BACKGROUND AND OBJECTIVES:The American Board of Pediatrics requires that proposed changes to the duration of pediatric subspecialty training must include a framework for competency assessment with a measurement component. We analyzed the clinical Entrustable Professional Activity (EPA) level of supervision ratings across 3-year pediatric fellowships to determine if trainees met the minimum thresholds for graduation after 2 years of fellowship training. METHODS:From spring 2019 through spring 2022, Clinical Competency Committees (CCCs) reported fellow supervision level ratings for all clinical EPAs, fellowship program directors (FPDs) assessed the scholarship EPA supervision level, and fellows self-reported their required level of supervision for all EPAs. Ratings were compared with minimum supervision level thresholds for fellow graduation previously identified by FPDs. We analyzed the proportion of fellows achieving these EPA supervision level thresholds after 2 and 3 years of training. RESULTS:CCCs reported ratings for 1538 second-year and 1505 third-year fellows. Fewer than 50% of fellows met clinical EPA supervision level thresholds for graduation after 2 years of training, increasing to 86%-100% across subspecialties at 3 years. Fellow self-assessment aligned well with CCC ratings. FPDs reported that 64%-68% of fellows across subspecialties met the scholarship EPA supervision level threshold for graduation after 2 years compared with 99%-100% at 3 years. CONCLUSIONS:As pediatric fellowships are currently structured and using an EPA assessment framework, many trainees are not ready to graduate after 2 years.

BACKGROUND:High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG.OBJECTIVE:To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group.DESIGN/METHOD:Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of mebendazole in combination with bevacizumab (10 mg/kg/dose) and irinotecan (150 mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles.RESULTS:Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50 mg/kg/day (n = 3), 100 mg/kg/day (n = 4), and 200 mg/kg/day (n = 3). One subject assigned to 100 mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n = 3) and lymphopenia (n = 4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10 months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4 months, respectively.CONCLUSION:Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200 mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

OBJECTIVES : To compare level of supervision (LOS) ratings of graduating pediatric residents with their assessments as fellows for the five Entrustable Professional Activities (EPAs) common to general pediatrics and the subspecialties and to determine if the difference between ratings from residency to fellowship is less for the QI and Practice Management EPAs, since the skills needed to perform these may be less context-dependent. METHODS : We compared ratings of graduating residents with their assessments as fellows using LOS data from two sequential EPA studies. RESULTS : There were 65 ratings from 41 residents at the first fellow assessment. At graduation, most residents needed little to no supervision for all EPAs with 94% (61/65) of ratings level four or five. In contrast, only 5/65 (8%) of the first fellow assessments were level four or five. The ratings difference for the QI and Practice Management EPAs was similar to the others. CONCLUSIONS : LOS ratings for the EPAs common to generalists and subspecialists reset as residents become fellows. There was no evidence that the QI and Practice Management EPAs are less context-dependent. This study provides additional validity evidence for using these LOS scales to assess trainees in pediatric residency and fellowship.

BACKGROUND AND OBJECTIVES Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors’ (FPD) perceptions of EPAs and Milestones. METHODS We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

BackgroundPegylated form of E. coli derived asparaginase (PEG) is a crucial component of pediatric ALL therapy. Patients who develop a hypersensitivity (HSR) reaction with PEG receive an alternative form - Erwinia asparaginase (EA). However, an international shortage in 2017 had made it challenging to treat these patients. We have developed a comprehensive strategy to address this need.Patients and methodsThis is a single center, retrospective analysis. All patients receiving PEG were premedicated to reduce infusion reactions. Patients who developed HSR underwent PEG desensitization. Patients were compared to historic controls.ResultsFifty-six patients were treated within the study period. There was no difference in the frequency of reactions before and after the adoption of universal premedication (p = 0.78). Eight patients (14.2%) developed either >= Grade 2 HSR or silent inactivation and 5 patients (62.5%) successfully underwent desensitization. The remaining three patients received EA asparaginase. This intervention led to a decrease in PEG substitution, with 3 patients (5.3%) requiring EA compared to 8 patients (15.09%) in the pre-intervention period. (p = 0.11) PEG desensitization was more cost effective than EA administration.ConclusionPEG desensitization is a safe, cost effective, and practical alternative in children with ALL and a Grade 2 or higher HSR.

SUCCESSFUL USE OF CRUSHED FORMULATION OF DABRAFENIB AND TRAMETINIB IN A PEDIATRIC GLIONEURAL TUMORTania Mamdouhi1, Anshul Vagrecha2, Alan A. Johnson1,3, Carolyn Fein Levy1,2, Mark Atlas 1,2, Julie I. Krystal 1,2 1 Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY2 Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children’s Medical Center, New Hyde Park, NY3 Department of Radiology, Division of Neuroradiology, Long Island Jewish Medical Center, New Hyde Park, NYCorresponding Author : Julie Krystal. Cohen Children’s Medical Center, 269- 01 76th Avenue, Suite 255, New Hyde Park, NY 11040. Jkrystal12@northwell.edu. Phone 718-470-3460. Fax 718-343-4642.Tables: 0Figures: 1Supporting Information Files : 0Short running title: Use of crushed formulation of dabrafenib and trametinibKeywords : Dabrafenib, Trametinib, BRAF, crushedData Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.

BACKGROUND:"Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS:Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS:Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ± 5% and 62 ± 5% for all patients, 61 ± 8% and 77 ± 7% for localized medulloblastoma, and 35 ± 7% and 52 ± 7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ± 6% and 89 ± 6% compared with 26 ± 6% and 53 ± 7% for classic and 38 ± 13% and 46 ± 14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ± 8% for ND and 21 ± 5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average. CONCLUSION:We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

Abstract INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is an aggressive and fatal pediatric brain tumor. Due to its difficult anatomic location and infiltrative nature, DIPGs are not surgically resectable and more than 90% of children die within two years of diagnosis. Historically, standard of care has consisted of clinical and radiological diagnosis followed by palliative radiation for symptomatic relief. Although tumor biopsy is not necessary for diagnosis, there is debate as to whether the procedure provides benefits that outweighs its risk. Recent studies have proposed that biopsy-driven molecular characterization of these tumors can inform prognosis and identify potential treatment targets that could lead to clinical breakthroughs. METHODS This study was a retrospective chart review of 26 patients treated for a DIPG diagnosis between July 1998 and July 2019 at Cohen Children’s Medical Center. We compared outcomes of biopsied vs. non-biopsied DIPG patients through quantitative data analyzing the number and types of treatment given. We analyzed post-surgical data regarding safety of DIPG biopsies which were performed by optical stereotactic needle biopsy or robot-assisted stereotactic biopsy procedures. RESULTS There were no permanent biopsy complications in any patient and biopsy did not delay treatment as average hospital stay was 1.5 days. All biopsies collected sufficient material for next generation sequencing analysis and revealed targetable mutations for available clinical trial therapies. 67% of patients were subsequently enrolled in clinical trials, 75% of which required biopsy results for enrollment. MGMT promoter methylation assay results in all tested DIPG biopsy cases indicated resistance to temozolomide, the most common treatment agent given to non-biopsied patients. CONCLUSION Biopsy of DIPG tumors is a safe and accurate procedure that does not delay treatment and identifies molecular targets for individualized therapy. The role of biopsy in DIPG patients allows for molecular characterization of DIPG tumors which informs and increases treatment options.

This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6 weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) Children and young adults < 22 years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54–59.4 Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116 mg/m2/day × 21 days of a 28-day cycle. Twenty-nine patients (age range 4–19 years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116 mg/m2/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. The RP2D of lenalidomide administered daily during radiation therapy is 116 mg/m2/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

Introduction Published curricula to teach communication skills for postgraduate fellows in oncology are few in number despite the fact that oncologists conduct many difficult discussions with their patients and their families. Such discussions may include disclosing initial diagnosis or relapse of a patient's cancer or relaying a poor prognosis or change to palliative care. Methods An eight-module course on communication in oncology practice was delivered over 2 months for palliative and oncology fellows and radiation oncology residents. Learners were given a precourse survey in which they were asked to rate their proficiency in various communication tasks. Each learner then participated in a videotaped precourse objective structured clinical exam (OSCE) on breaking bad news with standardized patients (SPs). The course took place over 8 weeks with weekly didactics and role-play. At the end of the course, a second OSCE took place. After the course was completed, the fellows again filled out a proficiency survey. Results Twenty-two learners participated over 2 years of this course. Participants reported a significant increase in perceived competence in all areas on the postcourse survey. SP feedback on OSCEs pre- and postcourse indicated improvement in skills for learners. Pre- and postcourse OSCE video assessment revealed a significant improvement in global communication skills. Discussion Initial data show that this course successfully improved communication skills and increased fellows' comfort level across several domains of communication. Future directions include validating our assessment tool, expanding the topic base, and investigating the impact on practice after course completion.

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

Tumors of the central nervous system (CNS) are the second most common group of cancers in childhood, accounting for 20% of all childhood malignancies, and affecting 35 per million children. A total of 60–70% of childhood CNS tumors arise from glial cells and tend not to metastasize outside the CNS. The relative frequency of specific CNS tumor types can be seen in Table 23.1.

BackgroundAtypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required.Materials and MethodsNineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction.ResultsNineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 219% and 26 +/- 10%, respectively. Five patients received irradiation at progression with only one long-term survivor.ConclusionA minority of children with CNS AT/RT treated on HS III may be long-term survivors without irradiation. More effective therapies are desperately needed. Pediatr Blood Cancer 2014;61:95-101. (c) 2013 Wiley Periodicals, Inc.

Humanism and professionalism are virtues intrinsic to the practice of medicine, for which we lack a standard, evidence‐based approach for teaching and evaluation. Pediatric hematology‐oncology (PHO) fellowship training brings new and significant stressors, making it an attractive setting for innovation in humanism and professionalism training.