The Outcome of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Experience from a Referral Center in South India.

Although improved survival in children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) has been demonstrated in trials, the outcome appears to be inferior in low- and middle-income countries (LMIC). Methods A file review of children aged ≤ 15 years diagnosed with Ph-ALL from 2010 to 2019 was performed. Minimal residual disease (MRD) was assessed by flow-cytometry. Real-time polymerase chain reaction (qRT-PCR) was used to quantify the BCR::ABL1 transcripts during treatment. Results The mean age of the 20 patients in the study was 91 months. Of 19 patients in whom the BCR::ABL1 transcript was confirmed, 10(50%) had P210, 7(35%) had P190, and two showed dual expression. The mean dose of imatinib that was administered was 294 ± 41 mg/m2/day. qRT-PCR for BCR::ABL1 was < 0.01% in all patients who were in remission or had a late relapse and was ≥ 0.01% in patients who had an early relapse. Two patients underwent HSCT. The 3-year event-free survival (EFS) was 35.0 ± 10.7%. Patients with a good prednisolone response (GPR) and a negative end-of-induction MRD demonstrated a superior EFS to those who lacked either or both (80.0 ± 17.9% vs. 16.7 ± 15.2%, P = 0.034). Conclusion The 3-year EFS of 20 children with Ph-ALL treated with chemotherapy and TKI was < 50%. An unusually high proportion of patients with p210 transcript expression; sub-optimal TKI dosing and lesser intensity of chemotherapy, due to the concern of high treatment-related mortality in LMIC are possible reasons for the poor outcome. Conventional treatment response parameters such as GPR and MRD predict outcomes in Ph-ALL. qRT-PCR for BCR::ABL1 may have a role in predicting early relapse. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01684-9.

What happens to children with acute lymphoblastic leukemia in low- and middle-income countries after relapse? A single-center experience from India.

Managing a child with acute lymphoblastic leukemia (ALL) after relapse is arduous in low- and middle-income countries. A file review of children aged ≤15 years diagnosed with relapsed ALL from 2010 to 2019 was performed. Classification of relapse followed the Berlin-Frankfurt-Münster (BFM) scheme. The majority of patients were treated with a modified ALL-REZ-BFM protocol. Of 764 children treated for ALL in the study period, 163 (21.3%) relapsed. The median age at relapse was 101 months (range: 8-297). The immunophenotype was B-ALL and T-ALL in 140 (86%) and 23 (14%) patients. The site of relapse was extramedullary, combined, and medullary in 46 (28%), 45 (28%), and 72 (44%) patients. Very early, early, and late relapses were observed in 57 (35%), 66 (40%), and 40 (25%) patients. The proportions of extramedullary and medullary sites were greater among patients with early and late relapses, respectively (p = 0.039). Eighty-four (52%) patients were treated with palliative intent. The 2-year event-free survival (EFS) of patients treated with curative intent was 36.3 ± 6.3%. The 2-year EFS for very early/early and late relapses were 18.2 ± 6.2% and 67.6 ± 10.4% (p < 0.001). The 2-year EFS did not differ between extramedullary, combined, and medullary relapses. Treatment-related mortality occurred in 14 (20%) patients. More than 50% of the patients with relapse were treated with the intent of palliation. Extramedullary relapses were more likely to be early and did not have a better outcome than medullary relapses. Children with late relapse had a fair chance of survival with chemotherapy.

Stories to Take the Edge Off Pain During Immunization for Preschoolers: A Randomized Controlled Trial.

IMPORTANCE: Fear and distress during immunization may lead to long-term preprocedural anxiety and nonadherence to immunization schedules. Pictorial stories provide a way of educating the parent and child about the procedure. OBJECTIVE: To determine the efficacy of pictorial stories in reducing pain perception among children and anxiety among mothers during immunization. DESIGN: Three-arm randomized controlled trial Setting: Immunization clinic of a tertiary care hospital in South India. PARTICIPANTS: Fifty children ages 5 to 6 yr, who reported to the hospital for measles, mumps, and rubella and typhoid conjugate virus vaccines. Inclusion criteria were that the child was accompanied by the mother and maternal knowledge of either Tamil or English. Exclusion criteria were child hospitalization in the past year or neonatal intensive care unit admission in the neonatal period. INTERVENTION: Pictorial story regarding immunization before the procedure that contained information related to immunization, coping strategies, and distraction techniques. OUTCOMES AND MEASURES: Pain perception was evaluated using the Sound, Eye, Motor Scale; the Observation Scale of Behavioral Distress; and the Wong-Baker FACES Pain Rating Scale (FACES). Maternal anxiety was measured using the General Anxiety-Visual Analog Scale. RESULTS: Of 50 children recruited, 17 were in the control group, 15 were in the placebo group, and 18 were in the intervention group. Children in the intervention group reported lower pain scores on the FACES (p = .04) compared with the placebo and control groups. CONCLUSIONS AND RELEVANCE: A pictorial story is a simple and cost-effective intervention to reduce pain perception among children. What This Article Adds: Pictorial stories may be a feasible, simple, and cost-effective intervention to reduce pain perception during immunization.

The Nutritional Trajectory of Children with Acute Lymphoblastic Leukemia: A 10-Year Follow up Study from a Referral Center in South India.

OBJECTIVE: Survivors of childhood acute lymphoblastic leukemia (ALL) are vulnerable to late adverse events such as obesity and an associated metabolic syndrome. METHODS: Children treated for ALL from 2002 to 2012 were included. BMI was calculated at diagnosis, end of treatment, and 5, 8, and 10-years from diagnosis. BMI-centiles were used to categorize the patients: underweight (<5th-percentile), normal (5th-85th percentile), overweight (85th-95th percentile), and obese (≥95th centile). RESULTS: The study included 179 children with ALL (median age: 59-months). The proportions of patients who were underweight, normal, overweight/obese, were 37%, 56% and 7%, respectively, at diagnosis; and 15%, 51% and 34%, respectively, at 5-years from diagnosis. The median (IQR) BMI Z-score at diagnosis was -1.12(-2.40, -0.26). The median (IQR) BMI z-score of the cohort was higher after 5 [0.22(-0.83,1.24), P < 0.001] and 10-years of diagnosis [0.30(-0.69,0.99), P < 0.001], respectively. The proportion of overweight/obese individuals was higher after 5 (34%, P < 0.001) and 10 (26%, P = 0.001) years. There was a significant correlation between the baseline BMI Z-score and that observed after 5-years (ρ = 0.49, P < 0.001), and 10-years (ρ = 0.55, P < 0.001). CONCLUSION: At 10-years of follow-up, >25% of children with ALL were overweight/obese. The BMI Z-score at the time of diagnosis continued to correlate with the Z-score after 10-years.

Long-Term Outcomes and Prognostic Factors Affecting Survival after Pulmonary Metastasectomy in Solid Tumors of Childhood: A Single Center Experience.

Introduction: This study assessed the long-term survival and the prognostic variables affecting survival following pulmonary metastasectomy (PM) secondary to childhood solid tumors. Materials and Methods: A retrospective analysis was done on 22 children who underwent PM for solid tumors between January 2007 and February 2020. The overall survival (OS) and event-free survival (EFS) at the end of the study period were noted. Tumor histology, completeness of resection, disease-free interval, laterality, location, number, and size of lung nodules were assessed for their significance in contributing to survival. Results: High-grade osteosarcoma (54.5%), followed by Wilms' tumor (18.2%), was the most common histological types. Unilateral nodules (59.1%) situated in a peripheral, sub-pleural location (91%) were the most common presentation. Pleural extension was noted in 12 (54.5%) patients. Synchronous pulmonary metastases were noted in 12 (54.5%) patients. Two developed metastases while undergoing chemotherapy and eight after the completion of therapy. The EFS and OS were both 31.8% at a median follow-up of 15.5 months (range 3-129 months). The median time required for an event to occur was 4 months (95% confidence interval [CI]: 1.4, 6.6 months) and median post-PM survival interval was 17 months (95% CI: 6.6, 27.4 months). Significant association was noted between preoperative tumor response to chemotherapy (P = 0.002) and survival. Conclusion: PM can improve survival in a select group of children with metastatic solid tumors. Favorable tumor response to chemotherapy was found to be a significant prognostic factors influencing survival.

Spectrum of COVID-19 Disease in Children: A Retrospective Analysis Comparing Wave 1 and Wave 2 from a Tertiary Hospital in South India.

OBJECTIVE: To describe COVID-19 in children and the differences between the two waves. METHODS: The electronic medical records of children younger than 16 y of age with laboratory-confirmed COVID-19 infection between June 1st 2020 and May 31st 2021 at Christian Medical College, Vellore were retrospectively reviewed. Demographic, clinical, and laboratory data were collected on a predesigned case record form and analyzed. RESULTS: A total of 988 children were diagnosed with confirmed COVID-19 during the study period. Of these, there were 585 children diagnosed during the 1st wave (June 2020-Feb 2021) and 403 children during the 2nd wave (March 2021-May 2021). It was found that loose stools and rash were significantly more frequent during the 1st wave and fever, cough, coryza, heart rate and temperature were significantly more during the 2nd wave. There was no significant difference between the two groups in terms of requirement of oxygen therapy, need for ICU admission, duration of ICU stay or hospital stay, or severity of illness. Mortality was significantly higher during the 2nd wave (0.3% vs. 2%). CONCLUSION: The COVID-19 pandemic among children during the 1st and 2nd waves were similar in severity, though there was a higher mortality during the 2nd wave.

Postchemotherapy tumor volume as a prognostic indicator in Wilms tumor: A single-center experience from South India.

BACKGROUND: Optimal risk stratification is the key to minimizing relapse and toxicity in children with Wilms tumor (WT). The study evaluated poor tumor volume response to chemotherapy as a risk factor that predicts relapse. PROCEDURE: Children with WT who were treated between 2005 and 2020 at the center were analyzed. Tumor volumes at the time of diagnosis and after preoperative chemotherapy were calculated from cross-sectional imaging. The International Society of Paediatric Oncology (SIOP)-WT-2001 protocol was used for treatment. The area under a receiver operating characteristic curve was estimated to ascertain the ability of tumor volume to predict relapse. RESULTS: Ninety-five patients with a median age of 40 months were included. A postchemotherapy tumor volume cutoff of 270 ml was ascertained to have the best predictive value for relapse. Patients with a tumor volume of <270 ml following preoperative chemotherapy had a better 3-year event-free survival (EFS) than those with a tumor volume of ≥270 ml (89.8% ± 4.0% vs. 57.4% ± 12.5%, p = .001). The data demonstrated that a tumor volume of ≥270 ml after chemotherapy was associated with an increased risk of relapse (hazard ratio [HR]: 5.3, p = .006). The EFS in patients with an epithelial or stromal type of histopathology was not affected by the tumor volume response (p = .437). Conversely, patients with other types of intermediate-risk histopathology who had a poor tumor volume response had an inferior survival (3-year EFS 51.4% ± 18.7%, p = .001). CONCLUSION: A postchemotherapy tumor volume cutoff of ≥270 ml emerged as a strong predictor of relapse in a low- and middle-income country (LMIC) center study of WT treated with the SIOP protocol.

A pragmatic diagnostic approach to primary intracranial germ cell tumors and their treatment outcomes.

Background: Primary intracranial germ cell tumors (ICGCT) are often diagnosed with tumor markers and imaging, which may avoid the need for a biopsy. An intracranial germ cell tumor with mild elevation of markers is seldom stratified as a distinct entity. Methods: Fifty-nine patients were stratified into three groups: pure germinoma (PG), secreting germinoma (SG) and non-germinomatous germ cell tumors (NGGCTs). Results: At 5 years, progression-free survival and overall survival of the three groups (PG vs SG vs NGGCT) were 91% versus 81% versus 59%, and 100% versus 82% versus 68%, respectively. There was no statistically significant difference in outcome among histologically and clinically diagnosed germinomas. Conclusion: A criterion for clinical diagnosis when a biopsy is not feasible is elucidated, and comparable outcomes were demonstrated with histologically diagnosed germinomas.

Lay abstract Intracranial germ cell tumors (ICGCTs) are rare brain tumors, which often require markers in blood or cerebrospinal fluid, imaging and a tissue biopsy to establish a diagnosis. However, when tissue sampling is not possible, tumor markers can sometimes be used to diagnose ICGCTs. The authors propose guidelines for a diagnosis and a novel subtype of ICGCT called secreting germinoma, which is also described. Fifty-nine patients were separated into three groups: pure germinoma (PG), secreting germinoma (SG) and non-germinomatous germ cell tumors (NGGCTs). At 5 years, progression-free survival and overall survival of the three groups (PG vs SG vs NGGCT) were 91% versus 81% versus 59%, and 100% versus 82% versus 68%, respectively. There was no significant difference in outcome among tumors diagnosed with markers in blood or cerebrospinal fluid and those diagnosed with a biopsy. The proposed guidelines for diagnosis need to be evaluated in future studies. SGs may not warrant aggressive treatment protocols as used in NGGCT, and their outcome as a distinct group needs to be explored in future studies.

Complete Peripheral Blast Clearance is Superior to the Conventional Cut-Off of 1000/µL in Predicting Relapse in Pediatric Pre-B Acute Lymphoblastic Leukemia.

Risk-stratification has contributed to a dramatic improvement in survival in pediatric acute lymphoblastic leukemia (ALL). This study evaluated the utility of prephase response and day 15 bone marrow when a minimal residual disease (MRD) assessment was available. A file review of children aged ≤ 15 years diagnosed with precursor-B ALL from 2014 to 2019 was performed. The protocol used for risk stratification and treatment was based on a UKALL-2003 backbone. All patients received one week of prephase therapy comprised of intravenous dexamethasone in the first 48 h followed by oral prednisolone. The median age of the 255 patients in the study was 5 years. Following the prephase, the peripheral blood absolute blast count was 0 and ≥ 1000/µL blasts in 141 (56%) and 29 (11%), respectively. Ten of 199 (5%) patients with an evaluable day 15 bone marrow had M3 status. At the end of induction, 30 (12%), 127 (50%) and 98 (38%) patients belonged to the standard-risk, intermediate-risk and high-risk (HR) groups, respectively. An M3 day15 bone marrow was the sole reason for escalation in three (3%) of the patients in the HR group. A lack of complete clearance of peripheral blood blasts post-prephase [HR: 2.45 (1.04-5.75), p = 0.040] and a positive MRD [HR: 3.00 (1.28-7.02), p = 0.011] independently predicted risk of relapse. Complete blast clearance is superior to the traditional cut-off of 1000/µL in predicting relapse. The role of a day 15 bone marrow morphology is diminished when an end of induction MRD is available.

A single assessment of methotrexate levels at 42 hours permits safe administration and early discharge in children with lymphoblastic lymphoma and leukemia receiving high-dose methotrexate.

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.

Clinical outcomes of children with Wilms tumor treated on a SIOP WT 2001 protocol in a tertiary care hospital in south India.

INTRODUCTION: Wilms tumor is the most common pediatric renal malignancy. While developed countries have had excellent survival, it remains poorer by comparison in developing countries. The aim was to analyze the clinical outcome of children with Wilms tumor managed in a developing country from 2004 to 2014 by the SIOP WT 2001 protocol. METHODS: Fifty-nine children with Wilms tumor managed by a SIOP WT 2001 regimen from 2004 to 2014 were analyzed. RESULTS: The median age at presentation was 36 months, and 59% were boys. The average size of the tumor at presentation was 523 mL. Inferior vena cava thrombus was present in 11, distant metastases in 18, and bilateral tumors in six. Preoperative chemotherapy was given to all children after a diagnostic core needle biopsy. Preoperative chemotherapy reduced the tumor size to a mean of 208 mL and resolved venacaval thrombus in eight. Fifty-five children underwent definitive surgery while two children died during preoperative chemotherapy and two remained inoperable. All surviving children received adjuvant chemotherapy with 17 receiving radiotherapy as well. The overall survival (OS) was 80% and the event-free survival (EFS) was 73% after a mean follow up of 42 months after completion of therapy. DISCUSSION: The tumor volumes at presentation and the incidence of venous tumor thrombosis in our cohort were much higher than those reported from developed countries. The incidence of metastatic disease at diagnosis (30.5%) was significantly higher than the 10-12% reported in Western data, but similar to that reported from various developing countries (14.1-31%). The OS in our cohort was 80% and the EFS was 73% with there being no events after 28 months. Although the survival rate for localized disease is similar to that in developed countries, the OS for metastatic disease was significantly less (50% vs. 75%). We also found that using an upfront posterior flank core biopsy was safe and beneficial for differentiating Wilms tumor from other pediatric renal tumors that are less chemosensitive. CONCLUSION: In a resource-restricted environment such as ours, the SIOP WT 2001 protocol has been found to show excellent results.

Lymphomatoid granulomatosis: A case series from South India.

CONTEXT: Lymphomatoid granulomatosis (LYG) is a rare B-lymphoproliferative disorder characterised by an angiocentric and angiodestructive pattern along with Epstein - Barr virus (EBV) association. It is one of the diagnostic challenges in lymphoma pathology. Deregulation of EBV immune surveillance is one of the narrated hypotheses in the literature. Extrapulmonary manifestations are rare with LYG. Morphological grading is done based on the number of EBV-positive B cells, which is useful to strategize treatment protocol. AIMS: We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings. SETTINGS AND DESIGN: This is the first case series from India in published literature. SUBJECTS AND METHODS: We reviewed cases of LYG diagnosed at our center for the past 11 years (2006-2016). A total of nine cases were included in this study. Histomorphology was studied in conjunction with immunohistochemistry and clinical details. Cases without classical morphology and negative for EBV immunostain were excluded from the study. RESULTS: There were nine patients in our study (7 males and 2 female; M:F ratio 3.5:1). The age of these patients ranged from 4 years to 57 years (mean age: 30 years). The most common site involved was the lung (4, 44%), followed by the skin (2, 22%), central nervous system (2, 22%) and lymph node (1, 11%). One patient had primary immunodeficiency. Another patient had undergone renal transplant 11 years before the development of the lesion. Angiocentricity and angioinvasion were appreciated in all nine cases (9/9) with necrosis in four cases (44%) and ill-defined histiocytic aggregates in three cases (33%). The histological features were as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%). CONCLUSION: LYG is a rare EBV driven angiodestructive disease with predominantly lung involvement as well as isolated extrapulmonary sites as seen in our study. It is often progressive and ultimately fatal in the absence of appropriate treatment. Grading of the lesion helps to initiate the appropriate treatment of choice.

Undifferentiated thymic carcinoma with intracranial metastasis in a two-year-old.

Thymic carcinoma with central nervous system involvement is very rare in children. A 27-month-old girl presented with a unilateral squint, vomiting, and behavioral changes. Imaging studies showed a silent anterior mediastinal mass and a large metastatic mass at the base of the skull. Biopsy of the anterior mediastinal mass confirmed an undifferentiated tumor consistent with thymic carcinoma. The child died within 3 months of the onset of symptoms, due to progression of the disease. These lethal tumors of unknown histogeneses and etiology are aggressive in nature, resistant to therapy, and have a rapidly fatal course.

Hepatotropic viruses as etiological agents of acute liver failure and related-outcomes among children in India: a retrospective hospital-based study.

BACKGROUND: Acute liver failure (ALF) is marked by a sudden loss of hepatic function and is associated with a high mortality rate in children. The etiology of ALF is shown to vary geographically. This study assessed the frequency of hepatotropic viruses as etiological agents of ALF in Indian children. METHODS: This retrospective study enrolled children aged 0-18 years with confirmed ALF admitted to Christian Medical College, Vellore and King Edward Memorial Hospital and Research Center, Pune between January 2003 and December 2005. The frequency of hepatotropic viruses as etiological agents in children with ALF aged ≤18 years was calculated with 95% confidence interval (CI). Descriptive analyses of demographic characteristics, clinical signs and symptoms of ALF, choice of treatment and outcomes were performed. RESULTS: Of 76 children enrolled, 54 were included in the per-protocol analyses. Mean age of children with ALF was 5.43 years (standard deviation = 3.62); 51.9% (28/54) were female. The percentage of children positive for anti-hepatitis A virus (HAV) IgM and hepatitis B surface antigen was 65.9% (27/41; 95% CI 49.4-79.9) and 15.9% (7/44; 95% CI 6.6-30.1), respectively. The final cause of ALF was HAV (36.3%) followed by hepatitis B virus (HBV; 8.8%). Before and during admission, encephalopathy was observed in 77.8% (42/54) and 63.0% (34/54) of children, respectively. A high number of children (46/54; 85.2%) required intensive care and ALF was fatal in 24.1% (13/54). The proportion of deaths due to HAV and HBV was 18.5% (5/27) and 57.1% (4/7), respectively. CONCLUSIONS: HAV and HBV were the most common etiological agents of ALF in Indian children. Primary prevention by vaccination against HAV and HBV in young children may be useful in the prevention of ALF due to viral hepatitis in India.

Caffey disease with raised immunoglobulin levels and thrombocytosis.

Infantile cortical hyperostosis (Caffey disease) is characterized by radiological evidence of cortical hyperostosis, soft tissue swellings, fever and irritability. We report a case of Caffey disease highlighting its presentation with thrombocytosis and high serum immunoglobulin level to alert physicians to use steroids cautiously in view of the known thrombocythemic effect of the drug. Raised Immunoglobulin also suggests that this syndrome could be infectious in origin.