Epilepsia Partialis Continua as a Sequelae of Measles Infection in Children With Hematolymphoid Malignancies.

PURPOSE: To share our clinical experience with the diagnosis and management of children with hematolymphoid malignancies presenting with epilepsia partialis continua (EPC) as a sequelae of measles infection. MATERIALS AND METHODS: In December 2022, a series of children in our hemato-oncology unit presented with focal status epilepticus with no conclusive evidence pointing toward any underlying etiology. One such child had a typical measles rash a few weeks before the onset of this focal status epilepticus. After a series of cases with a similar presentation, a clinical pattern suspicious for measles became evident. cerebrospinal fluid polymerase chain reaction was positive for measles virus with measles immunoglobin M detected in the serum. This led to the diagnosis of measles inclusion-body encephalitis in a series of children who presented with EPC over a period of 3 months. EPC is a rare manifestation of measles that is seen only in immunocompromised patients. RESULTS: Among the 18 children reported in this series, only 10 had a history of rashes. The rash was mostly transient and elicited only on retrospective history taking. Five of the 18 children who did not lose consciousness during the prolonged seizure episode survived the disease but had residual neurologic sequelae. Among the 18 children, two were unimmunized and immunization status could not be confirmed in three other children. CONCLUSION: This case series highlights the threats posed by measles infection in children with cancer who are immunosuppressed because of the underlying disease and ongoing chemotherapy. Loss of herd immunity because of declining measles immunization rates secondary to vaccine hesitancy and COVID-19 lockdown pose a greater risk of measles infection and its complications for patients with deficient immune systems.

KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1.

BACKGROUND: Pediatric core binding factor acute myeloid leukemia (CBF-AML), although considered a favorable risk subtype, exhibits variable outcomes primarily driven by additional genetic abnormalities, such as KIT mutations. PROCEDURE: In this study, we examined the prognostic impact of KIT mutations in 130 pediatric patients with CBF-AML, treated uniformly at a single center over 4 years (2017-2021). KIT mutations were detected via next-generation sequencing using a myeloid panel comprising 52 genes for most patients. RESULTS: Our findings revealed that KIT mutations were present in 31% of CBF-AML cases. Exon 17 KIT mutation was most commonly (72%) seen with notable occurrences at the D816 and N822 residue in 48% and 39% of cases, respectively. The 3-year cumulative incidence of relapse (CIR) and overall survival (OS) for patients with exon 17 KIT mutation were 36% and 40%, respectively, and was significantly worse in comparison to other site KIT mutations (3-year CIR: 11%; OS: 64%) and without KIT mutation (3-year CIR: 13%; OS:71%). Notably, the prognostic impact of KIT mutations was prominent in patients with RUNX1::RUNX1T1, but not in those with CBFB::MYH11 fusion. Additionally, a high KIT variant-allele frequency (VAF) (>33%) predicted for a higher disease relapse; 3-year CIR of 40% for VAF greater than 33% versus 7% for VAF less than 33%. When adjusted for site of KIT mutation and end-of-induction measurable residual disease, VAF greater than 33% correlated with poor OS (hazard ratio [HR]: 4.4 [95% CI: 1.2-17.2], p = .034). CONCLUSION: Exon 17 KIT mutations serve as an important predictor of relapse in RUNX1::RUNX1T1 pediatric AML. In addition, a high KIT VAF may predict poor outcomes in these patients. These results emphasize the need to incorporate KIT mutational analysis into risk stratification for pediatric CBF-AML.

Impact of Surveillance Imaging in Detecting Local and Metastatic Lung Recurrences Among Patients with Sarcomas of the Extremities: A Systematic Review and Meta-analysis.

BACKGROUND: The surveillance guidelines following treatment completion for patients with high-grade sarcomas of the extremities are based largely upon expert opinions and consensus. In the current meta-analysis, we aim to study the utility of surveillance imaging to diagnose local and metastatic pulmonary relapses among patients with extremity soft tissue sarcomas and primary bone sarcomas. PATIENTS AND METHODS: A meta-analysis was performed to assess the sensitivity, specificity and diagnostic odds ratio (DOR) of surveillance imaging to diagnose local and metastatic pulmonary relapse among patients with sarcoma of the extremities. In addition, impact of surveillance imaging on overall survival was assessed. Heterogeneity among eligible studies was evaluated by I2 statistics. Sensitivity analysis was assessed using influence plots and Baujat plots. RESULTS: Ten studies including 2160 patients with sarcoma were found eligible. For diagnoses of local recurrence based on surveillance imaging (nine studies, 1917 patients), the estimated sensitivity, specificity, and DOR were 13.6%, 99.5%, and 78.15, respectively. Only 16.7% of local recurrences were diagnosed based on imaging. For diagnoses of metastatic pulmonary recurrence (eight studies; 1868 patients), estimated sensitivity, specificity, and DOR were 76.1%, 99.3%, and 1059.9, respectively. A sensitivity analysis showed significant heterogeneity among included studies. None of the included studies showed an overall-survival benefit with the use of surveillance imaging. CONCLUSION: The current meta-analysis challenges the notion of routine use of imaging to detect local relapse, while favoring chest imaging, using either chest radiography or computed tomography scan, for surveillance. Further studies are required to study the ideal surveillance strategy including timing and imaging modality.

Treatment and follow-up of children with chronic myeloid leukaemia in chronic phase (CML-CP) in the tyrosine kinase inhibitor (TKI) era-Two decades of experience from the Tata Memorial Hospital paediatric CML (pCML) cohort.

Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long-term off-target toxicities of TKIs in children are scarce. In this single-centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long-term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow-up. Ten patients were switched to second-generation TKIs (2G-TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow-up of 84 (3-261) months, the 5-year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4-100) and 98.7% (95% CI: 96.9-100) respectively. Screening for long-term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long-term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long-term outlook of pCML.

Wilms Tumor in India: A Systematic Review.

Shyam SrinivasanBackground Cure rates of childhood malignancies are inferior in India compared with upper-middle-income countries. There is paucity of quality data addressing outcome of childhood Wilms tumor (WT) from India. This systematic review was conducted to assess the disease trends, treatment strategies, and outcome indicators in WT across India. Materials and Methods We conducted a systematic search of MEDLINE, Google Scholar, and SCOPUS database, and additionally screened International Society of Pediatric Oncology conference abstracts. Data concerning WT or nephroblastoma published from India were extracted. Results A total of 17 studies containing 1,170 patients were included in this review. Ninety-four percent of the studies were published after the year 2010. Advanced stage (III and IV) disease was seen in 46% of included patients. In seven studies, patients underwent a pretreatment biopsy before commencement of therapy. A hybrid approach consisting of "surgery first" in a selected subset and "neo-adjuvant chemotherapy" in all others was the most common treatment strategy adopted in half of the studies. The overall survival ranged between 48 and 89%. Key prognostic factors influencing survival across studies included increased tumor volume, metastatic disease, and unfavorable histology. Nonrelapse mortality (2.7-8.5%) was noted to be high. Conclusion Substantial proportion of children with WT from India present with advanced stages of the disease. Despite several limitations, the current systematic review showed a modest survival among Indian children with WT. Adopting strategies through collaboration to ensure early access to expert care along with involvement of social support team to improve compliance may further improve survival of WT in India.

Clinico-radiological profile, management and follow-up of methotrexate induced neurotoxicity in children with acute lymphoblastic leukemia.

Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.

Does granulocyte transfusion help pediatric cancer patients with sepsis?

Sepsis-related mortality continues to be a major concern while treating pediatric cancer patients, more so with the rise in the incidence of multidrug-resistant organisms (MDRO). In this retrospective study conducted between January 2021 and December 2022 at a tertiary cancer center in India, granulocyte transfusion was offered in addition to standard antimicrobial therapy to 64 children with hematolymphoid malignancy who developed 75 episodes of severe sepsis following intensive chemotherapy. Forty-four (83%) of 53 blood culture proven sepsis was caused by MDROs. Thirty-seven (70%) patients with blood culture proven sepsis cleared the organism after granulocyte transfusion. Thirty-day mortality was 25% for the entire study cohort and 32% for patients with MDRO sepsis.

Cardiac function in pediatric Ewing sarcoma during and after treatment: A longitudinal study.

BACKGROUND: While anthracycline therapy has been shown to improve outcomes in Ewing sarcoma, it may be associated with severe and even fatal cardiac dysfunction. We evaluated the burden and determinants of cardiac dysfunction in pediatric Ewing sarcoma (pES). METHODS: This retrospective study included children aged 0-18 years with pES treated at our center with the EFT 2001 protocol (anthracycline and cyclophosphamide containing regimen), with/without radiation therapy from January 2001 to December 2018. Cardiac dysfunction was defined as left ventricular (LV) ejection fraction with an absolute value <50%. RESULTS: Amongst 650 eligible patients (median age at diagnosis 12 years and median follow-up duration 69 months), 85 (13%) developed cardiac dysfunction, at a median 13 months (range: 1-168 months). The cumulative incidence of cardiac dysfunction was 5.7% at 12 months, 12% at 2 years, 13% at 3 years, 14% at 5 years, and 15 % at 10 years. At a median follow-up duration of 25 (range: 3-212) months, 21 (24.7%) patients had normalization of LV function, whereas nine (10.6%) patients died of cardiac causes. Older age at diagnosis (7-12 years OR 5.1, p = .01, 13-18 years, OR 3.9, p = .03), female sex (OR 2.3, p = .004), undernutrition (OR 2.9, p = .001), and chest wall location (OR 8.7, p = .08) were risk factors for cardiac dysfunction. CONCLUSIONS: Children with Ewing sarcoma have a high incidence of cardiac dysfunction, which continues to develop even years after therapy, underlining the need for life-long surveillance. Undernourished children are at a higher risk for cardiac dysfunction and need stringent monitoring.

Treatment of Pediatric Acute Promyelocytic Leukemia with Retinoic Acid and Arsenic Trioxide along with Chemotherapy.

OBJECTIVES: Outcomes of childhood acute promyelocytic leukemia (APL) have exceeded 90% in the era of differentiating agents. In resource-limited settings, early mortality secondary to coagulopathy remains a significant challenge. Differentiation syndrome is a unique complication of APL therapy that requires a high degree of suspicion for timely initiation of therapy. METHODS: A retrospective study of children ≤15 y of age with APL diagnosed between January-2013 and June-2019 treated at a tertiary cancer centre was conducted. Patients with a total leukocyte count ≥10,000/µL were risk stratified as high-risk. Treatment included differentiating agents, all-trans retinoic acid and arsenic trioxide along with chemotherapy. Baseline demographics, clinical complications and outcomes were analysed. RESULTS: Out of 90 patients treated, 48 (53%) had high-risk APL and 25 (28%) presented with significant bleeding manifestations. Response to therapy was excellent with 96% of evaluable patients achieving molecular remission by the end of consolidation phase. Differentiation syndrome occurred in 23 (25%) patients of which two expired. Early mortality rate was 5.5% and was due to severe hemorrhage most often at the time of presentation. The 3-y overall survival of the entire cohort was 91% (95% CI: 85-97%). Two of 4 patients with relapse of disease could be salvaged with only differentiating agents followed by autologous transplantation. CONCLUSIONS: Long-term outcomes of Indian children with APL are excellent. Timely management of coagulopathy and prompt initiation of differentiating agents along with appropriate cytoreductive measures is critical. Efforts to build academic-community partnerships to ensure timely diagnosis and emergency care in order to reduce early mortality are needed.

Prevalence and prognostic significance of IKZF1 deletion in paediatric acute lymphoblastic leukemia: A systematic review and meta-analysis.

IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have been described in childhood acute lymphoblastic leukemia (ALL) with varying prevalence often influenced by underlying cytogenetics and also shown to have diverse prognostic significance. We aimed to evaluate the prevalence and prognostic significance of IKZF1 deletion among childhood ALL. Electronic databases of MEDLINE, EMBASE and SCOPUS were searched and 32 studies found eligible. Estimated prevalence of IKZF1 deletion among BCR::ABL1 negative and BCR::ABL1 positive ALL patients was 14% (95%CI:13-16%, I2 = 79%; 26 studies) and 63% (95%CI:59-68% I2 = 42%; 10 studies) respectively. Most common site of IKZF1 deletion was whole chromosome (exon1-8) deletion in 32.3% (95%CI: 23.8-40.7%) followed by exon 4-7 deletion in 28.6% (95%CI: 19.7-37.5%). A positive minimal residual disease at the end of induction was more common among patients with IKZF1 deletion, odds ratio: 3.09 (95%CI:2.3-4.16, I2 = 54%; 15 studies). Event-free survival and overall survival were significantly worse for IKZF1 deletion, hazard ratio (HR): 2.10 (95%CI:1.90-2.32, I2 = 28%; 31 studies) and HR: 2.38 (95%CI:1.93-2.93, I2 = 40; 15 studies) respectively. In summary, the current meta-analysis highlights the frequency of IKZF1 deletion and its negative impact on survival in childhood ALL. Further studies exploring the influence of IKZF1 deletion in the presence of classical cytogenetic and other copy number alterations would further help in characterising its prognostic role.

Treatment outcomes and prognostic factors in children with hepatoblastoma using a risk-stratified approach.

BACKGROUND: Not all the significant progress made in the management of children with hepatoblastoma (HB) has translated into improved outcomes in limited-resource settings. There are limited data on outcomes in children with HB from India. METHODS: All patients diagnosed with HB between July 2013 and December 2020 were risk-stratified and treated as per International Liver Tumor Strategy Group (SIOPEL). Patients with standard-risk HB received cisplatin monotherapy and those with high-risk HB received alternating cycles of cisplatin and the combination of carboplatin plus doxorubicin. Data regarding demographic details, chemotherapy, surgery, liver transplantation, outcomes, prognostic factors, and toxicity were collected. RESULTS: Of 157 patients with HB, 117 (74%) were high risk, 31 (20%) were standard risk, and nine (6%) unknown. Patients with standard-risk disease had excellent outcomes, with 3-year event-free survival (EFS) and overall survival (OS) of 96% and 100%, respectively. Among high-risk HB, six underwent orthotopic liver transplantation of which four were alive at last follow-up. The 3-year EFS and OS of patients with high-risk disease was 56% and 66%, respectively. Outcomes of patients with PRETEXT IV (3-year EFS: 42%, 3-year OS: 50%) and metastatic disease (3-year EFS: 30%, 3-year OS: 50%) were dismal. Patients with serum alpha-fetoprotein (AFP) reduction greater than 90% following two courses of chemotherapy had favorable outcomes; 3-year EFS: 80% versus 58% (p = .013) and 3-year OS: 95% vs. 68% (p < .01). Only two (6%) of 31 patients with relapse/refractory HB were alive at a median follow-up of 36 months, and both had received salvage chemotherapy and surgery. CONCLUSIONS: While children with standard-risk HB had excellent outcomes, those with high-risk disease continue to do poorly. Serial monitoring of serum AFP values is a cost-effective and reliable predictor of outcomes. Orthotopic liver transplantation remains a viable option for inoperable disease in resource-limited settings as well.

Transarterial Chemoembolization (TACE) Combined With Sorafenib versus TACE in Patients With BCLC Stage C Hepatocellular Carcinoma - A Retrospective Study.

Objective: Advanced-stage hepatocellular carcinoma is a heterogeneous group with limited treatment options. TACE has been advocated recently by various study groups. The purpose of this study was to evaluate if TACE in combination with sorafenib, as well as TACE alone, was safe and efficacious in treating BCLC stage C HCC. Methods: A retrospective evaluation of the clinical data of 78 patients with BCLC stage C HCC who received either TACE-sorafenib (TS) combination therapy or TACE monotherapy as their first treatment was done. The two groups were compared in terms of radiological tumor response 1 month after the intervention. The two groups were also compared in terms of time to progression (TTP), overall survival (OS), and adverse events. Results: The disease control rate (44.9% and 25.8%, respectively, P = 0.09) was higher in the TS combination group than in the TACE monotherapy group after 1 month of treatment. The TS combination group had significantly superior TTP and OS than the TACE group (TTP was 4.6 and 3.1 months, respectively, P = 0.001), and OS was 10.1 and 7.8 months, respectively, P < 0.001). The TACE-S group had a greater cumulative survival time at 6 months, 9 months, and 1 year than the TACE group (97.9%, 51.1%, 25.7% vs. 90.4%, 51.6%, and 0%, respectively). Conclusion: TS combination therapy in advanced-stage (BCLC-C) HCC significantly improved disease control rate, TTP, and OS compared with TACE alone, without any significant increase in adverse reactions.

Prevalence and Clinical Outcome of FMS-Like Tyrosine Kinase Mutations Among Patients With Core Binding Factor-Acute Myeloid Leukemia: Systematic Review and Meta-Analysis.

BACKGROUND: Core binding factor acute myeloid leukemia (CBF-AML) belongs to favorable risk group in AML. However, approximately 50% of patients with CBF-AML remain incurable and their outcomes are also determined by the various co-occurring mutations. Though, FMS-like tyrosine kinase-3(FLT3) mutation in AML is associated with poor survival, the prevalence and prognostic significance of FLT3 mutations among CBF-AML is unknown. PATIENTS AND METHODS: We performed a systematic review and meta-analysis to assess the prevalence of FLT3 mutations (ITD and TKD) among patients with CBF-AML. The pooled prevalence of FLT3 mutations was estimated for patients with CBF-AML, t(8;21) and Inv(16). Pooled odds ratio was calculated to compare the prevalence of various FLT3 mutations within the 2 subsets of CBF-AML. A random effects model was adopted for analysis when heterogenicity existed (Pheterogenicity< 0.05 or I2 > 50%). Otherwise, a fixed effects model was used. RESULTS: The pooled prevalence of any FLT3 mutations among patients with CBF-AML was available from 18 studies and was 13% (95% CI: 10%-16%; I2 = 79%). Comparison of prevalence of FLT3 mutations between the 2 subgroups of CBF-AML showed that patients with t(8;21) had a higher prevalence of FLT3-ITD [pooled odds ratio(OR): 2.23 (95% CI:1.41-3.53, P < .01)] and lower prevalence of FLT3-TKD [pooled OR: 0.29 (95% CI:0.19-0.44; P < .01)] compared to patients with Inv(16). Additionally, we have discussed the prognostic significance of FLT3 mutations in CBF-AML patients. CONCLUSION: The prevalence of FLT3-TKD mutation was commoner among Inv(16) AML while FLT3-ITD mutation was commoner among t(8;21) AML. Uniform reporting of outcomes is essential to understand the prognostic significance of FLT3 mutations among CBF-AML.

Performance of shear wave elastography: A single centre pilot study of mixed etiology liver disease patients with normal BMI.

PURPOSE: To assess the performance of shear wave ultrasound elastography (SWE) for non-invasive grading of fibrosis in normal BMI patients with varied aetiology chronic liver disease. METHOD: Prospective SWE liver and spleen stiffness (LS, SS respectively) of 124 patients (94 men, mean age 45.4 ± 12.4 years, mean BMI 19.66 ± 1.49) with CLD of mixed aetiology, who underwent liver biopsy, between January 2019-20 was analysed using receiver operating curve (ROC) and classification analysis regression tree (CART) to determine fibrosis cut-off values and nominal logistical regression to quantify fibrosis. RESULTS: Of 124 patients, 50 (40%) had non-alcoholic steatohepatitis (NASH), 31 (25%) chronic hepatitis B (CHB) and 43 (35%) alcoholic liver disease (ALD) on biopsy. Overall mean LS and SS of the study population was 11.81 ± 5.9 and 16.88 ± 10.8 kPa, respectively. LS cut-off value <8 kPa was consistent with F0, 9-14 kPa for F1-F2 and >14.9 kPa for F3-F4 fibrosis on biopsy. On application of CART, LS value < 5.3 kPa was discriminative for NASH, 5.32 to <12.64 kPa for CHB, >12.64 kPa for ALD, SS <15.3 kPa was discriminative for NASH, 15.3-30 kPa for CHB and >30 kPa for ALD in our study population. CONCLUSION: SWE is a viable non-invasive tool for assessment of liver fibrosis grading in a population of mixed aetiology CLD. LS values in conjunction with SS are promising predictors of F2-F3 fibrosis with potential to discriminate select categories like CHB and NASH in such a population.