A surrogate molecular approach for the detection of Philadelphia chromosome-like B-acute lymphoblastic leukemia.

BACKGROUND: Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances. METHODS: Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA)neg B-ALL cases. At the end of induction therapy, flow cytometry-minimal residual disease (MRD) assay was used to quantify MRD positivity in Ph-like ALL cases. RESULTS: Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGAneg B-ALL cases were revealed by multiplex reverse transcriptase polymerase chain reaction. Among RGAneg B-ALL cases, 24% Ph-like ALL cases using nCounter NanoString were identified, with 48% CRLF2high cases with 45% CRLF2::P2RY8 and 18% CRLF2::IGH rearrangements(∼r) revealed by fluorescence in situ hybridization. In 52% of CRLF2low cases, 17% ABL1 and JAK2∼r 8% EPOR::IGH & PDGRFB∼r were identified. Ph-like ALL cases had higher total leukocyte count (p < .05), male preponderance (p < .05), and high MRD-positivity/induction failure compared with RGAneg B-ALL cases. Furthermore, in Ph-like ALL cases, 11 significant genes using quantitative polymerase chain reaction were identified and validated. CRLF2, IGJ, CEACAM6, MUC4, SPATS2L and NRXN3 genes were overexpressed and show statistical significance (p < .05) in Ph-like ALL cases. CONCLUSIONS: This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed. PLAIN LANGUAGE SUMMARY: Identification of recurrent gene abnormalities (RGA)neg B-acute lymphoblastic leukemia (B-ALL) cases using multiplex-reverse transcriptase polymerase chain reaction. Identification and characterization of Philadelphia (Ph)-like ALL cases using nCounter NanoString gene expression profiling and fluorescence in situ hybridization. Furthermore, Ph-like ALL cases were characterized according to CRLF2 expression and kinase-activating genomic alterations. Minimal residual disease of Ph-like ALL cases were quantified using flow cytometry-minimal residual disease assay. A surrogate molecular approach was established to detect Ph-like ALL cases from low- and middle-income countries.

Novel lncRNAs LINC01221, RP11-472G21.2 and CRNDE are markers of differential expression in pediatric patients with T cell acute lymphoblastic leukemia.

INTRODUCTION: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) poses significant challenges due to its aggressive nature and resistance to standard treatments. Long non-coding RNAs (lncRNAs) have emerged as potential biomarkers and therapeutic targets in leukemia. This study aims to characterize the lncRNA landscape in pediatric T-ALL, identify specific lncRNAs signatures, and assess their clinical relevance. METHODS: RNA sequencing was performed on T-ALL patient and control samples. Differential expression analysis identified dysregulated lncRNAs and mRNAs. Functional enrichment analysis revealed potential roles of these lncRNAs in cancer pathogenesis. Validation of candidate lncRNAs was conducted using real-time PCR. Clinical correlations were assessed, including associations with patients' clinical characteristics and survival outcomes. RESULTS: Analysis identified 674 dysregulated lncRNAs in pediatric T-ALL, with LINC01221 and CRNDE showing the most interactions in cancer progression pathways. Functional enrichment indicated involvement in apoptosis, survival, proliferation, and metastasis. Top 10 lncRNAs based on adjusted p value < 0.05 and Fold Change > 2 were selected for validation. Seven lncRNAs LINC01221, PCAT18, LINC00977, RP11-620J15.3, RP11-472G21.2, CTD-2291D10.4, and CRNDE showed correlation with RNA sequencing data. RP11-472G21.2 and CTD-2291D10.4 were highly expressed in T-ALL patients, with RP11-620J15.3 correlating significantly with better overall survival (p = 0.0007) at a median follow up of 32 months. The identified lncRNAs were further analysed in B-ALL patients. Distinct lncRNAs signatures were noted, distinguishing T-ALL from B-ALL and healthy controls, with lineage-specific overexpression of LINC01221 (p < 0.0001), RP11-472G21.2 (p < 0.001) and CRNDE (p = 0.04) in T-ALL. CONCLUSION: This study provides insights into the lncRNA landscape of pediatric T-ALL, offering potential diagnostic and prognostic markers. RP11-620J15.3 emerges as a promising prognostic marker, and distinct lncRNAs signatures may aid in the differentiation of T-ALL subtypes. Further research with larger cohorts is warranted to validate these findings and advance personalized treatment strategies for pediatric T-ALL patients.

Integrated analysis of transcriptome and genome variations in pediatric T cell acute lymphoblastic leukemia: data from north Indian tertiary care center.

INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with poor prognosis and inferior outcome. Although multiple studies have been perform on genomics of T-ALL, data from Indian sub-continent is scarce. METHODS: In the current study we aimed to identify the genetic variability of T-ALL in an Indian cohort of pediatric (age ≤ 12 years) T-ALL patients (n = 25) by whole transcriptome sequencing along with whole exome sequencing and correlated the findings with clinical characteristics and disease outcome. RESULTS: The median age was 7 years (range 3 -12 years). RNA sequencing revealed a definitive fusion event in 14 cases (56%) (including a novel fusions) with STIL::TAL1 in 4 (16%), followed by NUP21::ABL1, TCF7::SPI1, ETV6::HDAC8, LMO1::RIC3, DIAPH1::JAK2, SETD2::CCDC12 and RCBTB2::LPAR6 in 1 (4%) case each. Significant aberrant expression was noted in RAG1 (64%), RAG2 (80%), MYCN (52%), NKX3-1 (52%), NKX3-2 (32%), TLX3 (28%), LMO1 (20%) and MYB (16%) genes. WES data showed frequent mutations in NOTCH1 (35%) followed by WT1 (23%), FBXW7 (12%), KRAS (12%), PHF6 (12%) and JAK3 (12%). Nearly 88.2% of cases showed a deletion of CDKN2A/CDKN2B/MTAP genes. Clinically significant association of a better EFS and OS (p=0.01) was noted with RAG2 over-expression at a median follow up of 22 months, while a poor EFS (p=0.041) and high relapse rate (p=0.045) was observed with MYB over-expression. CONCLUSION: Overall, the present study demonstrates the frequencies of transcriptomic and genetic alterations from Indian cohort of pediatric T-ALL and is a salient addition to current genomics data sets available in T-ALL.

A regional virtual case discussion forum in pediatric oncology: Experience of the Pediatric Oncology East and Mediterranean Group.

BACKGROUND: The Pediatric Oncology East and Mediterranean (POEM) group that aims to share expertise among pediatric oncology providers across the Middle East, North Africa, and East Asia region initiated a virtual Case Discussion Forum (CDF) in 2013. METHODS: Meeting records from September 2013 till June 2021 were reviewed. Detailed minutes were available starting August 2016; case data were analyzed including diagnoses, purpose of presentation and recommendations. A 38-item survey assessing perception of benefits, challenges, and opportunities of the forum was distributed to members of the POEM group and results analyzed. RESULTS: A total of 140 cases were presented from 14 countries. After August 2016, 67 cases were presented, and those were analyzed regarding reasons for discussion, barriers, and recommendations. Details are presented in this report, and the most common challenges identified were related to histopathologic/molecular diagnosis (24%), imaging interpretation (18%), resource limitations (12%), and surgical difficulties (9%). A survey was distributed to all POEM members in 28 countries, and 76 responded. The main benefit reported was the provision of recommendations regarding treatment and evaluation, while the main challenges reported were time zone difference and workload. Recognized opportunities included conducting regionally relevant research studies based on clinical problems identified during discussions, and setting guidelines for resource-adapted treatment regimens. CONCLUSIONS: The POEM CDF identified areas for multi-institutional regional studies and led to a twinning project between two centers in the region for improving diagnostic infrastructure. Such forums can identify specific resource limitations in pediatric cancer and direct efforts for targeted capacity building.

Multi-criteria decision making to validate performance of RBC-based formulae to screen [Formula: see text]-thalassemia trait in heterogeneous haemoglobinopathies.

BACKGROUND: India has the most significant number of children with thalassemia major worldwide, and about 10,000-15,000 children with the disease are born yearly. Scaling up e-health initiatives in rural areas using a cost-effective digital tool to provide healthcare access for all sections of people remains a challenge for government or semi-governmental institutions and agencies. METHODS: We compared the performance of a recently developed formula SCS[Formula: see text] and its web application SUSOKA with 42 discrimination formulae presently available in the literature. 6,388 samples were collected from the Postgraduate Institute of Medical Education and Research, Chandigarh, in North-Western India. Performances of the formulae were evaluated by eight different measures: sensitivity, specificity, Youden's Index, AUC-ROC, accuracy, positive predictive value, negative predictive value, and false omission rate. Three multi-criteria decision-making (MCDM) methods, TOPSIS, COPRAS, and SECA, were implemented to rank formulae by ensuring a trade-off among the eight measures. RESULTS: MCDM methods revealed that the Shine & Lal and SCS[Formula: see text] were the best-performing formulae. Further, a modification of the SCS[Formula: see text] formula was proposed, and validation was conducted with a data set containing 939 samples collected from Nil Ratan Sircar (NRS) Medical College and Hospital, Kolkata, in Eastern India. Our two-step approach emphasized the necessity of a molecular diagnosis for a lower number of the population. SCS[Formula: see text] along with the condition MCV[Formula: see text] 80 fl was recommended for a higher heterogeneous population set. It was found that SCS[Formula: see text] can classify all BTT samples with 100% sensitivity when MCV[Formula: see text] 80 fl. CONCLUSIONS: We addressed the issue of how to integrate the higher-ranked formulae in mass screening to ensure higher performance through the MCDM approach. In real-life practice, it is sufficient for a screening algorithm to flag a particular sample as requiring or not requiring further specific confirmatory testing. Implementing discriminate functions in routine screening programs allows early identification; consequently, the cost will decrease, and the turnaround time in everyday workflows will also increase. Our proposed two-step procedure expedites such a process. It is concluded that for mass screening of BTT in a heterogeneous set of data, SCS[Formula: see text] and its web application SUSOKA can provide 100% sensitivity when MCV[Formula: see text] 80 fl.

Hematological, clinical, immunophenotypic characterization, and treatment outcomes of prognostically significant genetic subtypes of B-lineage acute lymphoblastic leukemia: A report of 1021 patients from India.

BACKGROUND: The published literature on hematological, clinical, flowcytometric-immunophenotyping, and minimal residual disease outcomes of the prognostically important genetic subtypes of acute lymphoblastic leukemia (ALL) is scarce from low-income countries. For newer classifications such as BCR::ABL1-like ALLs, the scarcity of patient-level data is even more pronounced. METHODS: The authors performed comprehensive detection of recurrent gene fusions and BCR::ABL1-like ALL cases followed by immunophenotypic profiling and obtained clinical outcome parameters for a large cohort (n = 1021) of patients from India. This cohort included a significant number of patients with BCR::ABL1-like ALL subtype and other genetic subtypes of ALL. RESULTS: Patients with BCR::ABL1-positive and BCR::ABL1-like ALL were significantly older, had male preponderance, and expressed a higher white blood cell count than BCR::ABL1-negative cases (p < .05). Logistic regression modeling of B-lineage-ALL (B-ALL) subtypes revealed that cluster of differentiation (CD)36 is a strong statistically significant predictive marker of BCR::ABL1-like ALL (p < .05). Furthermore, patients with BCR::ABL1-like ALLs show a significantly higher frequency of CD36 expression compared to BCR::ABL1-negative ALLs (p < .05). In terms of clinical symptoms, lymphadenopathy is a strong statistically significant predictive marker in BCR::ABL1-like ALLs compared to BCR::ABL1-negative ALL cases (p < .05). In terms of treatment outcomes, minimal residual disease (MRD) positivity in BCR::ABL1-positive ALL cases were statistically significant (p < .05), and BCR::ABL1-like ALL cases had high MRD-positivity as compared to BCR::ABL1-negative ALL cases but did not show statistical significance. CONCLUSIONS: The findings evince the use of novel therapies and personalized treatment regimens to improve the overall survival of the newer incorporated entities in B-ALLs. This is the first report characterizing the hematological, clinical, flowcytometric-immunophenotyping, and minimal residual disease outcomes of the prognostically significant subtypes of ALLs in patients from India. PLAIN LANGUAGE SUMMARY: Characterizing the hematological, clinical, flowcytometric-immunophenotyping, and minimal residual disease outcomes of the prognostically significant subtypes (n = 1021) of acute lymphoblastic leukemia (ALLs) in patients from India. We have made two independent logistic regression models of cluster of differentiation (CD) markers and clinical symptoms to differentiate prognostically significant subtypes of ALLs. Logistic regression analysis of CD markers revealed CD36 as a strong predictor in BCR::ABL1-like ALL cases compared to BCR::ABL1-negative ALL cases. Logistic regression analysis of clinical symptoms revealed lymphadenopathy significantly predicts BCR::ABL1-like ALLs (p < .05). In terms of treatment outcomes, BCR::ABL1-positive ALL had statistically significant minimal residual disease (MRD) (p < .05), and BCR::ABL1-like ALL cases had high MRD-positivity but did not show statistical significance as compared to BCR::ABL1-negative ALLs.

Molecular spectrum of inherited FVII deficiency in North India revealed a recurrent variant with a founder effect.

INTRODUCTION: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases. AIM: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency. METHODS: Retro-prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C) <50 IU/dl were subjected to targeted resequencing. After in-silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms. RESULTS: Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from .3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.-30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice-site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians. CONCLUSION: This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation.

Hematological and genetic profiles of persons with co-inherited heterozygous ß-thalassemia and supernumerary α-globin genes.

INTRODUCTION: Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (ß-thalassemia traits, ßTT) may rarely develop non-transfusion-dependent-thalassemia (NTDT) due to co-inheritance of supernumerary α-globin genes. Literature on phenotypic/genotypic features of these rare combinations is limited. MATERIALS AND METHODS: We studied the demographic, clinical, and laboratory data from 47 persons with co-inherited ßTT + supernumerary α-globin genes. HBB mutations were tested for by ARMS-PCR and/or Sanger sequencing, ααα(anti3.7) /ααα(anti4.2) and deletional α-thalassemia testing by multiplex gap-PCRs, and Xmn1G γ genotyping by PCR-RFLP. RESULTS: The 47 cases comprised 0.08% of 61 010 hemoglobinopathy screenings during the study period. Mean age was 31.9 ± 14.7 years (range 5.5-83 years), with 57.4% males. Thirty (63.8%) had NTDT-phenotype, 16 (34%) were asymptomatic/minimally symptomatic, and 1 became transfusion-dependent at the age of 20 years. Anemia/pallor and jaundice were the commonest complaints (76% each); 40% had required blood transfusions. Twenty-one had splenomegaly, 14 had hepatomegaly. Mean hemoglobin was 9.0 ± 1.9 g/dl (range 4.0-13.0). HbA2 was 5.1 ± 0.7% (3.4%-6.3%) and HbF% 4.2 ± 3.2% (0.5%-18.4%). Forty-four (93.6%) had αααanti3.7 , while 3 (6.4%) had αααanti4.2 triplications. HBB:c.92+5G>C (47%), HBB:c.27_28insG (14.9%), and HBB:c.47G>A (8.5%) were the commonest ß-globin mutations. One case showed HBB:c.-138C>T (ß++ ), while the rest had ß0 or severe-ß+ mutations. Symptomatic cases had significantly lower hemoglobins and higher HbF% than asymptomatic ones. CONCLUSION: This largest Indian and globally second-largest study reports the ßTT + ααα4.2 state for the first time in such genotypically-complex Indian cases. Supernumerary α-genes should be suspected in all ßTT with disproportionate clinical symptoms, mild-to-moderately elevated HbF, and unexplained anisopoikilocytosis.

A single-blinded, randomized controlled trial of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma.

BACKGROUND: Access to intra-arterial chemotherapy for retinoblastoma in low- and middle-income countries (LMICs) is limited. There is a need to optimize the efficacy of systemic chemotherapy for advanced intraocular retinoblastoma, particularly in LMICs. The aim was to compare the efficacy of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma. METHODS: The single-center, single-blinded, randomized study was conducted during 2019-2021. Patients with newly diagnosed group D or E retinoblastoma were randomized to receive vincristine, etoposide, and standard versus higher dose (<36 months: 18.6 vs. 28 mg/kg; ≥36 months: 560 vs. 840 mg/m2 ) carboplatin. Examination under anesthesia and ultrasonography was performed at diagnosis and following three cycles of chemotherapy. Group E eyes with poor likelihood of globe/vision salvage at diagnosis were excluded. RESULTS: Thirty-two eyes of 30 patients were analyzed: 17 group D and 15 group E eyes. The tumor response to chemotherapy with regards to regression pattern (p = .72), tumor shrinkage (diameter: p = .11, height: p = .96), subretinal seeds (p = .91), and vitreous seeds (p = .9) were comparable between the two treatment arms. The globe salvage (group D [82% vs. 67%; p = .58]; group E [12.5% vs. 29%; p = .57]) and salvage of meaningful vision (group D [100% vs. 75%; p = .13]; group E [100% vs. 50%; p = .48]) were comparable between standard and higher dose arms. No excess treatment-related toxicity was observed in the higher dose arm. CONCLUSIONS: Higher dose carboplatin-based intravenous chemotherapy did not result in superior globe or vision salvage in group D or E retinoblastoma.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

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, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-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 NUDT15 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 NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

Early mortality continues to be a barrier to excellent survival in childhood acute promyelocytic leukemia: a retrospective study of 62 patients spanning 17 years.

Data on childhood acute promyelocytic leukemia (APL) from low-and middle-income countries is limited. Early mortality is a concern and often not highlighted in clinical trials. The retrospective study was conducted on patients (≤12 years) with APL from 2003 to 2021 at a single center in India. Patients were treated with all-trans-retinoic acid (ATRA) and chemotherapy. Induction and three courses of consolidation were followed by maintenance for 2 years. In 2015, the protocol was updated with following modifications: (a) obtaining diagnostic cerebrospinal fluid at end-of-induction rather than at diagnosis, (b) administering intrathecal cytarabine regardless of risk-category, (c) risk-stratified administration of chemotherapy, and (d) inclusion of ATRA in all the cycles of consolidation. Sixty-two patients were diagnosed over the 17 years. The median age was 8 years (range: 0.9-12). Half had high-risk disease. Differentiation syndrome was observed in 32%, none being fatal. Eighteen (29%) patients died due to hemorrhage (83%) or septicemia (17%). Thirteen (21%) had early mortality (≤15 days), all due to hemorrhage. A platelet count <20 × 109/L predicted early mortality (odds ratio: 4.5; 95% CI: 0.9-22, p = 0.06). Treatment abandonment reduced from 23.5% during 2003-2015 to nil during 2015-2021 (p = 0.006). Three (8%) patients relapsed. The 4-year OS of all patients and the patients who survived >15 days was 70.1% and 89.6%, respectively. The 4-year EFS, including abandonment and early mortality, before and following updated protocol, was 61.4% and 65.5%, respectively (p = 0.77). Early mortality continues to be a barrier to an otherwise excellent survival in childhood APL. A significant reduction in treatment abandonment in recent years is gratifying.

Estimation of iron overload with T2*MRI in children treated for hematological malignancies.

Iron overload may contribute to long-term complications in childhood cancer survivors. There are limited reports of assessment of tissue iron overload in childhood leukemia by magnetic resonance imaging (MRI). A cross-sectional, observational study in children treated for hematological malignancy was undertaken. Patients ≥6 months from the end of therapy who had received ≥5 red-cell transfusions were included. Iron overload was estimated by serum ferritin (SF) and T2*MRI. Forty-five survivors were enrolled among 431 treated for hematological malignancies. The median age at diagnosis was 7-years. A median of 8 red-cell units was transfused. The median duration from the end of treatment was 15 months. An elevated SF (>1,000 ng/ml), elevated liver iron concentration (LIC) and myocardial iron concentration (MIC) were observed in 5 (11.1%), 20 (45.4%), and 2 (4.5%) patients, respectively. All survivors with SF >1,000 ng/ml had elevated LIC. The LIC correlated with SF (p < 0.001). MIC lacked correlation with SF or LIC. Factors including the number of red-cell units transfused and duration from the last transfusion were associated with elevated SF (p = 0.001, 0.002) and elevated LIC (p = 0.012, 0.005) in multiple linear regression. SF >595 ng/ml predicted elevated LIC with a sensitivity of 85% and specificity of 91.6% (AUC 91.2%). A cutoff >9 units of red cell transfusions had poor sensitivity and specificity of 70% and 75% (AUC 76.6%) to predict abnormal LIC. SF >600 ng/ml is a robust tool to predict iron overload, and T2*MRI should be considered in childhood cancer survivors with SF exceeding 600 ng/ml.

A higher tumor volume and undernutrition at diagnosis adversely affect the survival of children with Wilms tumor: A study of 200 patients.

BACKGROUND: Distinct prognostic factors for Wilms tumor (WT) in low- and middle-income countries need identification. METHODS: Retrospective study of patients with WT managed by the International Society of Pediatric Oncology (SIOP) approach for over 11 years (2005-2016) at a single center in Chandigarh, India. RESULTS: The study included 200 patients (median age: 33.5 months). The tumor stage (SIOP) distribution included stage I (30%), II (36%), III (14%), IV (17%), and V (3%). The histology-risk groups were low (8%), intermediate (84%), and high risk (9%). At diagnosis, 68 out of 190 (36%) patients were underweight. The median tumor volume at diagnosis was 481 ml (interquartile ratio [IQR]: 306.9, 686.8, n = 146). Following neoadjuvant chemotherapy, it reduced to 110 ml (IQR: 151.2, 222, n = 77). Treatment was abandoned in 20.5% of the patients. Treatment-related mortality occurred in 13 of 179 (7.2%) patients. Relapse occurred in 26 of 158 (16.5%) patients. The 3-year overall survival (OS) and event-free survival (EFS) of patients who completed therapy were 78.3 and 72%, respectively. The stage (p = .013) and histology (p = .023) influenced OS. A lower OS in stage II (75.4%) versus stage III disease (83.7%) suggested understaging. Patients with a higher tumor volume at diagnosis (p = .005; odds ratio [OR]: 0.99; 95% confidence interval [CI]: 0.99-1.00) or a lower weight-for-age z-score (p = .002; OR: 1.68; 95% CI: 1.21-2.33) had an increased risk of death or relapse. CONCLUSIONS: The 3-year OS and EFS of children who completed therapy were 78.3 and 72%, respectively. A higher tumor volume and lower weight-for-age z-score at diagnosis were identified as distinct adverse prognostic factors. A likely suboptimal lymph node assessment (intraoperative and histopathology) contributed to the understaging of stage III to II disease and reduced survival.

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

BACKGROUND: Inadequate numbers of trained healthcare 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 are vital for addressing these problems. METHODS: The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of the 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. 299 pediatric oncologists and 1,176 nurses treated 12,496 new PO patients/year, with a 1,451 beds 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 9 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 intra-regional 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. This article is protected by copyright. All rights reserved.

Outcome of pediatric germ cell tumor with comparison of carboplatin and cisplatin based regimens: A 10-year analysis.

Carboplatin is being advocated more frequently for treatment of childhood germ cell tumors (GCT), due to less long-term toxicity, and demonstrable equivalence in outcome as compared to cisplatin. This analysis presents the survival of GCT in a low middle-income country and compares two different chemotherapeutic regimens. A retrospective analysis of patient case records was carried out over 10-years (January 2007-December 2016). Chemotherapy regimen used was bleomycin, etoposide, and cisplatin (PEb) for initial 6-½ years and carboplatin, etoposide, and bleomycin (CEb) subsequently. Ninety patients with GCT were treated over 10-years. Malignant GCT was diagnosed in 69 (77%) patients, with 21(23%) having teratoma. The chemotherapy protocol was PEb in 38 (42%), CEb in 28 (31%) patients, while 24 patients were treated with surgery only. Stage 4 tumor was observed in 19 (21%) patients. Relapse or disease progression was seen in 11(12%). Overall and event-free survival at 5-years for the entire cohort was 77% and 73%, being similar with PEb (OS:77%; EFS:72.5%) vs. CEb (OS:69%; EFS: 69%). Significantly better overall survival was noted for patients with gonadal GCT) and non-stage 4 disease, while event-free survival was significantly better in patients with non-stage 4 disease. The chemotherapeutic regimen (PEb vs. CEb), very high AFP (value ≥10,000 IU/L), and risk stratification (low, intermediate, or high-risk disease) did not affect survival significantly. Carboplatin-based strategy was equivalent in our cohort to cisplatin-based strategy, and could be used safely in the LMIC set-up. The overall survival is suboptimal, with delayed presentation, abandonment, and relapse being barriers to survival.

Retrospective single-center experience with OEPA/COPDAC and PET-CT based strategy for pediatric Hodgkin lymphoma in a LMIC setting.

ABVD regimen for Hodgkin lymphoma (HL) is frequently used in children and young adults in low-middle income countries (LMIC). The feasibility and safety data for 'non-ABVD' protocols from LMIC is limited. The retrospective study was conducted in a single center in India. The Euronet PHL-C1 based protocol was administered during 2010-19. A PET-CT was performed at diagnosis and following two OEPA cycles. Radiotherapy was administered for inadequate PET response. During the 10-year period, 143 patients with HL were treated. The mean age was 7.8 ± 2.5 years. Bulky disease was observed in 82 (59%). Treatment abandonment was recorded in 13 (9.1%). The median follow-up duration was 46.4 months. An inadequate PET response was observed in 41/119 (34.4%), of which 56.1% received radiotherapy. Twelve (29.3%) patients who were supposed to receive radiotherapy received 2-cycles of COPDAC instead. Sixty-nine episodes of febrile neutropenia were observed in 54 patients. Treatment-related mortality (TRM) was observed in 7 (5.3%). The majority of episodes of febrile neutropenia (61%) and TRM (86%) occurred in the first cycle of OEPA. The 4-year event-free survival (EFS) and overall survival (OS) were 86.2 ± 3.4% and 93.5 ± 2.2%, respectively. Nine (6.3%) patients relapsed. Bulky disease lacked association with inadequate PET response (p = .800) or relapse (p = 1.000). OEPA/COPDAC regimen and response assessment by PET-CT permitted therapy reduction, including radiotherapy. Febrile neutropenia and resultant TRM (5.3%) are concerning and occurred frequently in the first cycle of OEPA. The support system for managing febrile neutropenia should be optimized for administering OEPA in LMIC.

Outcome and prognostic factors in childhood B non-Hodgkin lymphoma from India: Report by the Indian Pediatric Oncology Group (InPOG-NHL-16-01 study).

The literature on B-non-Hodgkin lymphoma (NHL) in India is restricted to individual hospital data. The study aimed to evaluate the epidemiology and outcome of B-NHL in our country. One hundred and ninety-one patients of B-NHL from 10 centers diagnosed between 2013 and 2016 were analyzed retrospectively. B/T lymphoblastic lymphoma and patients with inadequate data were excluded. The median age was 88 months (IQR: 56, 144) with an M:F ratio of 5.6:1. Undernourishment and stunting were seen in 36.5% and 22%. Primary site was abdomen in 66.5%. Hypoalbuminemia was noted in 82/170 (48.2%). Histological subtypes: Burkitt lymphoma (BL): 69.6%, Burkitt-like: 10.4%, and diffuse large B cell lymphoma (DLBCL): 13.6%, unclassified and others (6.4%). Stage distribution: I/II, 33 (17.3%), III, 114 (59.7%), and IV, 44 (23%). One-eighty-six patients took treatment. Protocols used were LMB and BFM in 160/186 (86%). At a median follow-up of 21.34 (IQR: 4.34, 36.57) months, the disease-free-survival (DFS) was 74.4% and event-free-survival (EFS) was 60.7%. Treatment-related mortality (TRM), relapse/progression and abandonment were 14.3%, 14.5%, and 8.4%, respectively. Bone marrow positivity, stage IV disease, and lactate dehydrogenase (LDH) > 2,000 U/l predicted inferior EFS. Stage IV disease, LDH > 2,000 U/l, bone marrow positivity, tumor lysis syndrome and low albumin predicted TRM; LDH retained significance on multivariate analysis for EFS and TRM [OR: 4.54, 95% CI: 1.14-20, p 0.03; OR 20, 95%CI: 1.69-250, p 0.017]. BL was the main histological subtype. High TRM and relapse/progression are hampering survival. An LDH > 2,000 U/l was adversely prognostic. These data demonstrate a need to develop a national protocol that balances toxicity and potential for cure.

Abdominal Wall Yolk Sac Tumor in a Child.

Midline vascular abdominal wall lesions are likely to be mistaken for vascular malformations in young children. We report a case of large yolk sac tumor located in the anterior abdominal wall just below xiphisternum in a 20-month-old girl diagnosed by raised serum alpha fetoprotein levels and fine-needle aspiration cytology. Preoperative chemotherapy helped in reducing its size allowing wide resection and primary wound closure. This case is reported for the unusual location and role of chemotherapy in management.

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

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.

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.

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).