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.

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.

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.

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.

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.

Differentiated thyroid carcinoma in children: A retrospective analysis of 125 pediatric cases from a single institution in India.

BACKGROUND: Thyroid carcinoma (TC) is extremely rare in children. We assessed the clinicopathological features, outcomes, recurrence pattern, and associated risk factors of differentiated thyroid carcinoma (DTC). METHODS: Children aged ≤14 years, pathologically diagnosed as DTC at a tertiary cancer institute between January 1998 and December 2015 were retrospectively analyzed. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS: During 18 years, 125 children with DTC were treated with a male:female ratio of 1:2.3. The median age was 12 years (2-14 years). Anterior neck swelling was the commonest presentation (72.8%). Histopathology revealed papillary thyroid carcinoma (PTC) in 123 children (98.4%). Extrathyroidal extension was seen in 32 children (25.6%). Sixty-eight children (54.4%) had nodal metastases and seven had distant metastasis. Relapse developed in 12 children. All were salvaged with subsequent surgery and radioiodine therapy. Eight children had persistent disease and one had a second malignant neoplasm. The median follow-up period was 9 years 1 month (1-20 years). Five-year recurrence-free survival (RFS) was 94.8% and 5-year overall survival was 100%. Larger tumors (p-value = .001), extrathyroidal extension (p-value = .001), and nodal metastasis (p-value = .022) were significant predictors for RFS in univariate analysis. CONCLUSIONS: Pediatric DTC showed aggressive behavior characterized by a high rate of extrathyroidal extension and nodal and pulmonary metastasis. Persistent disease should be distinguished from recurrent disease as DTCs with metastatic disease remain stable for long time and usually respond well to radioiodine therapy. Our study reaffirmed favorable prognosis despite aggressive presentation and even after relapse.

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.

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.

Primary Mediastinal Large B-Cell Lymphoma in a Child Presenting With Superior Mediastinal Syndrome and Chylous Pleural and Pericardial Effusion.

Primary mediastinal (thymic) large B-cell lymphoma is an aggressive B-cell lymphoma. It comprises <3% of all pediatric non-Hodgkin lymphomas (NHLs). Primary mediastinal (thymic) large B-cell lymphoma usually presents with serous pleural effusion, but presentation with chylous pleural and pericardial effusions is rare. We present a child who presented with features of a superior mediastinal syndrome. Biopsy of the mediastinal mass confirmed the diagnosis of large B-cell lymphoma. In view of nonimprovement of respiratory distress with chemotherapy and persistence of features of superior mediastinal syndrome, the child was evaluated and found to have massive pleural and pericardial effusion on imaging. Therapeutic thoracentesis and pericardiocentesis revealed chylous nature of the fluid.

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.

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.

Wolman Disease: A Mimic of Infant Leukemia.

BACKGROUND: Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management. OBSERVATION: An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c.1180_1184del" in the last exon (exon 10) of the lipase A (LIPA) gene. CONCLUSIONS: Hepatosplenomegaly and pallor resulting from nutritional deficiency or bone marrow involvement in Wolman disease can mimic infant leukemia.

Treatment of tumor lysis syndrome in children with leukemia/lymphoma in resource-limited settings-Efficacy of a fixed low-dose rasburicase.

Rasburicase is a novel drug used during the management of tumor lysis syndrome. In countries with limited resources, it is frequently given at a lower dose and only for the treatment of established tumor lysis syndrome and not as prophylaxis. A retrospective study was conducted in the department of pediatric oncology at a tertiary referral oncology center in south India to analyze the use of rasburicase over the past 3 years. Data of all the 18 children (< 14 years of age) who were given rasburicase for the management of hyperuricemia were collected and analyzed. With a mean rasburicase dose of 0.085 mg/kg, hyperuricemia was managed efficiently without the need for a hemodialysis in 16 children (88.8 %). The fall in mean serum uric acid levels after the administration of a single dose of rasburicase at 4, 24, and 48 hours was 31.18 %, 64.8 %, and 74.5 %, respectively. Rasburicase efficiently decreases the uric acid levels to a normal level within a short period. In resource-limited settings, rasburicase at a lower dose is a promising option for managing hyperuricemia in the event of a tumor lysis syndrome.

Wilms Tumor in a Child With Bilateral Polycystic Kidneys and PHACE Syndrome: Successful Treatment Outcome Using Partial Nephrectomy and Chemotherapy.

Congenital anomalies may be associated with Wilms tumor either as isolated anomalies or as part of a congenital malformation syndrome. Nephroblastoma occurring in association with polycystic kidneys is very rare. The optimal surgical management of nephroblastoma in the setting of polycystic kidneys is not defined because of the rarity of this presentation. PHACE syndrome includes posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of aorta, and eye abnormalities. We report a 17-month-old baby with bilateral polycystic kidneys and PHACE syndrome who developed nephroblastoma in the right polycystic kidney which was treated successfully with nephron-sparing partial nephrectomy and chemotherapy.

Double Philadelphia chromosome: a rare and sole abnormality in pediatric B-acute lymphoblastic leukemia.

The present study describes a 7-year-old male child who had attended the Pediatric Oncology Clinic of the Regional Cancer Centre, Thiruvananthapuram, Kerala, India, and was pathologically confirmed to have B-Acute Lymphoblastic Leukemia (B-ALL). Conventional cytogenetics analysis at diagnosis showed the presence of a double Philadelphia chromosome and the karyotype of the case was 47, XY, t(9;22)(q34;q11.2), + der(22)t(9;22). FISH, done as a molecular confirmation of the translocation, t(9;22)(q34;q11.2), and this case showed an additional fusion signal that confirms the presence of double Ph. As far as we are aware, this represents the initial and only  occurrence of an abnormality report regarding the double Philadelphia chromosome in pediatric B-ALL within India. The double Philadelphia chromosome in B-ALL has a very poor prognosis despite aggressive treatment with chemotherapy. This study reveals the importance of conventional and molecular cytogenetic analysis in risk stratification and prognosis prediction of pediatric B-ALL. The risk stratification based on the conventional and molecular cytogenetic analysis may be taken into consideration for deciding the treatment strategy for each patient.

Successful Treatment of Late Isolated Bone Metastasis in a Patient with Bilateral Retinoblastoma Using an Unconventional Method.

Though survival in bilateral retinoblastoma (RB) has improved due to advancement in diagnostics and treatment modalities, children require long-term follow-ups for recurrence and second malignancies. We report a case of bilateral RB in a 7-month-old baby who was treated with chemotherapy, transpupillary thermotherapy, and periocular carboplatin for both eyes following which there was complete regression of tumour. Six and a half years after treatment, the child presented with metastatic recurrence of tumour in the left ulna. He was treated successfully with chemotherapy, extracorporeal radiation and reimplantation therapy. A less aggressive treatment approach for isolated bone relapse may be considered in selected cases.

Higher incidence of syndrome of inappropriate antidiuretic hormone secretion during induction chemotherapy of acute lymphoblastic leukemia in indian children.

BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-known adverse effect of vincristine (VCR). Literature suggests that Asians are predisposed to develop SIADH following VCR administration. However, data regarding the occurrence of SIADH in children with malignancy are limited. This study aims to analyze the incidence, clinical picture, risk factors, management, and outcome of SIADH during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: A prospective study was conducted among the 166 newly diagnosed pediatric ALL patients who were treated at a tertiary cancer center in India between January 2015 and December 2015. Patients who developed hyponatremia during induction chemotherapy were further investigated for SIADH. RESULTS: The incidence of SIADH was 10.8% (n = 18) with a mean sodium level of 125 mEq/L (114-129 mEq/L). In the preceding 2 weeks, 72% of episodes were associated with the administration of two (n = 6) or three (n = 7) doses of VCR. One child presented with seizures. All the patients were managed with fluid restriction and only two patients required sodium correction with 3% saline. Girls older than 10 years of age showed a marginally significant correlation to develop SIADH (P-value = 0.059). CONCLUSION: We report a higher incidence of SIADH (10.8%) in Indian children, compared to that described in the literature, during induction chemotherapy for ALL. Regular monitoring of sodium levels during this period of chemotherapy is hence essential for the timely diagnosis and appropriate management of SIADH, which in turn will avert complications, including neurological symptoms secondary to SIADH.

Pediatric Primary Ovarian Angiosarcoma: From Rarity to a Realization.

BACKGROUND: Angiosarcoma is an uncommon high-grade sarcoma in children. Visceral angiosarcoma involving the ovary is extremely rare. Because of the lack of recurrent cytogenetic alterations, histopathological identification of this uncommon tumor in unusual sites like the ovary demands pathologic expertise. Complete surgical resection and radiotherapy are the chief treatment modalities determining survival, with chemotherapy contributing a minor role. CASE: We discuss a 11-year-old prepubertal girl who presented with primary angiosarcoma of the ovary. SUMMARY AND CONCLUSION: Early realization of such exceptional presentations of these tumors is needed to achieve the best treatment outcome.