Multi-institution analysis of tumor mutational burden and outcomes in pediatric central nervous system tumor patients.

BACKGROUND: Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making. METHODS: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. RESULTS: We identified 119 patients. Common tumor types included low-grade glioma (N = 51), high-grade glioma (N = 29), and medulloblastoma (N = 11). Common driver mutations included TP53 inactivation (N = 16), BRAF-KIAA1549 fusion (N = 16), FGFR1 amplification (N = 12), BRAF V600E mutation (N = 12), NF1 loss (N = 12), and H3F3A K28M mutation (N = 6). Median TMB was one mutation/megabase (mut/Mb, range = 0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high-grade tumors (p = .009, HR 84.3), and high-grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high-grade histology (p = .015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N = 15, 44%) than in low-TMB tumors (N = 19, 35%). CONCLUSIONS: High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

Allogeneic Bone Marrow Transplant as a Cure for Refractory T-Cell Large Granular Lymphocytic Leukemia in an Adolescent.

T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.

Myeloablative Carboplatin and Thiotepa With Autologous Stem Cell Rescue for Nonmedulloblastoma High-risk CNS Tumors in Young Children.

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.

Results of a pre-implementation analysis of Ethiopia's National Pediatric Cancer Registry.

In Ethiopia, cancer accounts for about 5.8% of total national mortality, with an estimated annual incidence of cancer of approximately 60,960 cases and an annual mortality of over 44,000 persons. This is likely an underestimation. Survival rates for pediatric malignancies are likewise suboptimal although exact figures are unknown since a national cancer registry is unavailable. The World Health Organization (WHO) provides recommendations for the creation of cancer registries to track such data. Here we describe our pharmacist-led, pre-implementation assessment of introducing an enhanced national pediatric cancer registry in Ethiopia. Our assessment project had three specific aims around which the methods were designed: 1) characterization of the current spreadsheet-based tool across participating sites, including which variables were being collected, how these variables compared to standards set by the WHO, and a description of how the data were entered and its completeness; 2) assessment of the perceptions of an enhanced registry from hospital staff; and 3) evaluation of workflow gaps regarding documentation. The hospital staff and leadership have generally positive perceptions of an enhanced pediatric cancer registry, which were further improved by our interactions. The workflow assessment revealed several gaps, which were addressed systematically using a three-phase implementation science approach. The assessment also demonstrated that the existing spreadsheet-based tool was missing WHO-recommended variables and had inconsistent completion due to the workflow gaps. A pediatric oncology summary sheet will be implemented in upcoming trips in patient charts to better summarize the patients' journey starting from diagnosis. This document will be used by the data clerks in an enhanced-spreadsheet to have a more complete data set.

Training pediatric hematologist/oncologists for capacity building in Ethiopia.

PURPOSE: A considerable barrier to global pediatric oncology efforts has been the scarcity and even absence of trained professionals in many low- and middle-income countries, where the majority of children with cancer reside. In 2013, no dedicated pediatric hematology-oncology (PHO) programs existed in Ethiopia despite the estimated annual incidence of 6000-12000 cases. The Aslan Project initiative was established to fill this gap in order to improve pediatric cancer care in Ethiopia. A major objective was to increase subspecialty PHO-trained physicians who were committed to practicing locally and empowered to lead programmatic development. METHODS: We designed and implemented a PHO training curriculum to provide a robust educational and clinical experience within the existing resource-constrained environment in Ethiopia. Education relied on visiting PHO faculty, a training attachment abroad, and extraordinary initiative from trainees. RESULTS: Four physicians have completed comprehensive PHO subspecialty training based primarily in Ethiopia, and all have remained local. Former fellows are now leading two PHO centers in Ethiopia with a combined capacity of 64 inpatient beds and over 800 new diagnoses per year; an additional former fellow is developing a pediatric cancer program in Nairobi, Kenya. Two fellows currently are in training. Program leadership, teaching, and advocacy are being transitioned to these physicians. CONCLUSIONS: Despite myriad challenges, a subspecialty PHO training program was successfully implemented in a low-income country. PHO training in Ethiopia is approaching sustainability through human resource development, and is accelerating the growth of dedicated PHO services where none existed 7 years ago.

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Bevacizumab in treating the cystic components of pediatric low-grade gliomas: A report of four patients.

Low-grade gliomas (LGG) are among the most common types of brain tumors in children and young adults. These tumors often consist of solid and cystic components. Bevacizumab is a documented treatment for progressive LGG, yet the impact of therapy on the cystic component of these tumors is unknown. We present four patients with prominently cystic LGG treated with bevacizumab at the time of progression. In each case, the cystic component responded to treatment. This is the first known study to investigate bevacizumab's impact on the cystic component of low-grade gliomas.

Successful reduced-intensity conditioning hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia in two children.

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare cause of bone marrow failure in children. We report two children who presented with pancytopenia, and were diagnosed with PNH with severe aplastic anemia. Both children underwent upfront, successful hematopoietic stem cell transplantation with reduced-intensity conditioning. One patient had a syngeneic donor, and one patient had a 10/10 matched unrelated donor. Neither patient developed graft versus host disease, infections, or recurrent PNH. Reduced-intensity conditioning hematopoietic stem cell transplantation is a reasonable therapy for PNH with marrow failure in children.

Parental coping in the context of having a child who is facing death: A theoretical framework.

ABSTRACTObjective:While improvements in healthcare have resulted in children with complex and life-threatening conditions living longer, a proportion of them still die. The death of a child puts parents at increased risk for anxiety, depression, and complicated grief. Increasing our understanding of the coping strategies that parents use under such extreme circumstances will enable us to best provide support to families, before and after a child's death. Our aim herein was to develop a theoretical framework of parental coping. METHOD: Evidence from the literature was employed to develop a theoretical framework to describe parental coping in the context of having a child with a life-limiting illness who is declining and facing eventual death. RESULTS: The reasoning and argument consists of three guiding elements: (1) the importance of approach as well as avoidance (as coping strategies) in the context of managing the extreme emotions; (2) the importance of the social aspect of coping within a family, whereby parents cope for others as well as for themselves; and (3) the importance of a flexible and balanced coping profile, with parents using different coping strategies simultaneously. Central to the proposed framework is that effective coping, in terms of adjustment, is achieved by balancing coping strategies: accessing different coping strategies simultaneously or in parallel with a specific focus on (1) approach and avoidance and (2) coping aimed at self and others. SIGNIFICANCE OF RESULTS: Understanding of parental coping strategies is essential for health professionals in order to support parents effectively.

Feasibility of Early Palliative Care Consultation for Children With High-Risk Malignancies.

BACKGROUND: Children with cancer suffer significant morbidity throughout therapy and often face an uncertain prognosis. Because palliative care teams can provide an additional layer of support with symptom management and communication, we conducted a prospective study assessing the feasibility of early palliative care consultation for children with high-risk malignancies. PROCEDURE: This study was part of a larger prospective study examining the impact of early palliative care consultation. Children were eligible if they were <22 years old and had a high-risk malignancy, recurrence, or required hematopoietic stem cell transplantation (HSCT). Data were collected from the medical record on diagnosis, days to consultation, acceptability of consultation to family/staff, and overall survival. Feasibility was defined as enrollment of >75% of eligible patients, palliative care consultation within 1 month of eligibility, and patient/family satisfaction. RESULTS: Twenty of 25 (80%) eligible patients were approached and received a palliative care consultation at initial diagnosis (7), recurrence (12), or time of HSCT (1). Median age of the children was 5 years (0.1-20 years). Median time from new diagnosis/recurrence to consultation was 12 days (2-180 days); 17 (85%) received the consultation within 30 days. Eleven (55%) of the 20 children died. Median time of consultation prior to death was 128 days (10-648 days). Ten of the 11 (91%) received their consultation >30 days prior to death. No families or oncologists declined an early consultation. CONCLUSIONS: Early palliative care consultation is feasible for children with high-risk cancer and is acceptable to children, families, and pediatric oncologists.

Correlation between progression free survival and dynamic susceptibility contrast MRI perfusion in WHO grade III glioma subtypes.

The purpose of this study was to determine whether dynamic susceptibility contrast MR perfusion relative cerebral blood volume (rCBV) correlates with prognosis of World Health Organization (WHO) grade III glial tumors and their different subtypes. Retrospective evaluation of pre-treatment tumor rCBV derived from dynamic susceptibility contrast MR perfusion was performed in 34 patients with histopathologically diagnosed WHO grade III glial tumors (anaplastic astrocytomas (n = 20), oligodendrogliomas (n = 4), and oligoastrocytomas (n = 10)). Progression free survival was correlated with rCBV using Spearman rank analysis. ROC curve analysis was performed to determine the operating point for rCBV in patients with anaplastic astrocytomas dichotomized at the median progression free survival time. For all grade III tumors (n = 34) the mean rCBV was 2.51 with a progression free survival of 705.5 days. The mean rCBV of anaplastic astrocytomas was 2.47 with progression free survival 495.2 days. In contrast, the mean rCBV for oligodendroglial tumors was 2.56 with a progression free survival of 1005.6 days. Although there was no significant correlation between rCBV and progression free survival among all types of grade III gliomas (P = 0.12), among anaplastic astrocytomas there was a significant correlation between pretreatment rCBV and progression free survival with correlation coefficient of -0.51 (P = 0.02). The operating point for rCBV in patients with anaplastic astrocytomas dichotomized at the median progression free survival time (446.5 days) was 2.86 with 78 % accuracy and there was a significant difference between the survival of patients with anaplastic astrocytomas in the dichotomized groups (P = 0.0009). Pre-treatment rCBV may serve as a prognostic imaging biomarker for anaplastic astrocytomas, but not grade III oligodendroglioma tumors.

Low-grade fibromyxoid tumor of the dura: A new entity?

Background: Low-grade fibromyxoid tumors are uncommon in children. Their differentiation from high-grade fibromyxoid tumors, as seen in adults, is imperative to diagnosis. Awareness of the entity and its subsequent behavior may guide management and predict outcomes. Case Description: We describe the case of a previously unreported low-grade fibromyxoid tumor of the cerebellum in an 8-year-old male. Extensive immunohistochemical, next-generation sequencing, and attempted DNA methylation profiling are reported. There has been no recurrence during the 6-year follow-up. Screening excluded multiple myxoid tumors, including low-grade fibromyxoid sarcoma. The findings suggest that, with gross total resection, the lesions may not recur. Conclusion: The case of fibromyxoid tumor with 6-year follow-up and the limited literature of similar tumors are reviewed.

Oral ketamine for children with chronic pain: a pilot phase 1 study.

OBJECTIVE: To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children. STUDY DESIGN: A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. RESULTS: Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment. CONCLUSION: Oral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.

Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature.

OBJECTIVE: Chronic cancer pain is often refractory and difficult to treat. Ketamine is a medication with evidence of efficacy in the treatment of chronic pain. DESIGN: This article presents a synthesis of the data on ketamine for refractory cancer pain in adults and children. RESULTS: There are five randomized, double-blind, controlled trials of ketamine use in cancer pain that demonstrate improvement in pain for some patients. There are six prospective, uncontrolled trials in cancer pain that also demonstrate improvement in pain scores for some patients. There are no randomized, controlled trials in children with cancer pain, although there are a few studies reflecting improved pain control with ketamine for children with cancer pain. Adverse events for adults on ketamine are most commonly somnolence, feelings of insobriety, nausea/vomiting, hallucinations, depersonalization/derealization, and drowsiness. However, when ketamine is combined with benzodiazepines, feelings of insobriety, hallucinations, and depersonalization/derealization are not reported. Children on ketamine have had few reported adverse effects, which include sedation, anorexia, urinary retention, and myoclonic movements. Recommended ketamine infusion dosages are from 0.05 to 0.5 mg/kg/h (intravenous or subcutaneous). Recommended oral dosages of ketamine are 0.2-0.5 mg/kg/dose two to three times daily with a maximum of 50 mg/dose three times daily. CONCLUSIONS: Despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain.

Impact of Delay Prior to Treatment in Ethiopian Children with Acute Lymphoblastic Leukemia.

Introduction: More than 85% of childhood malignancies occur in developing countries with less than a 30% cure rate as opposed to more than 80% cure rate in developed countries. This disproportionately significant difference might be due to delays in diagnosis, treatment initiation, lack of adequate supportive care, and treatment abandonment. We aimed to determine the impact of overall treatment delay on induction mortality of children with acute lymphoblastic leukemia treated at Tikur Anbessa specialized hospital (TASH). Methods: A cross-sectional study was conducted among children who were treated from 2016 to 2019. Children with Down syndrome and relapsed leukemia were excluded from this study. Results: A total of 166 children were included; most patients were males (71.7%). The mean age at diagnosis was 5.9 years. The median time interval from the onset of symptoms to the first TASH visit was 30 days and the median period from TASH's first clinic visit to diagnosis was 11 days. The median time to initiate chemotherapy after diagnosis was 8 days. The total median time from the first onset of symptoms to chemotherapy initiation was 53.5 days. Induction mortality was 31.3%. High-risk ALL and patients with an overall delay between 30 and 90 days were more likely to experience induction mortality. Discussion: Patient and healthcare system delay is high compared to most studies done and a significant association has been noted with induction mortality. Efforts to expand the pediatric oncology service in the country and efficient diagnostic and treatment approach need to be established to reduce mortality associated with overall delay.

Incidental brain lesions in children: to treat or not to treat?

Central nervous system (CNS) lesions that are discovered incidentally when imaging children for problems that were unrelated to the detected lesion pose a dilemma to physicians. Because there are few data on the outcome of such cases, we retrospectively reviewed the clinical course of a group of children followed at our institution with brain lesions found incidentally on neuro-imaging. A database of all children with brain lesions followed at the University of Rochester medical center from 2000 to 2010 was reviewed. Data were obtained regarding presentation, magnetic resonance imaging (MRI) features, treatment, progression-free survival, and overall survival of children with brain lesions found incidentally. Of the 244 children with brain lesions seen over this time period, 21 (8.6%) were found to have incidentally discovered brain lesions. Of these 21 children, 12 (57%) underwent surgical resection of their brain lesions. Ten patients (48%) had symptoms considered to be unassociated with the detected lesion. Lesions were found in the cerebellum (n = 7, 33%), midline (n = 5, 24%), and cerebrum (n = 9, 43%). All lesions were ≤5 cm in diameter. Eight patients (38%) had surgery at presentation, one because of imaging features suspicious for a posterior fossae ependymoma, and the seven others because of location in the posterior fossae or brain stem. Of the remaining 13 patients, five had progression of disease on serial MRI scans: four underwent surgery and the fifth was monitored and remained stable after the initial progression stabilized. Nine of the ten patients (90%) with posterior fossae lesions underwent surgery, while only three of 11 with supratentorial lesions underwent surgery (27%) (P = 0.006). The progression free survival was 94% at 12 months (95% CI 65-99%) and 71% at 24 months (95% CI 39-88%). At a median follow-up of 32 months, the overall survival was 100%. Incidentally detected CNS lesions are usually small. The outcome for children with such lesions is excellent. Close monitoring of these patients with serial MRIs may be a safe alternative to immediate biopsy and/or resection for select patients.

Spurious progression in pediatric brain tumors.

In this study, we sought to characterize post-therapy MRI changes mimicking progression, which we refer to as "spurious progression" (SP) in children with brain tumors. We analyzed whether SP is associated with particular tumor types or therapeutic modalities. Between 2000 and 2009, we identified 181 consecutive children <21 years of age at our center who were treated for brain tumors and had at least three MRI scans within a year after completing therapy. SP was defined as MRI abnormalities characterized by increase in size, enhancement, edema, or cystic changes within 12 months following therapy, and stabilization or improvement on subsequent imaging. One-hundred forty-one patients with brain tumors were evaluable. Fifty-six (40%) had imaging abnormalities initially suggestive of disease progression; of these, 34 (24%) had true disease progression (TP). The remaining 22 (16%) had SP based on either stability, decrease in enhancement, edema, size, or disappearance of these cystic or non-cystic abnormalities. SP occurred in patients with low grade (n = 20) and high grade lesions (n = 2). Median time to SP was 2.4 months (range, 0.7-8.3 months), with time to stability, decrease, or disappearance at a median of 4 months (range 1.4-7.7 months). Five patients were clinically symptomatic from SP and were treated with steroids, cyst drainage, and/or surgery. Therefore, SP occurs more commonly in children with low grade tumors, but can also occur with high grade brain tumors, regardless of therapeutic approach.