Capacity building for pediatric neuro-oncology in Pakistan- a project by my child matters program of Foundation S.

Introduction: Initiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant. Methods: We aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints. Results: A total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three. Discussion: The initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.

Prognostic impact of pre-referral tumor resection in unilateral Wilms tumor: A single-institute experience from a lower middle-income country.

INTRODUCTION: The objectives of this study were to evaluate the prognostic impact of pre-referral surgical resection of Wilms tumor (WT) performed at non-oncology centers, and to strategize an improved care plan for this very curable pediatric tumor. METHODS: In this study conducted in a large pediatric cancer center in Pakistan, we retrospectively reviewed the electronic medical records (EMR) of 149 patients with unilateral WT from September 2008 to August 2017. Based on treatment approach, patients were categorized into two groups: (i) pre-referral tumor resection (PTR: n = 75), and (ii) post-neoadjuvant chemo nephrectomy (PCN: n = 74). RESULTS: The proportion of metastatic disease in PTR and PCN groups was 33.3% and 35.1%, respectively. In the PTR subset, median time to admission after PTR was 5 weeks (mean 11, SEM 2.8, range: 2-202) weeks, with 53.3% (n = 40) presenting more than 4 weeks after PTR. Twenty patients had no cross-sectional imaging prior to PTR and underwent surgery after abdominal ultrasound only. On baseline imaging at our center, 58.7% (n = 44) of the PTR group had radiologically evaluable disease (four metastases only, 19 local residual tumor only, 21 both localized tumor and visible metastases). Disease staging was uncertain in 23 patients because of no or inadequate histology specimens and/or lymph node sampling in patients with no evaluable disease. Statistically significant differences were recorded for the two subsets regarding tumor volume, extent and nodularity, renal vein and renal sinus involvement, lymph node status, tumor rupture and histopathologic features, and tumor stage, with a 10-year event-free survival (EFS) for PCN and PTR of 74.3% and 50.7%, respectively (p < .001). In the PTR group, EFS for those presenting within 4 weeks and later was 91.4% versus 15.0%, respectively (p < .0001). CONCLUSION: Suboptimal pre-referral surgical intervention results in poor survival outcomes in unilateral WT. Our findings highlight the need for a comprehensive action plan for educating healthcare professionals engaged in WT diagnosis and referral process. PCN in a multidisciplinary team approach can reduce surgical morbidity and seems to be a better strategy to improve the survival rates in low-resource settings.

68Ga-DOTATATE PET in Restaging and Response to Therapy in Neuroblastoma: A Case Series and a Mini Review.

68Ga-DOTATATE PET/CT is widely used for the evaluation of neuroendocrine tumors. Some reports exist on its use in the management of neuroblastoma. Building on the prior reports as well as our previous experience in using this technique for initial staging, we propose to describe its practical benefits in restaging and response to therapy. We describe different aspects including supply logistics, preparation, spatial resolution, and other practical applications. Methods: We reviewed the medical records for 8 patients who were evaluated with 68Ga-DOTATATE PET/CT at our institution over 2 y. A note was made of the patient and disease characteristics and the indication for PET imaging, and the results were retrospectively analyzed for feasibility, logistics, radiation exposure, and utility in answering the clinical question. Results: Eight children (5 girls and 3 boys; age range, 4-60 mo; median age, 30 mo) diagnosed with neuroblastoma were imaged with 68Ga-DOTATATE PET/CT and 5 with 123I-metaiodobenzylguanidine (123I-MIBG) SPECT/CT over 2 y. Three 68Ga-DOTATATE PET scans were done for staging, 10 for response evaluation, and 2 for restaging. 68Ga-DOTATATE PET accurately identified neuroblastoma lesions suspected or seen on anatomic imaging. It has been shown to be more specific and more sensitive than 123I-MIBG and at times also MRI. It had better spatial and contrast resolution than 123I-MIBG. 68Ga-DOTATATE PET was better than 123I-MIBG SPECT/CT, CT, and MRI in the detection of early progression and viable tumor delineation for response assessment, as well as in target volume definition for external-beam radiotherapy and proton-beam radiotherapy. 68Ga-DOTATATE PET was also better at assessing bony and bone marrow disease changes with time. Conclusion: 68Ga-DOTATATE PET/CT offers added value and a superior edge to other imaging modalities in restaging and response assessment in neuroblastoma patients. Further multicenter evaluations in larger cohorts are needed.

Challenges in the Management of Wilms Tumor in a Developing Country: A Twenty Years' Experience From a Single Center in Pakistan.

BACKGROUND: Wilms Tumor (WT) is one of the most curable childhood cancers. High cure rates seen in the developed countries are not reproduced in developing countries. Lack of access to cancer treatment facilities, financial constraints, late presentation, and abandonment have previously been described. We reviewed our data over the last 20 years to highlight some of these challenges. METHODS: This is a retrospective chart review of children with WT at our center up to the age of 18 years between 1 November 1997 and 30 November 2017. Demographic details, presentation characteristics and treatment details were recorded. Factors associated with poor outcome were analyzed. RESULTS: Two hundred eleven children were registered; 117(55.5%) were males. Median age at presentation was 3 (range 0 to 18) years. Presentation data were available for 184/211 patients, staging details for 159/211 and metastatic status for 178/211. Of the available dataset, 60% presented without prior treatment, whereas 40% presented atleast after primary surgical excision. High-stage (stage III or above) disease was present in 79 (49.7%) patients; 61 (34.3%) was presented with metastases or recurrence; 63 (29.8%) abandoned or refused treatment; 99/172 (57.6%) patients finished treatment, 23 (13.4%) died during treatment, and 6 died before treatment. Of the 99 patients who finished treatment 83 (83.8%) are well off therapy; 15(15.2%) relapsed; 6 (40%) are alive after salvage therapy, while 9 (60%) died. CONCLUSIONS: Our data highlights the challenges of managing WT in resource poor environments. Prior surgery, incomplete staging work-up and abandonment are some of the most frequently encountered barriers. A multipronged approach is required to overcome these challenges.

The immune landscape of solid pediatric tumors.

BACKGROUND: Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. METHODS: We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. RESULTS: A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. CONCLUSIONS: We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults' tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.

Amino Acid PET Imaging with 18F-DOPA in the evaluation of Pediatric Brain Tumors.

Although MRI is the workhorse of brain tumor initial evaluation and follow-up, there is a growing amount of data recommending the incorporation of amino-acid PET imaging at different stages of the management of these patients. Recent nuclear medicine and neuro-oncology clinical practice recommendations support the use of amino-acid imaging in brain tumor imaging. Considering 18F-DOPA is FDA approved for the evaluation of parkinsonian syndromes, it could be used clinically for other valuable clinical indications such as brain tumor evaluations. This value seems to be well established in adults and has growing evidence for its use in pediatrics as well. We offer to present four pediatric brain tumor cases imaged with 18F-DOPA and review the literature.

Building the ecosystem for pediatric neuro-oncology care in Pakistan: Results of a 7-year long twinning program between Canada and Pakistan.

BACKGROUND: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes. METHODS: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article. RESULTS: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan. CONCLUSIONS: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.

Outcome of first relapse of Hodgkin lymphoma: single institution experience.

OBJECTIVE: To determine outcome of first relapse of Hodgkin lymphoma with standard dose chemotherapy, and to identify the prognostic factors predicting survival outcome in paediatric patients. METHODS: The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data of Hodgkin lymphoma patients who relapsed at least 3 months after the completion of initial treatment from January 2001 to December 2010. Probabilities of overall survival, event-free survival and cumulative incidence were calculated. Data was analysed using SPSS 21. RESULTS: Of the 43 patients, 31(72%) were males and 12(29%) were females. Mean age at relapse was 11±3.3 years (range: 4-17 years). In 31(72%) patients, early post-operative intraperitoneal chemotherapy was employed. Median follow-up of the cohort was 62 months (interquartile range: 4-187 months). Overall survival and event-free survival at 10 years was 23(54%) and 15(35%) respectively. On univariate analysis, initial disease stage (p=0.021), stage at relapse (p=0.003), treatment protocol (p=0.005), treatment responsiveness at initial two cycles of salvage chemotherapy (p=0.002) and at the end of treatment assessment (p=0.0009) were statistically significant factors. Multivariate cox regression analysis revealed disease stage at relapse (p=0.004), chemotherapy regimen (p=0.025) and end-of-treatment disease evaluation (p=0.005) as the significant variables. CONCLUSIONS: Improved outcome with early post-operative intraperitoneal chemotherapy regimen was noted for Hodgkin lymphoma patients who had disease-free interval >2 years.

68Ga-DOTATATE PET/CT for Neuroblastoma Staging: Utility for Clinical Use.

Metaiodobenzylguanidine (MIBG) imaging has been the standard for neuroblastoma staging for many decades. Novel agents such as 18F-DOPA and 68Ga-DOTATATE are being used nowadays in academic centers. During the coronavirus disease 2019 (COVID-19) pandemic, procurement of 123I-MIBG has proved particularly challenging, necessitating the use of 68Ga-DOTATATE PET. 68Ga-DOTATATE is Food and Drug Administration-approved for imaging of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Methods: 68Ga-DOTATATE PET/CT imaging was performed for staging of 3 pediatric patients with neuroblastoma at our institution. A review of the literature was also completed. Results: 68Ga-DOTATATE PET/CT scans were successfully performed on all patients. All patients showed 68Ga-DOTATATE-avid disease. PET scans showed an excellent spatial resolution and demonstrated high accuracy in concordance with current European Association of Nuclear Medicine guidelines. Conclusion: We have presented 68Ga-DOTATATE PET/CT imaging for staging of neuroblastoma and believe it can reliably be used as an alternative to 123I-MIBG. It has technical, clinical, and practical advantages making it an attractive option. Further multicenter studies are required before it can be recommended for standard clinical use.

Presenting symptoms and time to diagnosis for Pediatric Central Nervous System Tumors in Qatar: a report from Pediatric Neuro-Oncology Service in Qatar.

INTRODUCTION: There are no previous published reports on primary pediatric tumors of the central nervous system (CNS) in Qatar. We undertook this retrospective cohort study to review the diagnosis of CNS tumors in children in Qatar to analyze the presentation characteristics including symptoms, referral pathways, and time to diagnosis. METHODS: All children registered with Pediatric Neuro-Oncology service (PNOS) were included in the study. Data from the time of diagnosis (October 2007 to February 2020) were reviewed retrospectively. Presenting symptoms were recorded and pre-diagnosis symptom interval (PSI) was calculated from the onset of the first symptom to the date of diagnostic imaging. RESULTS: Of the 61 children registered with PNOS during the study period, 51 were included in the final analysis. Ten children were excluded because they were either diagnosed outside Qatar (n = 7) or were asymptomatic at the time of diagnosis (n = 3). The median age was 45 (range 1-171) months. Common tumor types included low-grade glioma (LGG) (47.1%) and medulloblastoma/primitive neuro-ectodermal tumors (PNET) (23.5%). Nine children had an underlying neurocutaneous syndrome. Thirty-eight patients (74.5%) had at least one previous contact with healthcare (HC) professional, but 27 (52%) were still diagnosed through the emergency department (ED). Presenting symptoms included headache, vomiting (36.2%), oculo-visual symptoms (20.6%), motor weakness (18.9%), seizures, ataxia (17.2% each), irritability, cranial nerve palsies (12% each), and endocrine symptoms (10.3%). Median PSI was 28 days (range 1-845 days) for all CNS tumors. Longest PSI was seen with germ cell tumors (median 146 days), supratentorial location (39 days), and age above 3 years (30 days). Tumor characteristics of biological behavior (high-grade tumor) and location (infratentorial) were significantly associated with shorter PSI, as were presenting symptoms of ataxia, head tilt, and altered consciousness. CONCLUSIONS: Although overall diagnostic times were acceptable, some tumor types were diagnosed after a significant delay. The awareness campaign, such as the "HeadSmart" campaign in the United Kingdom (UK), can improve diagnostic times in Qatar. Further research is required to better understand the reasons for the delay.

Critically Ill Pediatric Oncology Patients: What the Intensivist Needs to Know? Pediatric Critical Care Medicine.

Cancer is an evolving cause of morbidity and mortality in children worldwide. In recent decades, there has been a significant increase in the survival of children with cancer, after applying new methods and treatment protocols in practice. However, the complexity of the disease itself, as well as the intensity and toxicity of treatment is such that many children require admission to the pediatric intensive care unit (PICU) which should be well equipped and led by personnel who have adequate training and expertise to provide optimum care to these complex patients. Most oncology patients who require PICU admission categorized into oncological emergencies, and/or decompensation from treatment and its side effects. In this study, we provide a summary of the essential and most recent evidence-based recommendations from published reviews and articles to aid PICU physicians and to ensure the best treatment and outcome possible for the children with such disease. How to cite this article: Al Haj Moussa A, Maaz AUR, Faqih N, Sundaram M. Critically Ill Pediatric Oncology Patients: What the Intensivist Needs to Know? Pediatric Critical Care Medicine. Indian J Crit Care Med 2020;24(12):1256-1263.

Clinical characteristics and outcome analysis of pediatric B-cell non-Hodgkin's lymphoma. Experience with FAB-LMB 96 and UKCCSG B-cell NHL guidelines in a developing country.

AIM: To analyze the clinical characteristics of B-cell non-Hodgkin's lymphoma (NHL) patients and the therapeutic efficacy of French-American-British Lymphoma Malins de Burkitt 96 and the recent United Kingdom Children's Cancer Study Group B-cell NHL guidelines in the tertiary care hospital of a developing country. METHODS: Patients aged < or =18 years registered at our hospital between January 1995 and December 2006 with histologically proved B-Cell NHL were selected for retrospective analysis. RESULTS: Of the total of 131 patients registered, 122 patients were eligible for evaluation. Of these 95 had Burkitt's lymphoma, 22 diffuse large B-cell lymphoma and five had B-cell NHL not otherwise specified. The mean age was 8.4 years. Overall 42 children had a baseline weight less than the 10th centile. A total of 37 had uric acid >10 mg/dl and 55 had a lactate dehydrogenase level >500; 73 had stage III and 31 had stage IV while only four presented at stage I and 14 at stage II. The abdomen was the commonest site of disease. A total of 45 patients died; 28 due to infection, nine due to tumor lysis syndrome and six of uncontrolled disease. All deaths occurred within an average of 35 days from starting treatment. Our 5-year overall survival rate was 68 percent and our event-free survival was 55 percent. CONCLUSION: Late presentation with advanced disease, poor nutritional status and high risk of exposure to infective agents all contribute to the high mortality in patients treated with intensive protocols in resource-poor countries.