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.

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.

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.

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.

Costs of Care and Location of Death in Community-Based Pediatric Palliative Care.

Background: Children with complex chronic conditions (CCCs) are dying at home with increased frequency, yet the number of studies on the financial feasibility of community-based pediatric palliative care is limited. Objective: The objectives of this study were to (1) describe characteristics of patients who died in a community-based palliative care program and (2) evaluate cost differences associated with participant characteristics and location of death. Design: A retrospective cohort analysis of administrative and electronic medical record data was employed. Setting/Subjects: Children enrolled in the community-based pediatric palliative care program, CompassionNet, who died between 2008 and 2015 were included (N = 224). Measurements: Demographic data, program expense, and paid claims were extracted from an insurance provider database and clinical data from the electronic medical record. Results: Sixty-six (29%) of the children were <1 year old at death; 80 (36%) were 1-9 years old, and 78 (35%) were 10-22 years old. Malignancy was the most common primary CCC diagnosis for the 158 children/adolescents (n = 89, 56%), whereas neuromuscular conditions (n = 20, 30%) were most frequent for infants. Death at home occurred 21% of the time for infants, 48% for children of ages 1-9 years, and 46% for children of ages 10-22 years. The mean total cost in the final year of life for pediatric patients was significantly related to location of death, a malignancy diagnosis, and participation in Medicaid. The largest estimated difference was between costs of care associated with death at home ($121,111) versus death in the hospital ($200,050). Conclusions: Multidisciplinary community-based pediatric palliative care teams provide the opportunity for a home death to be realized as desired. Significant cost differences associated with location of death may support program replication and sustainability.

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.

Palliative and end-of-life care in glioblastoma: defining and measuring opportunities to improve care.

BACKGROUND: American Society for Clinical Oncology (ASCO) quality measures for terminal cancers recommend early advance care planning and hospice at the end of life. We sought to evaluate adherence to 5 palliative care quality measures and explore associations with patient outcomes in glioblastoma. METHODS: This is a retrospective analysis of 117 deceased glioblastoma patients over 5 years. Records were reviewed to describe adherence to palliative care quality measures and patient outcomes. Data regarding emotional assessments, advance directives, palliative care consultation, chemotherapy administration, hospice, location of death, and overall survival were collected. RESULTS: Median overall survival was 12.9 months. By the second oncology visit, 22.2% (26/117) had an emotional assessment completed. Advance directives were documented for 52.1% (61/117) by the third neuro-oncology visit (30/61 health care proxy), yet 26.5% (31/117) did not have any advance directive before the last month of life. With regard to other ASCO quality measures, 36.8% (43/117) had a palliative care consult; 94.0% (110/117) did not receive chemotherapy in the last 14 days of life; 59.8% (70/117) enrolled in hospice >7 days before death; and 56.4% (66/117) died in a home setting. Patients who enrolled in hospice >7 days before death were 3.56 times more likely to die in a home setting than patients enrolled <7 days before death or with no hospice enrollment (P = .002, [OR 3.56; 95% CI, 1.57-8.04]). CONCLUSIONS: Late advance directive documentation, minimal early palliative care involvement, and the association of early hospice enrollment with death in a home setting underscore the need to improve care and better define palliative care quality measures in glioblastoma.

Social Competence in Childhood Brain Tumor Survivors: Feasibility and Preliminary Outcomes of a Peer-Mediated Intervention.

OBJECTIVE: Evaluate the acceptability, feasibility, and preliminary outcomes of a peer-mediated intervention to improve social competence of brain tumor survivors and classmates. METHOD: Twelve childhood brain tumor survivors and 217 classroom peers in intervention (n = 8) or comparison (n = 4) classrooms completed measures of social acceptance and reputation at 2 time points in the year. The intervention (5-8 sessions over 4-6 weeks) taught peer leaders skills for engaging classmates. Individual and classroom outcomes were analyzed with analysis of covariance. RESULTS: Recruitment rates of families of brain tumor survivors (81%) and schools (100%) were adequate. Peer leaders reported satisfaction with the intervention. Preliminary outcome data trended toward some benefit in increasing the number of friend nominations for survivors of brain tumors but no changes in other peer-reported metrics. Preliminary results also suggested some positive effects on classroom levels of victimization and rejection. CONCLUSION: A peer-mediated intervention was acceptable to families of brain tumor survivors and feasible to implement in schools. Findings warrant a larger trial to evaluate improvements for children with brain tumors and their peers.

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.

Neurocognitive Changes after Sustained Ketamine Administration in Children with Chronic Pain.

INTRODUCTION: Ketamine has received attention recently as an agent for chronic pain. There are concerns, however, regarding the neurocognitive changes patients might experience after ketamine exposure. METHODS: This prospective, uncontrolled study describes the neurocognitive functioning of 11 children with chronic pain before and after 2 weeks of daily oral ketamine exposure. Neurocognitive assessment was performed at baseline, Week 2, and Week 14. We hypothesized that there would be declines in neurocognitive scores at either Week 2 or Week 14. RESULTS: No decline in neurocognitive function was detected in the children investigated. Mean scores for tests measuring executive function and memory were improved at Weeks 2 and 14 compared to baseline. DISCUSSION: This study did not detect any decline in neurocognitive scores in a small number of children exposed to 2 weeks of oral ketamine therapy. Randomized, controlled studies of the neurocognitive effects of ketamine in children are recommended to further investigate these preliminary findings.

Diffuse intrinsic pontine gliomas: treatments and controversies.

Diffuse intrinsic pontine gliomas (DIPGs) are a fairly common pediatric brain tumor, and children with these tumors have a dismal prognosis. They generally are diagnosed within the first decade of life, and due to their location within the pons, these tumors are not surgically resectable. The median survival for children with DIPGs is less than 1 year, in spite of decades of clinical trial development of unique approaches to radiation therapy and chemotherapy. Novel therapies are under investigation for these deadly tumors. As clinicians and researchers make a concerted effort to obtain tumor tissue, the molecular signals of these tumors are being investigated in an attempt to uncover targetable therapies for DIPGs. In addition, direct application of chemotherapies into the tumor (convection-enhanced delivery) is being investigated as a novel delivery system for treatment of DIPGs. Overall, DIPGs require creative thinking and a disciplined approach for development of a therapy that can improve the prognosis for these unfortunate children.

Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma.

BACKGROUND: The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective. METHODS: Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m(2)), was administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab. RESULTS: Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0-17.0 years). All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs, 6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4 patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients lived 663 and 481 days from the start of nimotuzumab. CONCLUSIONS: Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG patients appeared to benefit from anti-EGFR antibody treatment.