Optimising Palliative Care for Children with Metastatic Neuroblastoma and the Paediatrician's Role in a Shared Care Model - Proposal from a Regional Cancer Centre in India.

Objectives: The burden of advanced and metastatic cancer is high among children in developing countries, and palliative care (PC) services for children are sparsely available and poorly accessed. To estimate the burden of PC requirements in children with metastatic neuroblastoma (NB), and to evaluate the PC services offered. Materials and Methods: Retrospective analysis of case records of children 1-14 years diagnosed with metastatic NB from 1 January 2008 to 31 December 2017. Results: One hundred and nineteen patients with metastatic NB were included, of which 87 patients received PC consultation. Early PC referral occurred only in 13 patients (14.9%), and pain was the most prominent symptom. Shifting of care from oncology to PC occurred at disease relapse in 58 patients (66.6%) and at end-of-life in 16 patients (18.3%). Nausea/vomiting, constipation and abdominal distension were the most common symptoms during end-of-life. Seventy-one patients (85%) died of disease, median time to death being 9 months from diagnosis and 4 months from relapse. The mean time from initiation of PC to death was 4.2 months. Conclusion: Timely integration of PC and shared care incorporating the oncology team, PC team and local paediatricians can ease out transition in care, ensure a continuum of care and improve the quality of treatment delivered to children with metastatic cancer.

Older age, CNS leukaemic involvement and induction tumour lysis increases the risk of methotrexate (MTX)-induced neurotoxicity in childhood acute lymphoblastic leukaemia/lymphoma: Experience from a tertiary care centre in South India.

Methotrexate (MTX), although an indispensable part of contemporary treatment protocols for childhood acute lymphoblastic leukaemia (ALL)/lymphomas (LBL) in improving outcomes, can lead to serious neurotoxicity with long-term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX-induced neurotoxicity are not yet well defined. The aim of our study was to detect the incidence, risk factors and to assess the overall outcomes of MTX-induced neurotoxicity among large cohort of paediatric ALL/LBL patients treated on a uniform protocol. We conducted retrospective audit of medical records of 622 consecutive children (≤14 years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM-95 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX-induced neurotoxicity were identified using binary logistic regression analysis. Forty-three children were diagnosed with MTX-induced neurotoxicity with an incidence rate of 6.9%. More than two-thirds of them had high-grade MTX-induced neurotoxicity CTCAE v5.0 with a median age of 9 years (range: 9 months to 14 years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase-Ib consolidation (15%). Majority of these patients (84%, 36/43) were challenged again with MTX, with 11% (4/36) developing recurrence. Fifteen per cent had persistent neurological deficits at last follow-up. Univariate analysis found older age (age > 5 years) (p < 0.001), T-cell phenotype (p = 0.040), tumour lysis syndrome during induction (p < 0.001), baseline renal problems prior to MTX exposure (p < 0.001) and CNS leukaemic involvement (p < 0.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (>5 years), tumour lysis during induction and CNS leukaemia retained statistical significance (p < 0.05). Methotrexate-induced neurotoxicity during paediatric acute lymphoblastic leukaemia/lymphoma therapy is a transient phenomenon in majority and re-challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX-induced neurotoxicity during ALL/LBL treatment.

Clinical profile and outcome of children with anaplastic large cell lymphoma treated with short-course chemotherapy - ten years experience from a tertiary care center in a LMIC.

Anaplastic large-cell lymphoma (ALCL) constitutes 10-15% of non-Hodgkin lymphoma in children. With short-course chemotherapy, outcome has improved up-to 90% in developed-countries. There is limited-data on outcome of pediatric ALCL treated with ALCL99 protocol from low-middle income countries. Children ≤14 years, diagnosed with ALCL between 1st January 2007 and 31st December 2016 were analyzed. Details regarding clinical-presentation and treatment were recorded and outcome was analyzed. Fourteen-children were diagnosed. Median-age was 114 months (range 24 - 162 months). Male:female ratio was 3.6:1. Stage-I, II and III disease was seen in three (21.4%), three (21.4%), and eight (57.1%) children, respectively. Low, standard and high-risk disease was seen in two (14.2%), six (42.9%) and six (42.9%), respectively. All children were treated using ALCL99 protocol. Three (21.4%) children had disease-progression/relapse and five (35.7%) died (three from treatment-related mortality, and two from disease). At median follow-up of 54-months, four-year EFS and OS were 64.3% and 64.3%, respectively. Log-rank test demonstrated female gender (p = 0.005), stage-III disease (p < 0.001), visceral-organ involvement (p = 0.035), high-risk disease (p = 0.016) and, serum albumin ≤3.5 g/dL (p = 0.031) associated with significantly worse 4-year EFS. Cox-regression analysis demonstrated female gender associated with poor EFS (p = 0.02) and female gender and visceral-organ involvement associated with poor OS (p = 0.02, p = 0.011, respectively). Good survival could be achieved for children with ALCL using uniform treatment protocol in a resource-limited setting, especially among low and standard-risk children. Female-sex, high-risk disease, stage-III disease, visceral organ involvement and low albumin levels were associated with poor outcome, however these findings need to be corroborated in larger studies.

Loss of protective anti-HBs titers and seroconversion to hepatitis B vaccination in children during chemotherapy for acute lymphoblastic leukemia.

BACKGROUND: This study aimed to evaluate loss of protective anti-hepatitis B (HBs) titers and seroconversion to hepatitis B vaccine (HBV) during chemotherapy in children with acute lymphoblastic leukemia (ALL). METHODS: Anti-HBs titers were done at diagnosis. Patients were divided into two groups. Group I (protective titers >10 mIU/ml) received single double dose of HBV as booster. Titers were repeated at three time points: end of phase 1b, beginning of re-induction, and start of maintenance chemotherapy. Group II (nonprotective titers <10 mIU/L) received hepatitis B immunoglobulin (HBIG), prior to start of chemotherapy, followed by three double doses of HBV as booster. Titers were repeated at two time points: prior to first dose, and 4 weeks after third dose of vaccine. RESULTS: Total 125 patients were included: 88 in group I; 37 in group II. Among group I patients, 98.7%, 90%, and 84% retained protective titers at the three points, respectively. Subgroup analysis showed that those with initial titers greater than 100 mIU/L retained protective titers better than those with titers between 11 and 100 mIU/L (p = .0001). Among group II patients, 62% and 64% attained protective titers at the two points, respectively. CONCLUSIONS: HBV boosters helped maintain protective titers during intensive ALL chemotherapy in immunized children having titers more than 10 mIU/L, and more so if titer was more than 100 mIU/L. Therefore, we propose that cut off for protective anti-HBs titers be changed to greater than or equal to 100 mIU/L. Titers between 11 and 100 mIU/L may require combined active and passive immunization. Around one-third of group II patients who fail to attain protective titers may need frequent doses of HBIG.

High dose methotrexate containing regimen in pediatric non-metastatic extremity osteosarcoma patients: experience from a tertiary cancer center in India.

Methotrexate containing chemotherapy is less commonly used for treatment of osteosarcoma in resource limited settings. We present our experience with the administration of high dose methotrexate (HDMTX) containing chemotherapy over a period of three years. Children between 1 and 14 years of age with newly diagnosed nonmetastatic extremity osteosarcoma, registered in Pediatric Oncology Department of a tertiary care cancer center in South India between 1st January 2016 and 31st December 2018 and receiving MAP chemotherapy were included. Patients in this study received HDMTX at 12 g/m2. Twenty two patients were included. After neoadjuvant chemotherapy, 20 patients underwent surgery (limb salvage surgery in 16, amputation in 4). The median time from initiation of chemotherapy to surgery was 97.5 days. Eighteen of 22 patients (81.8%) completed planned chemotherapy in our cohort, one patient was lost to follow up after progression and three patients required change of chemotherapy due to toxicities. Of a total of 227 cycles of HDMTX infusions in 22 patients, delayed clearance occurred in 22 cycles (9.7%). Major toxicities were myelosuppression (30 episodes in 17 patients), blood stream infections (24 episodes in 15 patients) and mucositis (15 episodes in 10 patients). Hearing loss was documented in 7 patients. There was no treatment related mortality. Chemotherapy was completed in a median duration of 38.5 weeks. Administration of high dose methotrexate containing chemotherapy is feasible in pediatric patients with osteosarcoma, even in resource limited settings, if there are facilities for hydration, determination of methotrexate levels and good supportive care.

Outcomes of pediatric mixed phenotype acute leukemia treated with lymphoid directed therapy: Analysis of an institutional series from India.

There is limited data regarding pediatric mixed phenotype acute leukemia (MPAL) and there is no global consensus on its management yet. In this retrospective study, we analyzed the outcomes of children diagnosed with MPAL at our institute. This study included children ≤ 14 years with MPAL who presented to a tertiary cancer center in India from January 1st 2009 to December 31st 2015. Over a seven-year period, 1390 patients with leukemia presented to our institute of which 22 patients (1.5%) had MPAL. Sixteen patients (72.7%) had B/myeloid leukemia, while 4 (18.1%) and 2 (9%) patients had T/myeloid and B/T leukemia respectively. Twenty-one patients were treated with a modified BFM ALL 95 protocol. 76.1% (n = 16) of patients had a good prednisolone response (GPR) on day 8 and end-of-induction (EOI) marrow was in remission in 90.5% (n = 19). A poor prednisolone response (PPR) on day 8 correlated with an inferior relapse-free survival (25% vs 79.5%, P=.025). The 4-year event-free survival (EFS) and overall survival (OS) for the entire group was 60.8% and 64.9% respectively while the EFS for patients who had a GPR and remission at the EOI (n = 15) was 80% as compared to 16.7% in patients with PPR or induction failure. Lymphoid directed chemotherapy is seen to have good survival outcomes in pediatric MPAL. However, a PPR on day 8 or a positive EOI marrow may be an indication for more aggressive treatment.

Prevalence and Risk Factors for Metabolic Syndrome Among Childhood Acute Lymphoblastic Leukemia Survivors: Experience From South India.

BACKGROUND AND OBJECTIVES: Improved survival of childhood acute lymphoblastic leukemia (ALL) has diverted attention to the long-term consequences of the treatment; metabolic abnormalities being one of the most important issues. METHODS: Children diagnosed with ALL at age 14 years and younger at Regional Cancer Centre in South India who completed treatment and who were on follow-up for >2 years were enrolled in the study between April 1, 2018 and March 31, 2019. They were prospectively evaluated for the presence of metabolic syndrome (MS) and associated risk factors. RESULTS AND DISCUSSION: A total of 277 survivors of pediatric ALL were recruited during the study period. MS was present in 8.3% (n=23) and 6% (n=13) survivors by National Cholesterol Education Programme Adult Treatment Panel III (NCEPATP III) and International Diabetes Federation (IDF) criteria, respectively. The prevalence of overweight and obesity in the survivors was 9% and 13%. The prevalence of increased waist circumference, low high-density lipoprotein cholesterol, elevated triglycerides, elevated fasting glucose, and increased blood pressure were 10.5%, 28.9%, 24.9%, 2.5%, and 9%, respectively. Overweight/obese survivors were at an increased risk for developing MS (odds ratio=17.66; 95% confidence interval=6.2-50.16, P=0.001). Survivors who received cranial radiotherapy were at an elevated risk for having low high-density lipoprotein cholesterol (P=0.001). CONCLUSIONS: In our study, the prevalence of MS was higher in childhood ALL survivors, as compared with the general population. The study points to the need for regular screening of pediatric ALL survivors for early detection of MS, along with lifestyle modification in those with metabolic abnormalities, to curb the growing incidence of coronary artery disease.

Effect of imatinib on growth in children with chronic myeloid leukemia.

Imatinib is a preferred drug for pediatric Chronic Myeloid Leukemia (CML). Long-term use has inhibitory effects on other tyrosine kinase pathways causing off-target complications such as growth impairment. Our aim was to evaluate impact of long-term use on longitudinal growth in children with CML in Kerala. We hypothesized that the impact would be lesser compared to Northern India as Kerala has the lowest rates of underweight and stunting, with a high literacy rate and per capita income. Children ≤14 years of age, diagnosed with CML and received imatinib for at least 1 year were included. Girls >9 years of age and boys >11 years were considered pubertal. Height Z scores were derived using WHO AnthroPlus. Paired t test compared difference of Z scores in prepubertal and postpubertal age groups. Height Z scores were compared with mid-parental height and sibling height Z scores. Thirty-six children were included (M = 21; F = 15). Median duration of imatinib exposure was 84 months. Decrease in longitudinal growth affected children in both prepubertal and postpubertal age groups. Decrease in height Z scores was more in prepubertal age group when imatinib therapy was initiated (p = .0018). Of 10 patients currently above 19 years (of whom 8 were in pubertal age and 2 in prepubertal age at start of imatinib) none are stunted. Patient's height Z scores was lesser compared to sibling height Z scores (p = .027). Children on continuous imatinib showed a significant stunting when treatment was initiated during prepubertal age. There is a catch-up of growth as the final height reached is within normal limits of WHO reference values.

Iron Overload in Children with Leukemia Receiving Multiple Blood Transfusions.

OBJECTIVE: To find out prevalence of iron overload in children with leukemia at the end of treatment, and to identify factors affecting iron overload. METHODS: Children (age-1-14 y) treated for Leukemia of our center who completed treatment between January and August 2016 were included in the study. Serum ferritin and iron were measured at completion of treatment and total blood transfusion received throughout treatment was quantified. Serum ferritin >1000 ng/mL was considered as marker of transfusional iron overload. RESULTS: Out of 66 participants, 55 (83.3%) received red cell transfusions. Average transfused volume was 48 mL/kg, and patients with high-risk leukemia received more transfusions than standard-risk patients. 16 patients (24.2%) demonstrated transfusional iron overload. Total transfused volume and treatment intensity were significant factors associated with iron overload, and total transfused volume of >100 mL/kg (approximately 10 transfusions) was the most important determinant of transfusional iron burden. CONCLUSIONS: One-fourth of pediatric leukemia patients demonstrated iron overload at the end of treatment. These patients need to be monitored and followed-up after treatment to assess need for later chelation therapy.

Risk-based management strategy and outcomes of tumor lysis syndrome in children with leukemia/lymphoma: Analysis from a resource-limited setting.

BACKGROUND: Data from low- and middle-income countries on tumor lysis syndrome (TLS) in the pediatric population are limited. This study aims to analyze the clinical and biochemical characteristics and treatment outcomes of TLS in children with leukemia/lymphomas in a resource-limited setting. PROCEDURE: Children with intermediate risk (IRD) and high risk (HRD) for developing TLS were retrospectively studied at a tertiary cancer center in India. RESULTS: Over a three-year period, 224 children with acute leukemia/lymphoma having IRD (21.8%, n = 49) and HRD (78.1%, n = 175) were identified. TLS developed in 53.6% (n = 120) cases, of which 75% (n = 90) had laboratory TLS alone. Thirteen children had clinical TLS (C-TLS) at presentation while 17 patients progressed to develop C-TLS. TLS developed in 51% (n = 25) and 54.5% (n = 95) of children with IRD and HRD, respectively. Rasburicase was used in 8.5% (n = 19) cases and five children required hemodialysis. Two children (0.8%) expired during the course of TLS management. Multivariate analysis identified the presence of hyperuricemia as the single significant risk factor for developing TLS. When children in whom a 25% change in biochemical values from the baseline that falls within the normal range were excluded, 21.4% (48/224) cases were identified to have clinically relevant TLS (8% in IRD and 25% in HRD). CONCLUSION: With hydration, supportive care and judicious use of rasburicase, it is feasible to manage TLS efficiently in resource-limited settings. A modification of the TLS definition criteria would help to identify clinically relevant TLS.

Low-grade papillary adenocarcinoma of nasopharynx with expression of thyroid transcription factor-1: Case report and review of literature.

Low-grade papillary adenocarcinomas with expression of thyroid transcription factor-1 (TTF-1) are rare tumors of the nasopharynx, with only a few cases reported in the literature. These tumors have an excellent prognosis following complete surgical excision. We report a 13-year-old boy with this rare tumor in the nasopharynx. The patient underwent complete surgical excision of the tumor and was on follow-up without evidence of recurrence.

Mucoepidermoid carcinoma of parotid gland as a subsequent neoplasm in children treated for acute lymphoblastic leukemia.

We report two cases of mucoepidermoid carcinoma occurring as a second neoplasm following treatment for acute lymphoblastic leukemia. Both patients underwent parotidectomy as the primary treatment. One of them received irradiation in addition to surgery. We discuss the risk of developing MEC as a second malignancy, prognosis, and treatment options.

Guillain-Barre syndrome with acute lymphoblastic leukemia.

Guillain-Barre syndrome (GBS) is rarely reported in children with acute lymphoblastic leukemia and may be difficult to differentiate from vincristine induced neuropathy. We report two children with acute lymphoblastic leukemia on induction chemotherapy who developed GBS. The diagnostic issues and potential pathogenic mechanisms underlying GBS in pediatric patients with ALL are discussed.

Acute myeloid leukemia presenting as obstructive jaundice.

Jaundice as a presenting feature of pediatric acute myeloid leukemia is rare. We report two cases of AML who presented with obstructive jaundice, one with a malignant stricture at the common bile duct and other with a granulocytic sarcoma obstructing the bile duct. The prognosis is poor in these patients.