Characterizing age-related differences in Hodgkin lymphoma in children, adolescents and young adults.

Current studies describing younger children with Hodgkin lymphoma are limited by geographical region, small sample sizes and variable age groups. Although published data is lacking, there appears to be a trend toward a higher male to female ratio and a higher proportion of mixed cellularity subtype when compared to older cohorts. We performed a retrospective multicenter study utilizing the Pediatric Health Information System® database to evaluate patients aged 0-39 years with Hodgkin lymphoma. We identified 3,034 unique patients who met inclusion criteria. Younger age groups had a larger proportion of males, Hispanic/Latino ethnicity, and mixed cellularity subtype. Treatment-related complications, including mucositis, pain, bacterial infections, and thrombosis, were documented more frequently in older cohorts. We also found significant age-related differences in medical management. This study is the largest study evaluating age-related differences in patients with Hodgkin lymphomaand the first study to evaluate for differences in complicationsand supportive care management.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

Prevalence of Duffy null and its impact on hydroxyurea in young children with sickle cell disease in the United States.

Consistent with studies showing a high prevalence of the Duffy null phenotype among healthy Black Americans, this retrospective study found that Duffy null was present in >75% of a young and contemporary cohort of children with sickle cell disease (SCD) in the United States. Despite the potential for this phenotype to impact absolute neutrophil counts, hydroxyurea (HU) dosing, and outcomes, it was not associated with being prescribed a lower HU dose or having increased acute SCD visits early in the HU treatment course. Future studies are needed to confirm these findings in older children with SCD.

Improving Anticoagulation Care for Pediatric Oncology Patients: A Quality Improvement Initiative.

Background: Cancer is associated with increased venous thromboembolism in children. Risk factors for venous thromboembolism in this cohort include using central venous catheters, mass effect from underlying malignancy, chemotherapy, and surgery. Anticoagulation management in this cohort is challenging, given recurrent episodes of thrombocytopenia, the need for invasive procedures, and coagulopathy. A quality improvement (QI) initiative was developed to improve hematology consultation services and provide documentation of an individualized anticoagulation care plan for this high-risk cohort. Methods: Through the use of QI methods, interviews of stakeholders, expert consensus, and review of baseline data, a multidisciplinary team was organized, and key drivers relevant to improving access to hematology consultations and documentation of individualized anticoagulation care plans were identified. We used a Plan-Do-Study-Act model to improve hematology consultations and documentation of anticoagulation care plan (process measure). Outcome measures were bleeding and thrombosis recurrence/progression. Results: Seventeen patients with oncologic and venous thromboembolism diagnoses were included as baseline data. Slightly over half of these patients [53% (n = 9)] had a hematology consultation, and 7 (43.8%) had documentation of an anticoagulation care plan. After implementing QI methods, all 34 patients (100%) received hematology consultations and documentation of an anticoagulation care plan, and this measure was sustained for 1 year. Bleeding and thrombosis rates were similar in the baseline and post-QI cohorts. Conclusions: QI interventions proved effective in sustaining access to hematology consultations and providing anticoagulation care plans for patients with concomitant improved anticoagulation plan documentation for patients.

Comparison of Outcomes Between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents With Sentinel Lymph Node-Positive Cutaneous Melanoma.

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.

Variability in Surveillance Strategies Following Resection of Sacrococcygeal Teratoma.

INTRODUCTION: Surveillance following sacrococcygeal teratoma (SCT) resection varies. The purpose of this study was to describe the clinical characteristics and outcomes of patients undergoing SCT resection and examine current institutional practices to detect recurrence. METHODS: A single-institution retrospective review of children who underwent resection of an SCT from January 1, 2010 to December 31, 2020 was performed. Data were summarized and surveillance strategies compared between histopathologic subtypes using nonparametric methods. RESULTS: Thirty six patients (75.0% female) underwent SCT removal at a median age of 8 d. Histopathology revealed 27 mature teratomas (75.0%), eight immature teratomas (22.2%), and one malignant germ cell tumor (2.8%). Median postoperative follow-up was 3.17 y (interquartile range [IQR]: 2.31-4.38 y). Patients had a median of 2.32 clinic visits per year (IQR: 2.00-2.70), alpha-fetoprotein levels were obtained at a median of 2.01 times per year (IQR: 0-1.66), and surveillance imaging was performed at a median of 2.31 times per year (IQR: 0-2.84). Patients with immature teratomas had alpha-fetoprotein laboratories obtained more frequently than patients with mature teratomas (3.10 times/year versus 0.93 times/year, P = 0.001). There was no significant difference in the number of imaging studies obtained between groups. Two patients (5.6%) developed recurrence, which were identified on magnetic resonance imaging at 191 and 104 d postresection, respectively. CONCLUSIONS: Postoperative surveillance practices varied widely. Recurrence was noted in a single malignant case in the first year following resection. Multi-institutional studies are needed to determine the optimal surveillance strategy to detect recurrence of SCT.

Development of a Novel Massage Therapy Outcome Measure for Children and Young Adults Receiving Hematopoietic Cell Transplant.

Background: Children receiving hematopoietic stem cell transplantation (HCT) often experience an unfortunate sequalae of negative effects including pain, deconditioning, and anxiety. Massage therapy (MT) has demonstrated effective non-pharmacological management of fatigue, pain, and anxiety in patients undergoing cancer treatment. Existing studies have been limited by the lack of available MT-specific outcome measures to track responses to interventions. Purpose: This study aimed to describe the creation of a novel MT-specific outcome measure to be utilized in the pediatric acute-care setting and establish construct validity for this measure to assess clinical effectiveness of MT interventions. Setting: An oncology ward at a large pediatric tertiary medical center in the United States. Participants: A total of 58 children and young adults undergoing HCT. Research Design: Retrospective Cohort Study. Intervention: A panel of massage therapists created a novel outcome measure, OMPREP, for use in MT sessions and performed a literature review to ensure face validity of the tool. This outcome measure was administered to patients and data were collected retrospectively to assess construct validity. Results: A total of 1,333 MT sessions were completed (80.7% completion rate) with the novel OMPREP outcome measure utilized on 100% of visits. Mean engagement (p<.001), response (p<.001), and pain (p<.001) scores were all significantly greater at evaluation and discharge compared to the lowest observed scores post-HCT. Conclusion: The novel MT-specific outcome measure, OMPREP, was feasible and demonstrated construct validity when implemented in a pediatric acute-care setting by massage therapists. This new tool may offer a quantitative measure of MT-interventions and assist in tracking patient outcomes.

Peritoneal and Pleural Drains in Pediatric Hematopoietic Cell Transplant Recipients with Veno-Occlusive Disease are Safe and Do Not Adversely Impact Clinical Outcomes.

There is a lack of data on the safety and efficacy of peritoneal drain (PD) and chest tube (CT) in the management of effusions in stem cell transplant recipients with veno-occlusive disease (VOD). In this retrospective pediatric study, clinical outcomes and health resource utilization (HRU) were compared in 32 patients with VOD who had a PD (PD+) post-HCT versus 27 patients who did not (PD-). Nine patients also had a CT (7 PD+ and 2 PD-). PD + patients were more likely than PD-patients to have received myeloablative conditioning (100% vs. 85.2%; p = 0.04) and have severe or very severe VOD (100% vs. 56% p < 0.01). Mechanical obstruction (38%) and hypotension (38%) were common complications, and 13% developed peritonitis. While the frequencies of cardiac dysfunction and acute kidney injury were comparable between both groups, respiratory support and its median duration were higher in PD + patients. The hospital and intensive care unit length of stay, albumin use, and the duration of defibrotide and albumin therapy was significantly longer in PD + patients. At a median follow-up of 1.04 years (range:0.03-14.6), the 2-year overall survival was similar in both groups (53.8% vs. 51.5%; p = 0.73). Although PD use was similar between 1995 and 2007 vs. 2008-2021; (47% vs. 58%; p = 0.65), day+100 mortality was improved in recent years (53.3% vs. 17.8%; p = 0.01), coinciding with the use of defibrotide (0% vs. 84%; p < 0.01). PD in pediatric patients with VOD post-HCT, although associated with increased HRU, was safe when clinically indicated and did not adversely impact clinical outcomes.

Outcomes of a radiation sparing approach in medulloblastoma by subgroup in young children: an institutional review.

OBJECTIVE: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT.

Closing knowledge gaps among parents of children with sickle cell trait.

BACKGROUND: Despite needing to be informed about sickle cell trait (SCT) status to make informed reproductive decisions, more than 80% of adults with SCT, including parents of children with SCT who have a high prevalence of SCT, do not know their status. PROCEDURE: This was a prospective study of parents who received SCT telephone education from the state department of health and then completed SCTaware, a videoconference-administered SCT education program. The objectives were to evaluate knowledge after telephone education and explore if SCTaware closes knowledge gaps. Participants completed a demographic survey, a health literacy assessment, and reported their SCT status. They completed the Sickle Cell Trait Knowledge Assessment before receiving SCTaware, immediately after, and at follow-up visits; high knowledge was a score of 75% or higher correct. RESULTS: SCTaware and the initial surveys were completed by 61 parents; 45 completed the 6-month surveys. Only 43% of participants had high SCT knowledge after telephone education; 92% achieved high knowledge immediately after, and 84% continued with high knowledge at 6 months. Most parents reported they were aware of their SCT status after telephone education; 12 changed their response after receiving SCTaware. CONCLUSIONS: Our findings suggest that over half of parents have low SCT knowledge following telephone education, and many may be unaware of their status. SCTaware closes knowledge gaps, leads to high sustained knowledge, and is a potentially scalable tool. Future studies should refine SCTaware and determine if parents use their knowledge to inform their children and reproductive decisions.

Description of a Colocated Comprehensive Care Model for People With Sickle Cell and Comorbid Pulmonary Disease.

Comorbid pulmonary complications in people with sickle cell disease (pwSCD) are associated with high rates of morbidity and mortality, and poor access to care contributes to poor outcomes among this particularly high-risk pwSCD. Our purpose was to describe the population served and the resources required for hematology, pulmonary, nursing, respiratory therapy, social work, genetics, psychology, and school liaison providers to see these patients in an integrated clinic. We abstracted demographic, medication, clinical, and diagnostics data of the pwSCD seen at least once in this clinic from February 1, 2014 to December 10, 2020 from the electronic medical record and identified 145 unique pwSCD. Abnormal lung function and bronchodilator responsiveness were detected in 31% and 42% of participants respectively. Sleep abnormalities were found in over two-thirds of those screened and 65% had ≥1 previous acute chest syndrome episode. This clinic also allowed for direct provider communication and required relatively limited resources to serve a large number of severely affected pwSCD. Given the degree of abnormal respiratory variables detected and the limited resources required to implement this model, studies are warranted to evaluate whether it has the potential to improve outcomes in high-risk populations.

Prevalence and Risk Factors for Pulmonary Embolism in Pediatric Sickle Cell Disease: A National Administrative Database Study.

Patients with sickle cell disease (SCD) have a high risk for venous thromboembolism which is associated with increased risk of mortality. Studies examining risk of pulmonary embolism (PE) in children with SCD are lacking. This study was conducted in children with SCD between 0-21 years of age using a nationwide administrative database in the United States- Pediatric Health Information System (PHIS) from January 2010 to June 2021. Diagnostic codes and imaging, procedure, and pharmaceutical billing codes were used to identify PE and potential clinical, demographic, and utilization risk factors. Logistic regression analyses were performed to assess association between risk factors and PE. We identified 22,631 unique patients with SCD with a median age of 10.8 years (range: <0.1-20.9). A total of 120 (0.53%) patients developed a PE with median age of 17.4 years (range: 6.6-20.9) at PE diagnosis. Patients with PE had longer hospitalization and more frequent ICU admissions than patients without PE (p < 0.001). Risk factors significantly associated with PE on multivariable analysis included older age, prior history of central venous line (CVL), acute chest syndrome, and apheresis. Mortality was not significantly different between those with and without PE. The prevalence of PE in hospitalized children with SCD was estimated to be 0.53%. Patients with PE had higher healthcare utilization characteristics. Factors significantly associated with PE suggest that the risk for PE in SCD may be related to the severity of disease state. Future trials are needed for risk stratification and PE prevention strategies in children with SCD.

Intracardiac thrombi in pediatrics: anticoagulation approach and treatment outcomes.

Background: Intracardiac thrombi (ICT) are associated with significant morbidity and mortality. Anticoagulation is the first line of treatment and may be complemented by thrombectomy or thrombolysis. However, optimal anticoagulant duration remains ill-defined. High-risk features of ICT that may warrant long-term anticoagulation therapy have not been established. Objectives: To describe anticoagulation duration and patterns of ICT resolution. To identify potential risk factors for persistent ICT despite anticoagulation. Methods: A single-institution retrospective chart review identified patients diagnosed with ICT by echocardiogram between January 2014 and March 2022. Descriptive statistics and logistic regression were used. Results: Fifty-one patients with ICT were identified. Median age at diagnosis was 9.2 years (IQR, 0.4-15.2). The most common underlying diagnoses were congenital heart disease (41%), infection (25%), and malignancy (24%). The majority of ICT were in the right atrium (n = 30). The median longest ICT dimension was 1.5 cm (range, 0.4-4.0). The median duration of anticoagulation was 4.3 months (IQR, 2.2-9.1). Among 48 patients who received anticoagulation as first-line treatment, 32 had partial or complete response with 3 to 6 months of anticoagulation, while remaining 16 patients had no response to anticoagulation. Patients with a central venous line had a delayed resolution of ICT [hazards ratio = 0.45 (95% CI, 0.22-0.93)]. Conclusion: Our study demonstrates the wide variability in duration of anticoagulation for children with ICT. Majority of the individuals benefit from 3-to-6 month treatment; however, individuals with a central venous line may benefit from a longer course of anticoagulation. Further large-scale studies are recommended to validate our findings.

Immunohistochemical assessment and clinical, histopathologic, and molecular correlates of membranous somatostatin type-2A receptor expression in high-risk pediatric central nervous system tumors.

Introduction: 177Lu-DOTATATE, a radionuclide therapy that binds somatostatin type-2A receptors (SST2A), has demonstrated efficacy in neuroendocrine tumors and evidence of central nervous system (CNS) penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. Methods: SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by an experienced pathologist (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (<10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (Range: 0-12). Results: A total of 120 tumor samples from 114 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean ± SD: 7.5 ± 3.6 [n=38]) and meningioma (5.7 ± 3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3 ± 0.6 [n=3]), ETMR (1.0 ± 0 [n=3]), ependymoma (grades I-III; 0.2 ± 0.7 [n=27]), and high-grade glioma (grades III-IV; 0.4 ± 0.7 [n=23]). Pineoblastoma (3.8 ± 1.5 [n=4]) and other embryonal tumors (2.0 ± 4.0 [n=7]) exhibited intermediate, variable expression. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.5 ± 3.1) than SHH (5.0 ± 3.3) molecular subgroups (p=0.033). In a subset of paired primary and recurrent specimens from four patients, SST2A IHC scores remained largely unchanged. Discussion: High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

Constipation and GI diagnoses in children with solid tumours: prevalence and management.

OBJECTIVES: Despite continued development of targeted therapies for children with cancer, patients continue to experience an array of unwanted side effects. Children with solid tumours may experience constipation as a result of vinca alkaloid therapy, psychological stressors, periods of inactivity and opioid use. Our objective was to investigate the prevalence and treatment of constipation in hospitalised children with solid tumours treated with chemotherapy. METHODS: We retrospectively analysed data from 48 children's hospitals in the Pediatric Health Information System, extracting patients 0-21 years of age with a solid tumour diagnosis hospitalised from October 2015 through December 2019. RESULTS: We identified 13 375 unique patients with a solid tumour diagnosis receiving chemotherapy. Constipation was the most common gastrointestinal complaint with 8658 (64.7%; 95% Cl: 63.9% to 65.5%) having a constipation diagnosis or having received at least two laxatives during admission. Bone cancers had the highest percentage (69.9%) of patients with constipation, while Hodgkin's lymphoma had the lowest, although 52.1% of patients were affected. A total of 44% (n=35 301) of encounters received an opioid at some point during admission. Of patients receiving constipation medications, the most commonly prescribed was polyethyl glycol (n=25 175, 31.7%), followed by docusate (n=11 297, 14.2%), senna (n=10 325, 13.0%) and lactulose (n=5501, 6.9%). CONCLUSIONS: Constipation is the most common gastrointestinal issue that children with solid tumours experience while receiving chemotherapy in the inpatient setting. Increased attention should be given to constipation prophylaxis and treatment in children with solid tumours undergoing chemotherapy, particularly those identified as high risk.

Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics.

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome.

PURPOSE: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. METHODS: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. RESULTS: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n = 13; 31.7%), followed by posterior fossa (n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. CONCLUSION: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

Caregiver Perspectives on Patient Participation in Biological Pediatric Cancer Research.

Adolescent cancer patients and their caregivers have demonstrated willingness to participate in invasive biological sampling, either for their own potential benefit or for research purposes. However, many malignancies occur primarily in prepubescent patients and there are no similar studies in this population. Our study objective was to assess the willingness of caregivers to consent to research studies involving invasive biological sampling in children ≤ 13 years of age. Participants completed a survey assessing their willingness to allow various procedures both with and without clinical benefit to their children. Most respondents were willing to allow additional blood draws regardless of potential benefit to their children (95.6% were willing when there would be benefits and 95.6% were willing when there would not). Although the overall willingness was lower with other hypothetical procedures, the majority of respondents were still willing to allow additional biopsies for research purposes. Caregivers of young children with cancer will allow their children to undergo additional invasive procedures for research purposes. This willingness decreased with more invasive procedures without potential direct benefit, but interest remained in more than half of participants. Caregivers for young patients with cancer should be approached for participation in future biological/correlative studies.

Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report.

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

Factors influencing outcomes of older children with medulloblastoma over 15 years in Peru, a resource-limited setting.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-to-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997-2008 and 2009-2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, whereas prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The 5-year OS was 62% (95% CI: 53%-74%), while EFS was 57% (95% CI: 48%-69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31-60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009-2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03). CONCLUSIONS: Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009-2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.