Lack of complete response pretransplant is not associated with inferior overall survival for stage 4a metastatic retinoblastoma.

BACKGROUND: Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC-ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre-ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival. PROCEDURE: We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC-ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24). RESULTS: The degree of postinduction response prior to ASCT did not affect outcome, with 5-year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field. CONCLUSION: OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma.

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.

Patterns of relapse for children with localized intracranial ependymoma.

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.

Long-term outcomes of adult medulloblastoma patients treated with radiotherapy.

Medulloblastoma (MB) is rare in adults and treatment guidelines are consequently not well-established. Few modern series have reported long-term follow-up and treatment sequelae. We examined long-term outcomes of adult MB patients at one institution. Records of 29 consecutive patients (18 male, 11 female) aged ≥ 18 years who received radiotherapy (RT) for primary MB from 1990 to 2016 were reviewed. Median age at diagnosis was 28 years (range 18-72 years). Seventeen patients were standard risk and 12 were high risk. Nineteen patients had gross total resection, seven had subtotal resection, and three had biopsy only. Median craniospinal irradiation and boost doses were 36 Gy (range 23.4-39.6 Gy) and 55.8 Gy (range 54-59.4 Gy), respectively. Of 24 patients receiving chemotherapy, 20 received concurrent + adjuvant and 4 received adjuvant only. At median follow-up of 9.0 years (range 1.1-20.5 years), five patients recurred: four in the posterior fossa and one in both the posterior fossa and above the tentorium. Five patients died: two of disease progression and three after possible treatment complications (seizure, lobar pneumonia, and multifactorial sepsis). At last follow-up, 23 patients were alive with no evidence of disease. Long-term effects include executive dysfunction (n = 17), weakness/ataxia (n = 16), and depression/anxiety (n = 13). Kaplan-Meier estimates of 10-year overall survival and failure-free survival are 83% (95% confidence interval [CI] 59-93%) and 79% (CI 55-91%), respectively. Despite encouraging disease control in this cohort, long-term sequelae may limit quality of life. Multimodality pediatric regimens using lower RT doses may be considered to reduce treatment-related morbidity.

A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). CONCLUSIONS: cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

Reduced-volume radiotherapy for patients with localized intracranial nongerminoma germ cell tumors.

Craniospinal irradiation is standard radiotherapy (RT) for localized intracranial nongerminoma germ cell tumors (NGGCT). Given its toxicity, there is interest in using smaller fields. We examined outcomes of NGGCT patients receiving reduced-volume RT at a single institution. Records of 16 patients who received reduced-volume RT as part of definitive treatment between 1996 and 2016 were reviewed. Median age at presentation was 10.8 years (range 4.6-41.0 years). Ten patients had pineal tumors and 6 had suprasellar tumors. All received chemotherapy and 9 patients received second-look surgery thereafter. RT volume was tumor-only to a median of 54 Gy (range 50.4-54 Gy) in 3 patients and whole-ventricle irradiation to a median of 30.6 Gy (range 30.6-36 Gy) with a boost to 54 Gy in 13 patients. Median follow-up was 4.1 years (range 1.9-19.3 years). Three patients recurred locally at a median 9.9 months (range 9.6-10.6 months) after diagnosis, and one of these developed leptomeningeal relapse after 30 months. One patient expired from disease 2.6 years post-diagnosis and another due to stroke 19.3 years post-diagnosis. Fourteen patients are alive with no evidence of disease. Kaplan-Meier estimates of the 4-year overall survival and failure-free survival are 92% (95% confidence interval [CI], 57-99%) and 81% (95% CI 53-94%), respectively. Excellent disease control was observed in these patients with no initial relapses outside of these RT fields. The results of ACNS1123 may better delineate patterns of failure and identify subgroups likely to benefit from this approach.

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.

BACKGROUND: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. PROCEDURE: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m2 /day) and temsirolimus (25-75 mg/m2 IV weekly) were investigated. RESULTS: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. CONCLUSIONS: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

Retrospective Evaluation of Palifermin Use in Nonhematopoietic Stem Cell Transplant Pediatric Patients.

BACKGROUND: Palifermin has been proven to decrease the frequency of severe oral mucositis in adult patients with sarcoma and metastatic colorectal cancer receiving chemotherapy. The impact of palifermin on the incidence of mucositis in nonhematopoietic stem cell transplantation (HSCT) pediatric population receiving chemotherapy has never been reported to date. PATIENTS AND METHODS: This is a retrospective analysis of pediatric patients who received palifermin as secondary prophylaxis to prevent chemotherapy-induced mucositis at Memorial Sloan Kettering Cancer Center from January 1, 2008 to 2014. Data from electronic medical records on days to mucositis resolution, use of opioids, use of total parenteral nutrition, duration of hospitalization, and antibiotics are collected and presented here. RESULTS: A total of 18 patients received palifermin for secondary prophylaxis after developing mucositis from the prior chemotherapy cycle. Mucositis did not reoccur in the subsequent cycle for 13 of the 18 patients. The majority of patients who received palifermin prophylaxis had decreased opioids and antibiotics use and decreased duration of hospitalization. Six of the 7 patients previously requiring total parenteral nutrition due to mucositis had decreased supplemental nutritional needs following the use of palifermin. CONCLUSION: Palifermin may provide benefit as secondary prophylaxis in pediatric patients to prevent chemotherapy-induced mucositis.

Intensity-Modulated Radiation Therapy With Dose Painting: A Brain-Sparing Technique for Intracranial Germ Cell Tumors.

BACKGROUND: We sought to assess patterns of failure in pediatric patients with intracranial germ cell tumors (GCT) treated with intensity-modulated radiation therapy with dose painting (DP-IMRT). PROCEDURE: Between July 2007 and October 2013, 11 patients with localized GCT-five germinomas and six nongerminoma GCT (NGGCT)-received definitive treatment with DP-IMRT. Three representative patients were selected for replanning with (i) whole ventricular irradiation (WVI) with opposed lateral beams plus IMRT to the primary tumor and (ii) sequential IMRT. These plans were compared to the patients' original DP-IMRT plans for dosimetric analyses. RESULTS: Four patients with germinoma received radiation therapy alone: 45 Gy in 1.8 Gy fractions to the primary tumor and 25 Gy in 1.0 Gy fractions to whole ventricles using a dose-painting plan. One patient with germinoma received a reduced dose of 30.6 Gy to the primary tumor after neoadjuvant chemotherapy. Patients with NGGCT (n = 6) underwent multimodality treatment including chemotherapy (n = 6) and surgery (n = 3). These patients received 54 Gy to the primary tumor and 32.4-36 Gy to the whole ventricles. Dosimetric analyses showed DP-IMRT delivered decreased mean dose to whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With median follow-up of 4 years, 3-year failure-free survival was 100% for patients with germinoma and 67% for patients with NGGCT. One patient with a pineal NGGCT experienced a local recurrence within the high dose-volume while another experienced an isolated biochemical failure. CONCLUSIONS: DP-IMRT is dosimetrically superior to standard IMRT techniques for sparing of normal tissues. Disease control in this small series appears at least comparable to published results.

Extraneural metastases of medulloblastoma: desmoplastic variants may have prolonged survival.

BACKGROUND: Extraneural metastases from CNS medulloblastoma are rare and poorly described. The purpose of this study is to describe the clinical and radiological characteristics of a large single institution series of patients with medulloblastoma who developed extraneural metastases. PROCEDURE: We retrospectively reviewed a departmental database over a 20 year period for all patients with medulloblastoma who developed extraneural metastases. Chart and imaging reviews were performed, and overall survival (OS) estimated by the Kaplan-Meier method. RESULTS: We found 14 patients with medulloblastoma and extraneural metastases. The median age at initial diagnosis was 16.3 years (range, 3.2-44.2), and the most common subtype was desmoplastic (n = 6, 42.9%). After initial gross total resection, most patients received radiation therapy alone (n = 10, 71.4%). Metastases to bone were most common (n = 11, 78.6%) followed by metastases to bone marrow (n = 6, 42.9%), usually to the spine. The median time from initial diagnosis to first extraneural metastasis was 1.5 years (range, 0.2-17.4), and the median OS from extraneural metastasis to death was 3.3 years (range, 0-18). The Kaplan-Meier estimate of 5 year OS from extraneural metastasis diagnosis was 40.0% (95% CI, 20.2-79.2). CONCLUSIONS: Extraneural metastases from medulloblastoma may rarely develop after initial diagnosis to involve bone and bone marrow. We found that desmoplastic variant extraneural tumors had longer survival than nondesmoplastic variants, suggesting that histopathological and more recent molecular subtyping have important roles in determining the prognosis of medulloblastoma patients.

Marker (+) CNS germ cell tumors in remission: are surveillance MRI scans necessary?

BACKGROUND: Patients with marker (+) CNS germ cell tumors are usually followed with both surveillance MRI scans and serum tumor markers. We hypothesized that patients with elevated serum tumor markers at diagnosis who achieve a complete biochemical and radiological remission may not need surveillance MRI scans. PROCEDURE: We retrospectively identified 31 patients with CNS germ cell tumors who presented with an elevated serum tumor marker at the time of diagnosis. We reviewed the records of those patients who (1) achieved a complete biochemical and radiological remission and (2) later suffered tumor recurrence to determine whether the recurrence was detectable biochemically, radiologically, or via both modalities. RESULTS: Nine patients suffered tumor recurrence following initial remission. All 9 had elevated serum tumor markers at recurrence and 8 had MRI evidence of recurrence. The 1 patient with isolated biochemical evidence of recurrence developed MRI evidence of recurrence 15 months later without intervening treatment. One other patient (not one of the 9) had a secondary malignancy (anaplastic astrocytoma) identified by brain MRI scan. CONCLUSIONS: Patients with CNS germ cell tumors who present with elevated serum tumor markers at diagnosis and achieve a complete biochemical and radiological remission may not need surveillance MRI scans to monitor for recurrence, but MRI scans may be considered to monitor for secondary malignancy. If other series replicate these findings, surveillance via monitoring of serum tumor markers only could be done and omission or reduction of the frequency of surveillance MRI scans could save a significant amount of money.

A case of mannitol hypersensitivity.

Mannitol is used for increased intracranial pressure and prevention of nephrotoxicity. We present a case report of a patient who experienced an anaphylactic response to mannitol and review the literature.

Diffusion-weighted imaging to assess treatment response in a child with trilateral retinoblastoma.

Trilateral retinoblastoma (TRb) is a rare condition in which children with bilateral retinoblastoma develop primary midline intracranial neuroblastic tumors. The intracranial lesions are difficult to follow after treatment due to residual mass-like enhancement that may represent persistent tumor or treated disease. We highlight a case where close evaluation of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) characteristics accurately depicted the extent of treated disease versus residual tumor after chemotherapy.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters.

The microscope - the classical tool for the investigation of cells and tissues - remains the basis for the classification of tumors throughout the body. Nowhere has this been more true than in the grading of astrocytomas. In spite of the fact that our parents warned us not to judge a book by its cover, we have continued to assume that adult and pediatric malignant gliomas that look the same, will have the same mutations, and thus respond to the same therapy. Rapid advances in molecular biology have permitted us the opportunity to go inside the cell and characterize the genetic events that underlie the true molecular heterogeneity of adult and pediatric brain tumors. In this paper, we will discuss some of the important clinical differences between pediatric and adult gliomas, with a focus on the molecular analysis of these different age groups.

Next-generation sequencing of cerebrospinal fluid for clinical molecular diagnostics in pediatric, adolescent and young adult brain tumor patients.

BACKGROUND: Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests. METHODS: We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. RESULTS: We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient's disease course. CONCLUSIONS: We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.

Reirradiation for recurrent medulloblastoma.

BACKGROUND: Previously irradiated recurrent medulloblastoma (MB) is a highly lethal disease. Reirradiation is often not considered secondary to its potential toxicity and uncertain efficacy. Analysis of retreatment could help identify the feasibility and role of reirradiation for recurrent MB. METHODS: Thirteen patients who underwent at least 1 course of reirradiation at the authors' institution as a component of management after recurrence were identified, and their medical records were analyzed. RESULTS: At first diagnosis, all patients underwent surgical resection and radiation, with 69% of patients receiving chemotherapy. Median time to initial failure was 50 months (range, 14-103 months). Reirradiation subsite breakdown was as follows: posterior fossa, 46%; supratentorial/whole brain, 31%; spine, 23%; craniospinal, 8%. Median cumulative dose was 84 grays (range, 65-98.4 grays). Of 11 patients completing a full course of reirradiation, there were 6 failures, with 3 in the reirradiation field. Kaplan-Meier estimates of progression-free and overall survival since time of first recurrence were 48% and 65%, respectively at 5 years. Of patients without gross disease at reirradiation, 83% were without evidence of disease at last follow-up. With a median follow-up of 30 months, reirradiation was well tolerated, with only 1 case of asymptomatic, in-field radiation necrosis. CONCLUSIONS: The results in this series are promising, but must be interpreted with caution given the limitations. Reirradiation provided most benefit to patients with no evidence of disease after surgical re-resection, and least to patients with gross disease. Important considerations for reirradiation toxicity development include duration between radiation courses and patient age. Further study of reirradiation as part of trimodality therapy is warranted.

Novel use of zolpidem in cerebellar mutism syndrome.

Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery seen primarily in pediatric patients after resection of medulloblastoma. CMS is characterized by mutism, ataxia, hypotonia, and irritability. Currently, there is no therapy of proven efficacy. Zolpidem, although primarily used as a sedative, has been shown to alleviate mutism and promote arousal in similar neurologic and psychiatric disorders. Here, we describe a child with severe CMS in whom zolpidem seemed to increase arousal, accelerate the resolution of mutism, and decrease emotional lability. Our report suggests that clinicians should consider using zolpidem for patients with CMS.

Stepwise Strategic Mitigation Planning in a Pediatric Oncology Center During the COVID-19 Pandemic.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reached the United States in January 2020. Located in New York City (NYC), MSK Kids, at Memorial Sloan Kettering Cancer Center services, is one of the largest pediatric cancer centers in the U.S., caring for children, teenagers, and young adults with cancer, immune deficiencies, and blood disorders. Methods: Implementation for infection mitigation and ongoing care of patients included: (1) the creation of a strategic planning team of physicians, advanced practice providers, nurses, and administrators to develop guidance and workflows, (2) continuous reassessment of patients' needs for hospital services and visit frequency, (3) the use of telemedicine to replace in-person visits, (4) the use of satellite regional centers to manage patients living outside NYC, (5) pre-screening of patients prior to visits for risks and symptoms of coronavirus disease 2019 (COVID-19) infection, (6) day-of-service screening for risks or symptoms of COVID-19 infection, (7) surveillance testing of children and their caregivers, and (8) creation of cohort plans for the management of COVID-19 positive and uninfected patients within the same institution, in both the outpatient and inpatient settings. Results: We describe the timeline for planning mitigation during the first weeks of the pandemic, and detail in a stepwise fashion the rationale and implementation of COVID-19 containment efforts in the context of a large pediatric oncology program. Discussion: Our experience offers a model on which to base strategic planning efforts at other pediatric oncology centers, for continued preparedness to combat the threat posed by SARS-CoV-2 worldwide.

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.