Predictors of neurocognition outcomes in children and young people with primary brain tumor presenting to tertiary care hospitals of Karachi, Pakistan: a prospective cohort study.

INTRODUCTION: Primary brain tumors are a common cause of morbidity and mortality in children and young people (CYP) globally. Impaired neurocognitive function is a potential severe consequence in primary brain tumor (PBT) survivors. There are no in-depth studies from low- and middle-income countries (LMICs) to inform management and follow-up. The research questions of this study were as follows: Are the sociodemographic factors (lower age of CYP, female gender, low socioeconomic status, low parental education), disease-related factors (high grade of tumor, presence of seizures, presence of hydrocephalous), and treatment-related factors (adjuvant therapy, no surgical intervention, post-treatment seizures, placement of shunts) associated with decline in neurcognition outcomes 12 months post-treatment in CYP with PBTs? METHODS: A prospective cohort study was conducted from November 2020 to July 2023 at the Aga Khan University Hospital and Jinnah Postgraduate Medical Centre, tertiary care hospitals in Karachi, Pakistan. All CYP aged 5 to 21 years with a newly diagnosed PBTs were eligible. The neurocognition assessment was undertaken by a psychologist at two points, i.e., pre-treatment and at 12 months post-treatment using validated tools. The verbal intelligence was assessed by Slosson Intelligence tool, revised 3rd edition (SIT-R3), perceptual reasoning by Raven's Progressive Matrices (RPM), and the Processing Speed Index by Wechsler Intelligence Scale (WISC V) and Wechsler Adult Intelligence Scale (WAIS-IV). The data were analyzed by STATA version 12 software. Generalized estimating equation (GEE) was used to determine the factors associated with the mean change in 12 months post-treatment verbal and non-verbal neurocognition scores. Unadjusted and adjusted beta coefficients with their 95% confidence intervals were reported. RESULTS: A total of 48 CYPs with PBTs were enrolled, 23 (48%) of them were lost to follow-up and 10 (21%) died. The remaining 25 (52%) were reassessed 12 months after treatment. On multivariable analysis, a significant decline in verbal intelligence scores at 12 months was predicted by post-treatment seizures beta = - 20.8 (95% CI, - 38.2, - 3.4), mothers having no formal educational status and lower household monthly income. Similarly, a significant decline in perceptual reasoning scores was also predicted by post-treatment seizures beta = - 10.7 (95% CI, - 20.6, - 0.8), mothers having no formal education and having lower household monthly income. Worsening of processing speed scores at 12 months post-treatment were predicted by tumor histology, post-treatment seizures beta = - 33.9 (95% CI, - 47.7, - 20.0), lower educational status of the mother, and having lower household monthly. However, an improvement was seen in processing speed scores after surgical tumor resection. CONCLUSION: In this novel study, the post-treatment mean change in verbal and non-verbal neurocognition scores was associated with sociodemographic, tumor, and treatment factors. These findings may have potential implications for targeted early psychological screening of higher risk CYP with PBTs. Identification of these predictors may serve as a foundation for developing more cost-effective treatment thereby alleviating the burden of neurocognitive morbidity. However to establish generalizability, future research should prioritize larger-scale, multicountry studies. (Trial registration: ClinicalTrials.gov Identifier: NCT05709522).

Socio-demographic and antenatal risk factors of brain tumor in children and young people: A matched case-control study from Karachi, Pakistan.

Background: Brain tumors are a common cause of morbidity, disability, cognitive deterioration and mortality in children, even after treatment. Little is know about the specific causes. The study aimed to assess potential socio-demographic and antenatal factors in primary brain tumor (PBTs) in children and young people (CYP) in Karachi, Pakistan. Designs and methods: A single center hospital based matched case control study in Karachi, Pakistan. Cases were defined as CYP aged between 5 and 21 years with any histological type and grade of primary brain tumor of any histology, stage or grade. Data were collected from parents of 244 patients at the selected center between 2017 and 2021 via telephonic interview. Controls were 5-21 years old CYP admitted with non-oncological diagnoses matched on age and sex. Matched Odds Ratios for predictors of brain tumor in children were derived. Those of statistical significance were included in a multivariable logistic regression model. Results: In the adjusted model, lower paternal education (matched adjusted odds ratio (maOR) 2.46; 95% CI 1.09-5.55), higher household monthly income (maOR 3.4; 95% CI 1.1-10.2), antenatal paternal use of addictive substances (maOR 19.5; 95% CI 2.1-179.8), and antenatal maternal use of analgesics during pregnancy (maOR 3.0; 95% CI 1.2-7.9) were all independently predictive of brain tumors. Conclusion: This matched case-control study found novel associations between maternal use of analgesics, paternal use of addictive substances, higher household income, and lower paternal education and Primary Brain Tumors in Children and Young People. Longitudinal multicenter studies will be required to test these associations prospectively.

Case Study of Pediatric Cerebral Sinus Venous Thrombosis Center of a Low Middle-Income Country.

Pediatric cerebral venous sinus thrombosis (CVST) is rare but a potentially fatal disease requiring its understanding in local setting. In this study, we observed the clinical course, management, and outcome of pediatric patients with sinus thrombosis in a tertiary care center at Pakistan. Patients between age 0 to 18 years of both genders diagnosed with sinus thrombosis during 2011 to 2020 were included. Data was collected through in-house computerized system and SPSS version 19 was used for analysis. Of 143492 pediatric admissions, 32 (21 males and 11 females) patients with a median (IQR) age of 4.5 years (0-16) had CVST. This is equivalent to 18.5 CVST events per million pediatric admissions. Adolescents were mostly affected, and the overall mortality was 7%. Primary underlying disorders were infections (59%), hematological neoplasms (12.5%), thrombotic thrombocytopenic purpura (3%) and antiphospholipid syndrome (3%). Activated protein C resistance (44%) was the most common inherited thrombophilia. Twenty-one (66%) patients were anemic with a mean (±SD) hemoglobin of 9.0 g/dL (±2.3). Regression analysis showed a positive association of anemia with multiple sinus involvement (P-value 0.009) but not with duration of symptoms (P-value 0.344), hospital stay (P-value 0.466), age (P-value 0.863) or gender (P-value 0.542) of the patients. SARS-COV2 was negative in patients during 2020. Adolescents were primarily affected by sinus thrombosis and infections was the predominant risk factor for all age groups, with a low all-cause mortality. A high index of clinical suspicion is required for prompt diagnosis and intervention.

Risk Assessment and Outcome of Venous Thromboembolism in Pediatric Population in an Academic Care Center of a Low-Middle Income Country.

Venous thromboembolism (VTE) is a recognized complication of hospital stay in young patients in many developed countries, but such an information is largely unavailable from a low middle-income country (LMIC). This study aimed at identifying the frequency, risk factors, treatment options and outcome of deep venous thrombosis/pulmonary embolism (DVT/PE) in pediatric population in a tertiary care center from a LMIC. International classification of disease, ninth revision (ICD-9) was used to identify VTE in patients aged 0-18 years during January 2011 to September 2019. In-house computerized system was used to collect data for demographics, clinical and laboratory details. SPSS version 19 was used to analyzed data. The study was approved by Institutional ethical review committee (3872-Pat-ERC-15). During the study period, 134617 pediatric patients were hospitalized, DVT/PE was observed in 77 unique patients (47 males and 30 females) with a median (IQR) age of 14 (5-16) years equivalent to 5.9 VTE events /10,000 hospital admissions. Malignancy, community acquired infections and autoimmune diseases were the predominant risk factors (75%) in adolescent age-group while surgery for congenital heart anomalies was the primary reason (71%) in infants. Overall, lower extremity thrombosis was the most frequent (51%) followed by pulmonary embolism (25%). and upper extremity thrombosis (24%). Enoxaparin and unfractionated heparin were mainly used to treat VTE and all-cause mortality was 13% in the cohort studied. We observed substantial VTE events in pediatric patients during their hospital stay in a tertiary care center of a low-middle income country.

Establishment of a thalassaemia major quality improvement collaborative in Pakistan.

OBJECTIVES: The aim of this study was to establish multidisciplinary care for patients with transfusion-dependent thalassaemia (TDT) by creating a TDT quality improvement (QI) collaborative in a resource-constrained setting. This study presents our initial experience of creating this collaborative, the baseline characteristics of the participants, the proposed QI interventions and the outcome metrics of the collaborative. DESIGN AND SETTING: TDT QI collaborative is a database comprising patients with TDT from four centres in Karachi, Pakistan. Study variables included symptoms of cardiac or endocrine dysfunction, physical examination including anthropometry and Tanner staging, chelation therapy, results of echocardiography, T2* cardiac MRI (CMR) and serum ferritin. The main outcome of this collaborative was improvement in TDT-related morbidity and mortality. Interventions addressing the key drivers of outcome were designed and implemented. RESULTS: At the time of reporting, the total number of patients in this database was 295. Most patients reported cardiac symptoms corresponding to New York Heart Association class 2. Approximately half (52%, n=153) of the patients demonstrated severe myocardial iron overload (T2* <10 ms). Majority of the patients (58%, n=175) were not on adequate chelation therapy. There was no difference in echocardiographic measures of systolic and diastolic left ventricle among the different spectrums of iron overloaded myocardium. CONCLUSION: Using T2* CMR and endocrine testing, we have identified significant burden of iron siderosis in our patients with TDT. Lack of adequate iron load assessment and standardised management was observed. Interventions designed to target these key drivers of outcome are the unique part of this QI-based TDT registry.

Clinical Features and Treatment Outcomes of Children With Anaplastic Large Cell Lymphoma in Pakistan: A Multicenter Study.

BACKGROUND: Different approaches have been adopted in the treatment of anaplastic large cell lymphoma (ALCL); there is a lack of consensus with regard to standard treatment. Because of paucity of data from low and middle-income countries, we reviewed the clinical features and treatment outcomes of children with ALCL. METHODS: All ALCL patients under 16 years of age diagnosed from 2005 to 2015 at Aga Khan University Hospital and The Indus Hospital were identified. Clinical features and treatment outcomes were analyzed. RESULTS: Thirty-two (n=32) patients met the inclusion criteria. Cervical Lymphadenopathy was the most common presentation (34.3%, n=11). Advanced disease was seen in 68.7% (n=22) (stages III and IV). Fourteen (42.4%) were treated on ALCL-99, 30.3% (n=10) on multicenter protocol-842 regimen, 9% (n=3) on adriamycin-prednisolone-oncovin (doxorubicin, prednisone, vincristine) regimen, and 16% (n=5) were treatment abandonments. Five-year overall survival was 70.6% (95% confidence interval: 47.8%-84.9%), and 5-year event-free survival (EFS) considering treatment abandonment and death as an event was 52.3 % (95% confidence interval: 23.5%-74.8%). CONCLUSIONS: Significant therapy-related mortality (27.7%) was observed. Treatment abandonment and therapy-related toxicity were the major barriers for better outcomes. However, less intensive outpatient regimens, such as adriamycin-prednisolone-oncovin regimen, may decrease the number of hospitalizations, hence reducing treatment abandonment in the low and middle-income country.

Primitive myxoid mesenchymal tumor of infancy with brain metastasis: first reported case.

INTRODUCTION: Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a recently diagnosed entity, with only a handful of cases reported to date. CASE DESCRIPTION: Herein, we present the occurrence of this tumor in a 2-year-old boy, initially diagnosed as primitive neuroectodermal tumor of the extremity and treated with chemotherapy and surgical resection. He later presented with a cerebellar lesion, and biopsy was consistent with PMMTI. CONCLUSION: While there have been previous cases of PMMTI reported with loco-regional metastatic spread, to our knowledge, there is no known incidence of distant metastasis with involvement of the central nervous system, which makes this case the first of its kind.

Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major.

BACKGROUND: Endocrinopathy due to iron overload is the most common morbidity whereas myocardial siderosis causing toxic cardiomyopathy is the leading cause of mortality among patients with transfusion dependent thalassemia major (TDTM). If detected early, this can be treated with aggressive chelation. T2* cardiac magnetic resonance imaging (CMR) guided chelation protocols are now the gold standard but have limited availability in low and middle-income countries. We hypothesized that markers of endocrine dysfunction would correlate with T2* CMR and can be used to predict the severity of myocardial siderosis and guide chelation therapy. METHODOLOGY: We undertook a multicenter retrospective study of 280 patients with TDTM to assess the prevalence of endocrinopathies and the predictive value of a number of individual and composite markers of endocrinopathy with T2* CMR. RESULTS: The prevalence of hypogonadism, stunting, hypoparathyroidism, and hypothyroidism was 82%, 69%, 40%, and 30%, respectively. The sensitivity of hypogonadism and stunting predicting severe myocardial siderosis was 90% and 80%, respectively. CONCLUSION: We conclude that clinical markers of endocrine dysfunction, especially hypogonadism (positive likelihood ratio [LR+] = 1.4, 95% confidence interval [CI] = 1.0-1.9; positive predictive value [PPV] = 77%, 95% CI = 70-82; negative predictive value [NPV] = 57%, 95% CI = 34-77] and stunting (LR+ = 1.3, 95% CI = 1.1-1.6; PPV = 64%, 95% CI = 60-69; NPV = 55%, 95% CI = 45-64) in TDTM can predict severe myocardial siderosis and can potentially guide chelation therapy, especially where access to T2* CMR is limited.

Delayed Methotrexate Clearance Despite Carboxypeptidase-G2 (Glucarpidase) Administration in 2 Patients With Toxic Methotrexate Levels.

High-dose methotrexate has been a treatment for osteosarcoma; however, its nephrotoxic effects are considerable. Carboxypeptidase-G2 (glucarpidase) was approved by the US Food and Drug Administration in 2012 for treatment of toxic methotrexate levels. We report our experience using glucarpidase under compassionate use before Food and Drug Administration approval in 2 patients who had delayed methotrexate clearance and prolonged kidney injury despite glucarpidase administration. Our results show that patients with methotrexate toxicity may require repeated doses of glucarpidase in addition to supportive measures, such as dialysis.

Burden of Cardiac Siderosis in a Thalassemia-Major Endemic Population: A Preliminary Report From Pakistan.

OBJECTIVE: To describe the initial experience and demographics of T2* cardiac magnetic resonance-based myocardial-iron quantification of transfusion-dependent thalassemia-major (TM) patients from Pakistan and the correlation with serum ferritin. METHODS: Eligible TM patients presenting between April 2014 and April 2015 to Aga Khan University Hospital, Pakistan, for T2*CMR were included. The severity of myocardial-iron deposition was defined as follows: normal T2*>20 ms, mild-moderate T2*10 to 20 ms, and severe T2*<10 ms. Cardiac symptoms were classified using the NYHA functional classification. Echocardiographic systolic and diastolic functions were performed. Continuous variables were presented as the median (minimum-maximum value). Correlation was measured using the Spearman rank correlation. Multivariate logistic regression was used to determine factors associated with the NYHA functional class. RESULTS: A total of 83 patients (49 male and 34 female) with TM, age 19 (5 to 45) years at presentation for T2*CMR, were reviewed. At presentation, 70% of the patients were classified as NYHA class II or worse. T2*<20 ms was observed in 62.6% of the patients, with 47% showing severe iron deposition (T2<10 ms). No correlation of T2*<20 ms (r=-0.157, P=0.302) and T2*<10 ms (r=-0.128, P=0.464) was observed with serum ferritin. On multivariate analysis, lower T2* values correlated with a worsening NYHA functional class. CONCLUSIONS: There is a high prevalence of severe myocardial iron load in Pakistani TM patients. Serum ferritin did not correlate with T2* values. Lower T2* was the only clinical factor associated with the NYHA functional class.

Acute appendicitis in acute leukemia and the potential role of decitabine in the critically ill patient.

Acute appendicitis in children with acute leukemia is uncommon and often recognized late. Immunocompromised host state coupled with the importance of avoiding treatment delays makes management additionally challenging. Leukemic infiltration of the appendix though rare must also be considered. Although successful conservative management has been reported, surgical intervention is required in most cases. We present our experience with acute appendicitis in children with acute leukemia and a case of complete remission of acute myeloid leukemia with a short course of decitabine. Decitabine may serve as bridging therapy in critically ill patients who are unable to undergo intensive chemotherapy.

Age-related toxicity in patients with rhabdomyosarcoma: a report from the children's oncology group.

On the Fourth Intergroup Rhabdomyosarcoma study, older children experienced excessive neurotoxicity, whereas younger children had increased myelosuppression. The purpose of this study was to determine whether the same pattern of toxicity was seen on the successor study when use of growth factor was required and dosing of chemotherapy was different by performing a retrospective cohort analysis on patients treated on Children's Oncology Group protocol D9803. Toxicity data were analyzed by stratifying children into 4 age groups. The frequency of grade 3/4 neurotoxicity, myelosuppression, infection, and mucositis was predicted for each age group. The cumulative doses of vincristine and cyclophosphamide administered were measured as percent of protocol-prescribed dose. Adolescents (aged 15+) were more likely to experience neurotoxicity compared with younger patients (odds ratio, 3.6; P<0.0001). There was no difference in myelosuppression, infection, or mucositis. The mean percent protocol-prescribed doses administered for vincristine and cyclophosphamide did not differ much by age group. Adolescents experienced more neurotoxicity with vincristine compared with younger patients. No differences in other toxicities were observed between age groups. As adolescents received at least 85% of protocol-prescribed doses of vincristine, it is difficult to attribute the poorer survival in this age group to inadequate protocol-delivered therapy.

High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Body mass index (BMI), at diagnosis has been associated with lower survival and increased toxicity in cancer patients. We analyzed the effect of BMI at diagnosis on therapy related toxicities and outcome in pediatric osteosarcoma patients treated on Children's Oncology Group (COG) trial INT0133. PROCEDURES: All patients enrolled on COG-INT0133 with height, weight and toxicity information were eligible. BMI was expressed as age and gender specific percentiles using height and weight at diagnosis. Patients were classified into high, normal and low BMI groups. Logistic regression models were used to analyze toxicities; Kaplan-Meier curves were created to assess event free (EFS) and overall survival (OAS). RESULTS: Seven hundred and ten patients met eligibility criteria. BMI distribution was: 447 normal BMI, 74 low BMI, and 189 high BMI. Renal toxicity was higher in the high BMI group (OR = 2.7, 95% CI 1.2-6.4, P = = 0.01) only during one of the courses of therapy. Compared to the normal BMI group, patients with high BMI had significantly worse OAS at 5 years compared to those with normal BMI, 69.7% versus 80.5% (HR = 1.6, 95% CI 1.1-2.2, P = 0.005) and a trend towards worse event-free survival at 3 years 66.2% versus 75.5% (HR = 1.3 95% CI 0.9-1.8, P = 0.05). There was no difference in EFS or OAS in patients with low BMI compared to patients with normal BMI. CONCLUSIONS: High BMI at diagnosis is associated with worse OAS in patients with osteosarcoma. No clinically significant differences in toxicity were observed in the various BMI groups.

Diffuse large B-cell lymphoma in an adolescent female presenting with Epstein-Barr virus-driven hemophagocytic lymphohistiocytosis: a case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis is characterized by multisystem inflammation, resulting from prolonged and intense activation of macrophages, histiocytes and CD8+ T-cells. Due to its variable presentation and non-specific findings, timely diagnosis can be challenging. This condition has been associated with malignancies, most commonly with lymphomas and leukemias of T-cell lineage. This case report represents the less commonly associated B-cell lymphomas. We also highlight the difficulties in managing hemophagocytosis with an evolving malignancy. This case report will add to the increasing literature on the diagnosis, complications and management of this complex disorder. CASE PRESENTATION: A 15-year-old Caucasian girl, previously diagnosed with Crohn's disease and treated with 6-mercaptopurine, developed Epstein-Barr virus infection-driven hemophagocytic lymphohistiocytosis. The diagnosis was challenging due to her critical illness and the lack of enough features to fulfill diagnostic criteria at presentation (moderately elevated ferritin, normal coagulation profiles and normal triglycerides). While receiving therapy for hemophagocytic lymphohistiocytosis, she developed bulky cervical lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma. Therapy for lymphoma was initiated and she tolerated the therapy well. CONCLUSION: Hemophagocytic lymphohistiocytosis is a rare disorder, but potentially lethal if not diagnosed and treated in a timely manner. Our case highlights the importance of considering this diagnosis in critically ill patients who may not initially fulfill formal diagnostic criteria. In patients diagnosed with hemophagocytic lymphohistiocytosis, occult malignancies should be aggressively ruled out as they can manifest prior to the hemophagocytic lymphohistiocytosis diagnosis or appear during the treatment phase. An accurate diagnosis is also important because management of Epstein-Barr virus-driven hemophagocytic lymphohistiocytosis and Epstein-Barr virus-driven lymphoma differs due to the difference in pathophysiology and the involvement of different immune cell lines.

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience.

Graft versus host disease (GVHD) remains a major cause of mortality and morbidity after matched unrelated hematopoietic stem cell transplantation (HSCT). Campath-1 H (alemtuzumab), a humanized monoclonal antibody to CD52 antigen, is thought to reduce GVHD incidence through in vivo T-cell depletion. Through the same mechanism it can potentially increase the risk of relapse by reducing the graft versus leukemia effect and possibly increase the risk of infection due to delayed immune recovery. A retrospective case analysis of 17 pediatric matched unrelated HSCTs done in our institution between January 2003 and June 2009 with Campath-1H as part of the pretransplant conditioning regimen was conducted. Grade I-II acute GVHD was noted in 29.4% of the HSCTs. No patient developed chronic GVHD. All but one patient with severe aplastic anemia engrafted. A relapse of primary disease was noted in 35.3% of the transplants. Three patient deaths were due to relapse and 1 due to disseminated varicella infection. Overall survival was 100% and 94% at 100 days and 1 year, respectively. Our experience suggests Campath-1H used as part of pretransplant conditioning regimen in pediatric unrelated HSCTs effectively reduces the risk of serious GVHD with no apparent increase in life-threatening infections or relapse compared with that reported with conventional regimens. Larger studies, with longer duration of follow-up, are required to further assess its role with regards to graft versus leukemia effect and to establish if the decreased incidence of GVHD and infectious complications is sustained in larger cohorts.