-high) were noted in 11/15 (73%) tested. TSAT/Hepcidin ratio was low in 13/15 (87%). Genetic analysis of TMPRSS6 gene by NGS revealed variations in 15/17 (88%) cases. 10/15 cases with variations harbored a common splice site INDEL that was noted to be pathogenic SNP (MAF-0.19) on case-control association study in combination with other known missense SNPs with an odds ratio of 6.38 and relative risk 2.66 (p- < 0.01).
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http://dx.doi.org/10.1016/j.bcmd.2021.102569DOI Listing
July 2021

Diagnostic accuracy and cytomorphological spectrum of Wilms tumour in fine needle aspiration biopsy cytology samples supplemented with cell blocks.

Pediatr Blood Cancer 2021 Jul 21;68(7):e28996. Epub 2021 Mar 21.

Department of Cytology and Gynaecological Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Objective: Paediatric malignant renal neoplasms are subjected to neoadjuvant chemotherapy as per Societe Internationale d'Oncologie Pediatrique; International Society of Pediatric Oncology (SIOP) protocol. An accurate tissue diagnosis is required prior to institution of chemotherapy, and hence the aim of this study was to evaluate the diagnostic accuracy of fine needle aspiration biopsy cytology (FNABC) along with cell block histology.

Materials And Methods: A retrospective audit of all paediatric renal neoplasms diagnosed by FNABC between 2015 and 2019 was performed. Histopathology correlation was done wherever available. WT cases were subjected to detailed cytomorphological evaluation.

Results: A total of 121 cases of paediatric renal neoplasms including 109 WT, four clear cell sarcoma, one malignant rhabdoid tumour and three mesoblastic nephroma were evaluated. The age range was 4 weeks to 8 years. FNABC samples were adequate for diagnosis in 120 of 121 cases (99.18%) and a definitive cytological diagnosis was achieved in 117 cases (96.7%). The specificity and sensitivity for a cytopathological diagnosis of WT were 98.7% and 97.4%, respectively. On detailed cytomorphological analysis of 68 histopathology-proven WT, 40 (58.8%) cases were triphasic, 23 (35.3%) were biphasic and four were composed of blastema only. The corresponding cell blocks provided additional information over the conventional smears in 23 (33.8%) cases, with epithelial or mesenchymal elements recognised and evidence of rhabdomyoblastic differentiation.

Conclusion: FNABC along with cell block histology is highly accurate for diagnosis of WT and other malignant paediatric renal neoplasms and is recommended as the technique of choice in centres with cytopathology expertise for establishing a cellular diagnosis prior to commencement of neoadjuvant chemotherapy.
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http://dx.doi.org/10.1002/pbc.28996DOI Listing
July 2021

Survival in patients with high-risk neuroblastoma treated without autologous stem cell transplant or dinutuximab beta.

Pediatr Hematol Oncol 2021 May 23;38(4):291-304. Epub 2021 Feb 23.

Pediatric Hematology-Oncology Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

The majority of patients with high-risk neuroblastoma (HR-NB) in low- and middle-income countries (LMIC) do not have access to autologous stem cell transplant (ASCT) and dinutuximab. Consolidation with nonmyeloablative chemotherapy is not well-defined, and the outcomes are variable. We report a single-center outcome of patients with HR-NB, treated with nonmyeloablative consolidation. A tabulated compilation of similar reports is included. A retrospective chart review of patients with HR-NB was performed from January 2009 till June 2016. Patients were treated on the backbone of HR-NBL1/SIOPEN protocol. Treatment included induction with rapid-COJEC, surgery, followed by consolidation. Consolidation involved 4 cycles of topotecan, vincristine, and doxorubicin (TVD) instead of ASCT. Infusion of vincristine and doxorubicin were modified for ease and to enable administration in the clinic. Subsequent treatment included radiotherapy to the primary tumor and differentiation therapy with isotretinoin. Over 7½ years, 28 patients with HR-NB were treated. Two (7%) patients had therapy-related mortality. A relapse or disease progression occurred in 11 (39%) patients at a median duration of 17 months (IQR: 5, 18). Treatment abandonment was observed in 4 (14%) patients. The median follow-up of disease-free patients was 49 months (IQR: 45, 79). Patients with relapse were not treated further. A 4-year EFS of 29.3% was observed when 4-cycles of TVD were administered instead of ASCT in patients with HR-NB. The study and the review will aid decision-making for care of patients in LMIC while considering the options of treatment for HR-NB if access to ACST and dinutuximab is lacking.
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http://dx.doi.org/10.1080/08880018.2020.1850955DOI Listing
May 2021

Epigenetic analysis reveals significant differential expression of miR-378C and miR-128-2-5p in a cohort of relapsed pediatric B-acute lymphoblastic leukemia cases.

Int J Lab Hematol 2021 Feb 3. Epub 2021 Feb 3.

Department of Hematology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Introduction And Objective: Epigenetic changes play a major role in mediating chemoresistance and relapse in pediatric ALL, and hence in current pilot study, we tried to identify DNA methylation, miRNA expression, and copy number variations (CNVs) in a cohort of relapse pediatric B-ALL cases.

Methodology: DNA methylation, miRNA expression, and CNV analysis were performed in a total of 14, 16, and 18 cases as diagnosis-relapse samples. Briefly, DNA methylation was performed using Infinium HumanMethylation850 chip and data analyzed using RnBeads. miRNA was sequenced on illumina NextSeq500 platform for 20M 75bp SE reads and analyzed by DESeq2. CNVs were assessed by MLPA assay using the ALL P-335 probemix kit and analyzed by coffalyzer.net.

Results: On methylation analysis, oncogenes MYCN, MYB, and EGFR and tumor suppressor genes MDM4 & BCL11B were found differentially expressed as compared to controls (p-0.03). In addition, protooncogenes-AXL, HCK, MED12, and ETS2-were hypomethylated/overexpressed in 4 or more cases (P < .05). miRNA analysis revealed significant differential expression of miR-128-2-5p and miR-378C (p-4.4e-15 and p-6.4E-12) in relapse samples. CNV analysis revealed that frequency of good and intermediate/poor risk CNV profile at diagnosis was nearly equal (40% vs 60%). However, CDKN2A/2B and IKZF1 gene CNVs if present in initial diagnostic clone usually persisted in relapse clone.

Discussion And Conclusion: Our pilot study highlights two miRNAs (miR-128-2-5p and miR-378C) as possible candidate biomarkers of relapsed B-ALL. However, these miRNAs and hypomethylated protooncogene signature noted in our data needs validation in a larger series of B-ALL.
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http://dx.doi.org/10.1111/ijlh.13477DOI Listing
February 2021

Diagnostic values of Ga-labelled DOTANOC PET/CT imaging in pediatric patients presenting with paraneoplastic opsoclonus myoclonus ataxia syndrome.

Eur Radiol 2021 Jul 6;31(7):4587-4594. Epub 2021 Jan 6.

Department of Pediatric Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Objectives: Opsoclonus myoclonus ataxia (OMA) syndrome, also known as "Kinsbourne syndrome" or "dancing eye syndrome," is a rare, paraneoplastic entity which may be associated with pediatric neuroblastic tumors and carry a grave prognosis. We aimed to evaluate the role of Ga DOTANOC PET/CT for detecting neuroblastic tumors in patients with OMA syndrome.

Methods: We retrospectively evaluated the Ga-DOTANOC PET/CT data of pediatric patients presenting with OMA syndrome from March 2012 to November 2018. A somatostatin receptor (SSTR)-expressing lesion with corresponding morphological change on CT image was considered PET-positive, while no abnormal SSTR expression or lesion was noticed in PET-negative patients. Histopathology and/or clinical/imaging follow-up (minimum one year) was considered a reference standard for comparing the PET/CT findings. The results of Ga-DOTANOC PET/CT were also compared with I MIBG whole-body scintigraphy, which was available in five patients.

Results: Of 38 patients (13 males, 25 females, aged 3-96 months), 18 (47.3%) had SSTR-expressing lesions (PET-positive), and histopathology revealed neuroblastic tumors in 17/18 lesions (neuroblastoma 14, ganglioneuroblastoma 2, and ganglioneuroma 1) and reactive hyperplasia in 1/18. The remaining 20/38 (52.6%) patients did not demonstrate SSTR-expressing lesions (PET-negative) and had an uneventful follow-up. The average SUVmax of the PET-positive lesions was 10.3 (range 2.8-34.5). The PET/CT results revealed 17 true-positive, one false-positive, 20 true-negative, and zero false-negative. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 100%, 95.2%, 94.4%, 100%, and 97.3% respectively.

Conclusions: Ga-DOTANOC PET/CT identified neuroblastic tumors with a high diagnostic accuracy in our cohort compared to histology and follow-up.

Key Points: • Opsoclonus myoclonus ataxia (OMA) syndrome or "dancing eye syndrome" is a rare paraneoplastic entity which may be associated with pediatric neuroblastic tumors with a grave prognosis. • I/I MIBG imaging has a proven role for functional imaging in neuroblastoma or patients with OMA, but the role of Ga-DOTANOC PET/CT is not yet studied. • 68Ga-labelled DOTANOC PET/CT (SSTR) imaging, in our cohort, was able to positively identify neuroblastic tumors with high diagnostic accuracy when compared with histology.
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http://dx.doi.org/10.1007/s00330-020-07587-xDOI Listing
July 2021

Unilateral solid-cystic renal mass in an infant: Highlighting the cytological mimics.

Cytopathology 2021 May 5;32(3):378-382. Epub 2021 Jan 5.

Department of Histopathology, PGIMER, Chandigarh, India.

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http://dx.doi.org/10.1111/cyt.12951DOI Listing
May 2021

Entomophthoramycosis: A diagnostically challenging presentation of liver space-occupying lesion.

SAGE Open Med Case Rep 2020 6;8:2050313X20971405. Epub 2020 Nov 6.

Pediatric Hematology Oncology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Entomophthoramycosis, a rare fungal infection, can mimic various clinical entities. We present a case of entomophthoramycosis affecting a 3-year-old male masquerading as liver tumour, diagnosed on stereotactic biopsy and later on resected specimen. He improved following partial hepatectomy and antifungal therapy. A high index of suspicion and heightened awareness regarding its unique morphological characteristics are required for appropriate management.
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http://dx.doi.org/10.1177/2050313X20971405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656861PMC
November 2020

Pediatric bone marrow failure: Clinical, hematological and targeted next generation sequencing data.

Blood Cells Mol Dis 2021 03 5;87:102510. Epub 2020 Nov 5.

Pediatric Hematology Oncology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Objective: In this study, clinico-hematological, genetic and outcome profile of children with BMF was evaluated to delineate the underlying genotype and phenotype.

Design: Cases were evaluated as two groups: Group 1 (n = 56; DBA-23, FA-18, DC-2, UBMFS-13) included children with suspected IBMFS based on clinical phenotype and accessible lab investigations and Group 2 (n = 53) included children with IAA treated with IST. Targeted NGS was carried out in a subset of these children (n = 42) and supplemented with WES wherever required.

Results: We identified causative mutation in overall 15 of 27 tested children (55.5%) in group 1 and 2 of 15 tested children (13.3%) in group 2. In DBA, a mutation was noted in 50% cases with involvement of RPS 19 (75%) and RPL5 (25%) genes. Phenotypic abnormalities were present in 69.5% and response to steroids in 68.4% of cases at a median follow up of 33 months. In children with IAA, overall response (complete + partial) was present in 51% at a median follow up of 23 months. The 3-year OS and FFS for the cohort of IAA were 68% and 48% respectively. Targeted sequencing could also pick up germline mutations in 50% of UBMFS cases and nearly 19% of IAA cases.
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http://dx.doi.org/10.1016/j.bcmd.2020.102510DOI Listing
March 2021

An Evaluation of a Fluorescence In Situ Hybridization Strategy Using Air-dried Blood and Bone-marrow Smears in the Risk Stratification of Pediatric B-Lineage Acute Lymphoblastic Leukemia in Resource-limited Settings.

J Pediatr Hematol Oncol 2021 05;43(4):e481-e485

Unit of Paediatric Haemato-oncology, Department of Paediatrics, Advanced Paediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Cytogenetic abnormalities (CAs), one of the strongest influencers of therapeutic outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), can be identified by different techniques. Despite several technological advances, many centers with resource-limited settings continue to use either reverse-transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) to identify prognostically relevant CAs. We evaluated a simple and cost-effective triple-probe FISH strategy on air-dried blood and bone-marrow smears and compared its performance with a multiplex RT-PCR-based approach in the prognostication of pediatric BCP-ALL patients. Three hundred twenty BCP-ALL patients were tested prospectively and in parallel by FISH on air-dried blood or bone-marrow smears and RT-PCR. The FISH strategy correctly diagnosed all genetic abnormalities identified by RT-PCR. Prognostically relevant genetic abnormalities were missed by RT-PCR in 24 (8.1%) patients. In another 20 children (6%), with samples inadequate for RT-PCR testing (dry taps or due to poor sample quality), a successful FISH testing could be performed on bone-marrow aspirate or trephine-imprint smears. In addition, FISH detected ploidy changes, which could be confirmed by FxCycle Violet-based flow-cytometry. FISH testing on air-dried smears identified more prognostically relevant CAs, provided information on the ploidy status, and could be successfully performed in children with difficulty in bone-marrow sampling.
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http://dx.doi.org/10.1097/MPH.0000000000001892DOI Listing
May 2021

Emergence of a prominent myeloid clone in a ZNF384-rearranged B-cell precursor acute lymphoblastic leukaemia post-corticosteroid pre-phase therapy.

Pediatr Blood Cancer 2020 12 19;67(12):e28513. Epub 2020 Jul 19.

Unit of Paediatric Haemato-oncology, Department of Paediatrics, Advanced Paediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1002/pbc.28513DOI Listing
December 2020

A high frequency of Gilbert syndrome (UGT1A1*28/*28) and associated hyperbilirubinemia but not cholelithiasis in adolescent and adult north Indian patients with transfusion-dependent β-thalassemia.

Ann Hematol 2020 Sep 16;99(9):2019-2026. Epub 2020 Jul 16.

Department of Hematology, PGIMER, Level 5, Research Block A, Sector 12, Chandigarh, 160012, India.

Hyperbilirubinemia and pigment gallstones are frequent complications in transfusion-dependent β-thalassemia (TDβT) patients. Bilirubin production and clearance are determined by genetic as well as environmental variables like ineffective erythropoiesis, hemolysis, infection-induced hepatic injury, and drug- or iron-related toxicities. We studied the frequency of the Gilbert syndrome (GS), a common hereditary cause of hyperbilirubinemia in 102 TDβT patients aged 13-43 years (median 26 years). Total and unconjugated hyperbilirubinemia were frequent (81.4% and 84.3% patients respectively). Twenty (19.6%) patients showed total bilirubin > 3.0 mg/dL; 53 (51.9%) had an elevation of either alanine or aspartate aminotransferase, or alkaline phosphatase liver enzymes. Nineteen (18.6% of the 92 tested) were positive for hepatitis B or C, or HIV. The mean total and unconjugated bilirubin levels and AST, ALT, and ALP levels in patients positive for hepatitis B or C were not significantly different from negative cases. Eighteen patients (17.7%) had GS: homozygous (TA)7/7 UGT1A1 promoter motif (the *28/*28 genotype), 48 (47.1%) were heterozygous (TA)6/7. Total + unconjugated bilirubin rose significantly with the (TA)7 allele dose. Fourteen (13.7%) patients had gallstones. There was no significant difference in total/unconjugated bilirubin in patients with/without gallstones and no significant differences in frequencies of gallstones within the three UGT1A1 genotypes. This largest study in Indian TDβT patients suggests that GS should be excluded in TDβT cases where jaundice remains unexplained after treatable causes like infections, chelator toxicity, or transfusion-related hemolysis are excluded. GS was not associated with gallstones, possibly due to a lower incidence of cholelithiasis overall, a younger age cohort, or other environmental factors.
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http://dx.doi.org/10.1007/s00277-020-04176-2DOI Listing
September 2020

The importance of enteral nutrition to prevent or treat undernutrition in children undergoing treatment for cancer.

Pediatr Blood Cancer 2020 06;67 Suppl 3:e28378

Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Columbia University Irving Medical Center, New York, New York.

Nutrition therapy is a therapeutic approach to treating medical conditions and symptoms via diet, which can be done by oral, enteral or parenteral routes. It is desirable to include nutritional interventions as a standard of care in pediatric cancer units (PCUs) at all levels of care. The interventions are dependent on available resources and personnel across all clinical settings. Enteral nutrition is easy, inexpensive, uses the gastrointestinal tract, maintains gut mucosal integrity, and allows for individualized nutritional strategies. This narrative review describes enteral nutritional interventions for children undergoing cancer treatment and is aimed at PCUs of all levels of care located in a low- and middle-income country.
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http://dx.doi.org/10.1002/pbc.28378DOI Listing
June 2020

Challenges in the management of localized Ewing sarcoma in a developing country.

Pediatr Hematol Oncol 2020 Oct 19;37(7):610-619. Epub 2020 Jun 19.

Paediatric Haematology Oncology unit, Department of Paediatrics.

Survival in pediatric Ewing sarcoma (ES) lags in low- and middle-income countries (LMICs). This study analyzed factors contributing to a lower outcome in an LMIC center. A retrospective case review of children with localized ES treated from January 2011 till December 2017 was performed. Neoadjuvant chemotherapy with alternating cycles of vincristine, doxorubicin, cyclophosphamide; and ifosfamide, etoposide was administered 3-weekly for 48 weeks. Reassessment was planned for week 12, followed by local therapy (surgery/radiotherapy or both) tailed by adjuvant chemotherapy. Forty-eight patients with mean age 8 years (range: 0.7-14) were evaluated. Extremity and central axis tumors were seen in 25 (52%) and 23 (48%) patients. Three patients died of neutropenic sepsis and five abandoned therapy. Local therapy included primary surgery, radiotherapy and a combination of surgery and radiotherapy in 7 (16%), 20 (45%) and 17 (39%) patients. The 3-year event-free survival (EFS) and disease-free survival (DFS) for the cohort were 47.7 ± 11% and 57.6 ± 11.2%. Time to local therapy >16 weeks was associated with inferior DFS local therapy administered within 16 weeks [46.6 ± 12.4 63.9 ± 19.4, =.046]. Older age, axial site, large size and incomplete surgical resection did not predict relapse/progression. Patients who received wide local excision, as local therapy, had 100% DFS. Coordinated efforts to ensure timely therapy can improve outcome in pediatric ES. Abandonment and treatment-related mortality (TRM) are additional challenges that need to be tackled in LMICs.
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http://dx.doi.org/10.1080/08880018.2020.1772912DOI Listing
October 2020

Oncology care in a lower middle-income country during the COVID-19 pandemic.

Pediatr Blood Cancer 2020 08 15;67(8):e28438. Epub 2020 Jun 15.

Pediatric Hematology Oncology Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1002/pbc.28438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323035PMC
August 2020

Inherited Bleeding Disorders in North Indian Children: 14 years' Experience from a Tertiary Care Center.

Indian J Hematol Blood Transfus 2020 Apr 21;36(2):330-336. Epub 2019 Nov 21.

1Division of Pediatric Hemato-Oncology, Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012 India.

Inherited bleeding disorders are not uncommon in pediatric practice: most of them being chronic, require lifelong replacement therapy. To frame a management policy, it is essential to assess the load and pattern of bleeding disorders in the local population. However, there is paucity of data reporting the clinical spectrum of coagulation and platelet function disorders in Indian children. Hence to find out the exact burden and clinico-investigational profile of these patients we conducted this study. In this retrospective case review, detailed clinical information was extracted from case records in 426 children with a suspected diagnosis of hereditary bleeding disorder registered in the Pediatric Hematology clinic of a tertiary referral centre over a period of 14 years (1998-2011) and pooled for analysis. In our cohort prevalence of hemophilia A, hemophilia B, platelet function disorders, von Willebrand disease and other rare factor deficiencies were 72%, 11%, 7%, 4% and 4% respectively. Common clinical spectrum included skin bleeds, arthropathy, mucosal bleeds. 10% had deeper tissue bleeding and 16% received replacement therapy at the first visit. Nearly 3/4th of cases were lost for follow up after the initial visit. Hemophilia A was the commonest inherited bleeding disorder in our population. Skin bleeds and arthropathy were common clinical presentations. Factor replacement therapy was restricted to a minority. There is an urgent need for establishing centres of excellence with administrative commitment for factor replacement therapy for comprehensive management of such children in resource-limited countries.
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http://dx.doi.org/10.1007/s12288-019-01233-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229128PMC
April 2020

Imatinib-Induced Hypogammaglobulinemia in Children and Adolescents with Chronic Myeloid Leukemia.

Pediatr Hematol Oncol 2020 Sep 4;37(6):539-544. Epub 2020 May 4.

Pediatric Hematology-Oncology Unit, Dept. of Pediatrics, Advanced Pediatrics Center, Chandigarh, India.

Imatinib-induced tyrosine kinase inhibition extends beyond the BCR-ABL mutation, resulting in adverse effects. We evaluated hypogammaglobulinemia as a potential 'off-target' action of imatinib in children with CML. A cross-sectional, observational study was performed. Patients with CML in chronic phase, age <18-years at diagnosis, receiving imatinib for a duration exceeding 6-months were enrolled. Serum immunoglobulin G, A, and M were measured by end-point nephelometry. Thirty patients were enrolled. The mean age at diagnosis was 10.4 ± 3.1 years (range: 5-18). The mean age at enrollment was 16.4 ± 4.1 years (range: 9-23). The median dose of imatinib was 287.5 mg/m (IQR: 267.3, 345.0). The median duration of imatinib-therapy was 6-years (IQR: 3.0, 10.3). The median (IQR) normalized levels of IgG, IgA, and IgM were 33.0% (IQR: -12.8, 58.7), 28.1% (IQR: -17.0, 90.1) and 15.9% (IQR: -9.3, 40.5), respectively. The IgG, IgA, and IgM levels were reduced in 9 (30%), 8 (27%), and 10 (33%) patients, respectively. Five (17%) patients had pan-hypogammaglobulinemia. We suggest checking immunoglobulin levels in patients with CML receiving imatinib with recurrent/unusual infections.
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http://dx.doi.org/10.1080/08880018.2020.1759739DOI Listing
September 2020

Autologous stem cell transplant for high-risk neuroblastoma: Achieving cure with low-cost adaptations.

Pediatr Blood Cancer 2020 06 20;67(6):e28273. Epub 2020 Mar 20.

Department of Pediatrics, Pediatric Hematology-Oncology Unit, Advanced Pediatrics Center, Chandigarh, India.

Background: The majority of patients in low- and middle-income countries (LMIC) are unable to receive optimal therapy, including autologous stem cell transplant (ASCT) for high-risk neuroblastoma. Management is intensive and multidisciplinary; survival is often poor. We report a single-center outcome of high-risk neuroblastoma, with adaptations optimized for LMIC.

Procedure: The study was retrospective. Patients were treated on the backbone of the high-risk neuroblastoma study-1 of SIOP-Europe (HR-NBL1/SIOPEN) protocol with ASCT. Adaptations incorporated to decrease cost, requirement for inpatient admission, infections, and faster engraftment included (a) optional outpatient administration for rapid-COJEC, (b) two sessions of stem-cell apheresis, (c) storing stem cells at 2-6°C without cryopreservation for up to 7 days, (d) no central lines, (e) no antibacterial/antifungal/antiviral prophylaxis, (f) omitting formal assessment of cardiac/renal/pulmonary functions before ASCT, and (g) administration of pegylated granulocyte colony-stimulating factor on Day +4.

Results: Over 5 years 9 months, 35 patients with high-risk neuroblastoma were treated. Rapid-COJEC was administered over a median duration of 80 days (interquartile range: 77, 83). Conditioning regimen included melphalan (n = 7), oral busulfan-melphalan (Bu/Mel; n = 6), or intravenous Bu/Mel (n = 22). The median viability of stem cells stored for 6 days (n = 28) was 93% (range: 88-99). Two (5.7%) patients had ASCT-related mortality. The 3-year overall and event-free survival was 41% and 39%, respectively. A relapse occurred in 20 (57%) patients. Treatment abandonment was observed in one (3%) patient.

Conclusions: Administration of therapy in a disciplined time frame along with low-cost adaptations enables to manage high-risk neuroblastoma with low abandonment and an encouraging survival in LMIC. Stem cells can be stored safely without cryopreservation for up to 7 days.
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http://dx.doi.org/10.1002/pbc.28273DOI Listing
June 2020

PEST domain NOTCH mutations confer a poor relapse free survival in pediatric T-ALL: Data from a tertiary care centre in India.

Blood Cells Mol Dis 2020 05 5;82:102419. Epub 2020 Mar 5.

Pediatric Hematology-Oncology Unit, Dept. of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

A comprehensive genotype-phenotype analysis of pediatric T-ALL data was performed. 33 confirmed pediatric (≤12 y) T-ALL samples were evaluated for oncogenic transcripts: TLX-1, TLX-3, common fusion of STIL-TAL1, NOTCH1 mutations and copy number variations (CNVs). Mean WBC was 235.69 × 10/μL. TLX1 and TLX-3 overexpression detected in 1 (3%) and 7 (21%) patients and STIL-TAL1 in 8 (27%). NOTCH1 mutations were noted in 17 (52%), of which 12 (71%) in HD domain and 6 (35%) in PEST domain (including one case with mutations in all three domains). Commonest CNVs were CDKN2A (85%) and CDKN2B (75%). Relapse occurred in 8 (24%) patients. The median follow-up was 15 months (range: 0.5-36). Bulky liver (p = 0.025), day 35 marrow (p = 0.004) and NOTCH mutation (p = 0.046) were predictive of time to an event. RFS was significantly poor for cases with PEST Vs. HD domain mutations (50% Vs. 85%) (p = 0.0009). Though cases with PEST domain NOTCH mutations had poor RFS, the OS was not influenced by NOTCH mutation positivity.
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http://dx.doi.org/10.1016/j.bcmd.2020.102419DOI Listing
May 2020

BRAF V600E mutation in childhood Langerhans cell histiocytosis correlates with multisystem disease and poor survival.

Blood Cells Mol Dis 2020 05 30;82:102356. Epub 2019 Aug 30.

Department of Paediatrics, India. Electronic address:

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia of children with systemic involvement and poor outcome. The altered RAS-RAF-MEK-ERK cell signalling pathway due to somatic mutation of BRAF V600E is the most common genetic abnormality associated with the disease. In the current study, we highlight the frequency of BRAF V600E in our cohort of LCH cases (n = 31) and its relation with clinical outcome. On Real-Time PCR and Sanger sequencing, BRAF V600E was detected in 6/31 (19%) patients. All cases positive for BRAF V600E mutation had multisystem involvement/disseminated disease compared to BRAF mutation negative cases (100% v/s 41%, p = 0.0348). Univariate analysis also revealed significant correlation of mutation positivity with risk category (p = 0.09). The event free survival and overall survival at 36 months for BRAF mutation positive group compared to mutation negative group was 17% v/s 72% (Log rank test p = 0.0110) and 32.5% v/s 82% (p = 0.0330), respectively. In our study, BRAF V600E positivity was low (19%) however, all positive cases had multisystem involvement and a poor three year survival confirming BRAF V600E to be a poor prognostic marker.
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http://dx.doi.org/10.1016/j.bcmd.2019.102356DOI Listing
May 2020

Assessment of nutritional status in children with cancer: A narrative review.

Pediatr Blood Cancer 2020 06 25;67 Suppl 3:e28211. Epub 2020 Feb 25.

Pediatric Oncology Unit, Department of Pediatrics, Steve Biko Academic Hospital and University of Pretoria, Pretoria, South Africa.

A child's appropriate development stems in large part from proper nutrition. Malnutrition is an adverse prognostic factor in children with cancer, and its prevalence is highly variable. Currently, there is no standardized definition and assessment method of nutritional status in pediatric oncology. A complete nutritional assessment includes anthropometry, biochemical, clinical, and dietary assessments. In this article, we explore these methods and suggest practical approaches for pediatric cancer units depending on the levels of care that these can provide. We also advise on the monitoring and follow-up of children with cancer during and after treatment, and discuss potential areas for future research.
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http://dx.doi.org/10.1002/pbc.28211DOI Listing
June 2020

Massively parallel variant characterization identifies alleles associated with thiopurine toxicity.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5394-5401. Epub 2020 Feb 24.

Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, deficiency was identified as a genetic cause of thiopurine toxicity, and -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
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http://dx.doi.org/10.1073/pnas.1915680117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071893PMC
March 2020

Next-Generation Sequencing-Based Diagnosis of Unexplained Inherited Hemolytic Anemias Reveals Wide Genetic and Phenotypic Heterogeneity.

J Mol Diagn 2020 04 6;22(4):579-590. Epub 2020 Feb 6.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

Determination of the cause of inherited hemolysis is based on clinical and stepwise conventional laboratory tests. Patients with obscure etiology require genetic diagnosis, which is time-consuming, expensive, and laborious, mainly because of numerous causal genes. This study enrolled 43 patients with clinical and laboratory evidence of unexplained hemolytic anemia. Initially, 13 patients were tested using a commercial (TruSight One) panel, and remaining cases underwent targeted sequencing using a customized 55-gene panel. Pyruvate kinase deficiency was found in eight, glucose-6-phosphate dehydrogenase (G6PD) deficiency in three (G6PD Guadalajara in two and p.Tyr227Ser: novel, named as G6PD Chandigarh), and glucose-6-phosphate isomerase (GPI) deficiency in two (GPI:p.Arg347His and p.Phe304Leu: novel, named as GPI Chandigarh). Three patients had Mediterranean stomatocytosis/macrothrombocytopenia, and two had overhydrated stomatocytosis. Xerocytosis was found in three patients, whereas six had potentially pathogenic variants in membrane protein-coding genes. Overall, 63% cases received a definite diagnosis. Timely determination of etiology was helpful in diagnosis, genetic counseling, and offering a prenatal diagnosis. Therapeutic implications include performing or avoiding splenectomy that may ameliorate the anemia in many but also predispose to thrombosis in other groups of patients. This first study on the genetic spectrum of unexplained hemolytic anemia from the Indian subcontinent also represents, currently, one of the largest cohort worldwide of such patients.
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http://dx.doi.org/10.1016/j.jmoldx.2020.01.007DOI Listing
April 2020
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