A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas.

PURPOSE: 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) PATIENTS & METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Level of Supervision for the Entrustable Professional Activities Common to General Pediatrics and the Subspecialties Decreases from Residency to Fellowship.

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.

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

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.

Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial.

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 ±â€…5% and 62 ±â€…5% for all patients, 61 ±â€…8% and 77 ±â€…7% for localized medulloblastoma, and 35 ±â€…7% and 52 ±â€…7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ±â€…6% and 89 ±â€…6% compared with 26 ±â€…6% and 53 ±â€…7% for classic and 38 ±â€…13% and 46 ±â€…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 ±â€…8% for ND and 21 ±â€…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.

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue.

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Randomized trial of high-dose methylprednisolone versus intravenous immunoglobulin for the treatment of acute idiopathic thrombocytopenic purpura in children.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) is an acquired disorder characterized by immune-mediated platelet destruction. The authors performed a prospective, randomized trial comparing intravenous immunoglobulin (IVIG) with high-dose intravenous methylprednisolone in the treatment of children with acute ITP. The primary aim of the study was to compare the rate of platelet increase produced by either intervention. A decision to treat was based on the clinical presentation and not an arbitrary platelet count. In general, enrolled patients exhibited extensive bruising and platelet counts less than 10 x 10 /L (10,000/microL). PATIENTS AND METHODS: Seventy-seven consecutive patients, for whom the attending hematologist determined acute treatment was warranted, were studied. Forty-two patients received IVIG (1 g/kg/dose x2) and 35 received methylprednisolone (30 mg/kg/dose x3). Patients who exhibited an increase in platelet count of more than 50,000/microL after the first IVIG dose or the second methylprednisolone dose did not receive the second IVIG dose or the third methylprednisolone dose, respectively. Patients' ages ranged from 6 months to 15 years. Platelet counts were evaluated at presentation, 24, 48, 72 hours, 1 week, and 2 to 4 weeks. RESULTS: Eighty percent of patients treated with IVIG and 60% of patients treated with methylprednisolone demonstrated an increase in platelet count of 50,000/microL or more within 48 hours. Both IVIG and methylprednisolone therapy increased platelet counts significantly above pretreatment values. In the methylprednisolone group, the mean baseline platelet count was 4,600/microL, which rose to 14,000/microL after 24 hours, 38,000/microL after 48 hours, and 65,000/microL after 72 hours. The IVIG group had a mean baseline platelet count of 4,200/microL, which rose to 32,000/microL after 24 hours, 69,000/microL after 48 hours, and 146,000/microL after 72 hours. When compared with methylprednisolone, IVIG therapy produced a greater rise in platelet counts at 24, 48, and 72 hours, with no difference at 1 week or later time points. No serious bleeding was noted in either treatment group. CONCLUSIONS: Both IVIG and methylprednisolone produce a significant early rise in platelet count that is somewhat greater with IVIG. However, the higher platelet counts produced by IVIG may not justify the additional cost and potential risks of this agent.