Recurrence Patterns and Surveillance Imaging in Pediatric Brain Tumor Survivors.

Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in pediatric central nervous system (CNS) tumors. The frequency of neuroimaging surveillance varies without a standardized approach. A single-institutional retrospective cohort study evaluated the frequency of recurrences. This study included 476 patients with the majority diagnosed with low-grade glioma (LGG) (n=138, 29%), high-grade glioma (HGG) (n=77, 16%), ependymoma (n=70, 15%), or medulloblastoma (n=61, 13%). LGG, HGG, and ependymoma patients more commonly had multiply recurrent disease ( P =0.08), with ependymoma patients demonstrating ≥2 relapses in 47% of cases. Recurrent disease was identified by imaging more often than clinical symptoms (65% vs. 32%; P =<0.01). Patients diagnosed with meningioma demonstrated the longest mean time to first relapse (74.7 mo) whereas those with atypical teratoid rhabdoid tumor and choroid plexus carcinoma tended to have the shortest time to relapse (8.9 and 9 mo, respectively). Overall, 22 patients sustained first relapse >10 years from initial diagnosis. With a higher tendency toward detection of tumor recurrence/progression on MRI surveillance in comparison to clinical progression, surveillance imaging is necessary in routine follow up of pediatric CNS tumor survivors. With some relapses >10 years from initial diagnosis, imaging beyond this time point may be useful in particular tumor types. While the study is limited in outcome analysis, earlier detection of recurrence would lead to earlier initiation of treatment and implementation of salvage treatment regimens which can impact survival and quality of life.

Using IT to Improve Outcomes for Children Living With Cancer (SyMon-SAYS): Protocol for a Single-Institution Waitlist Randomized Controlled Trial.

BACKGROUND: Children and adolescents with cancer may experience multiple disease- and treatment-related symptoms that negatively affect health-related quality of life. Routine symptom surveillance thus constitutes an important component of supportive care in pediatric oncology. The Symptom Monitoring and Systematic Assessment and Reporting System in Young Survivors (SyMon-SAYS) system will administer, score, interpret, and display the results of symptom assessments captured weekly using patient-reported outcomes presented via the electronic health record (EHR) portal between clinic visits in oncology ambulatory settings, when patients are likely to be more symptomatic. This study is testing a digital system for routine symptom surveillance that includes EHR-based reports to clinicians and alerts for severe symptoms. OBJECTIVE: In this randomized trial, we are examining the effects of the SyMon-SAYS system on perceived barriers to symptom management, self-efficacy, and symptom severity. Better self-management and timely clinical intervention to address symptoms promote adherence to treatment plans, strengthen child and parent self-efficacy, improve interactions between children, parents, and their clinical providers, and optimize clinical outcomes. METHODS: The SyMon-SAYS system is integrated into the EHR to streamline the presentation of symptom scores and delivery of alerts for severe symptoms to clinicians using EHR (Epic) messaging functionalities. Children (aged 8 to 17 years) complete the weekly symptom assessment and review the symptom report by logging into the patient portal (Epic MyChart). This single-institution waitlist randomized controlled trial is recruiting 200 children (aged 8-17 years) with cancer and their parents, guardians, or caregivers. Participating dyads are randomly assigned to receive the intervention over 16 weeks (Group A: 16-week SyMon-SAYS intervention; Group B: 8-week usual care and then an 8-week SyMon-SAYS intervention). Analyses will (1) evaluate the efficacy of SyMon-SAYS at week 8 and the maintenance of those effects at week 16; (2) evaluate factors associated with those efficacy outcomes, including contextual factors, adherence to the SyMon-SAYS intervention, demographic characteristics, and clinical factors; and (3) evaluate predictors of adherence to the SyMon-SAYS intervention and preference of SyMon-SAYS versus usual care. RESULTS: Data collection is currently in progress. We hypothesize that at 8 weeks, those receiving the SyMon-SAYS intervention will report decreased parent-perceived barriers to managing their children's symptoms, increased parent and child self-efficacy, decreased child symptom burden, and ultimately better child health-related quality of life, compared to waitlist controls. Feasibility, acceptability, and engagement from the perspectives of the children with cancer, their parents, and their clinicians will be examined using mixed methods. CONCLUSIONS: We anticipate that this system will facilitate prompt identification of problematic symptoms. Additionally, we hypothesize that with the availability of graphical symptom reports over time, and timely provider responses, children or parents will become better informed and take an active role in managing their symptoms, which will further improve clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04789720; https://clinicaltrials.gov/study/NCT04789720. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50993.

Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047).

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG. PATIENTS AND METHODS: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose. RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT. CONCLUSIONS: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.

Immunobiology and Cytokine Modulation of the Pediatric Brain Tumor Microenvironment: A Scoping Review.

Utilizing a Scoping Review strategy in the domain of immune biology to identify immune therapeutic targets, knowledge gaps for implementing immune therapeutic strategies for pediatric brain tumors was assessed. The analysis demonstrated limited efforts to date to characterize and understand the immunological aspects of tumor biology with an over-reliance on observations from the adult glioma population. Foundational knowledge regarding the frequency and ubiquity of immune therapeutic targets is an area of unmet need along with the development of immune-competent pediatric tumor models to test therapeutics and especially combinatorial treatment. Opportunities arise in the evolution of pediatric tumor classification from histological to molecular with targeted immune therapeutics.

Cardiac dysfunction in medulloblastoma survivors treated with photon irradiation.

Background: Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment often includes a combination of surgical resection, craniospinal irradiation (CSI), and chemotherapy. Children who receive standard photon CSI are at risk for cardiac toxicities including coronary artery disease, left ventricular scarring and dysfunction, valvular damage, and atherosclerosis. Current survivorship guidelines recommend routine echocardiogram (ECHO) surveillance. In this multi-institutional study, we describe markers of cardiac dysfunction in medulloblastoma survivors. Methods: A retrospective chart review of medulloblastoma patients who had photon beam CSI was followed by ECHO between 1980 and 2010 at Lurie Children's Hospital and Dana-Farber/Boston Children's Hospital. Results: During the 30-year study period, 168 medulloblastoma patient records were identified. Included in this study were the 75 patients who received CSI or spinal radiation and ECHO follow-up. The mean age at CSI was 8.6 years (range, 2.9-20), and the mean number of years between radiation therapy (RT) completion and first ECHO was 7.4 (range, 2-16). Mean ejection fraction (EF) was 60.0% and shortening fraction (SF) was 33.8%. Five patients (7%) had abnormal ECHO results: three with EF <50% and two with SF <28%. Conclusion: The majority of medulloblastoma patients who received CSI have relatively normal ECHOs post-treatment; however, 7% of patients had abnormal ECHOs. The implication of our study for medulloblastoma survivors is that further investigations are needed in this population with a more systematic, longitudinal assessment to determine predictors and screenings.

Pediatric spinal intramedullary anaplastic myxopapillary ependymoma: a case report.

A 6-year-old girl presented with a 1-week history of progressive upper and lower extremity weakness and bilateral upper extremity dysesthesia. Imaging demonstrated a 4.7 × 1.2-cm enhancing intramedullary lesion in the cervical spine from level C2 to C5 with associated cystic components and syringomyelia. The patient underwent a C2-C5 laminoplasty, with gross total resection of the intramedullary lesion. Histological analysis showed small to medium-sized epithelioid cells, with predominantly a solid architecture focally infiltrating into the adjacent spinal cord tissue. Focal papillary differentiation was present along with peri-vascular pseudorosettes, mucin microcysts, and globules of dense collagen. Focal anaplasia was noted with mitosis (5/10 HPF), focal necrosis, and elevated Ki67 10-15%. These findings were consistent with a myxopapillary ependymoma with anaplastic features. CSF cytology was negative for tumor cells. MYCN amplification was not present. She was treated with targeted proton-beam radiation therapy. This is the fourth case of an intramedullary anaplastic myxopapillary ependymoma to date, and the first case in the cervical spine reported in the literature.

Refractory Epilepsy as a Late Effect of Chemoradiation in Childhood Cancer: A Case Series.

BACKGROUND: Seizures are a common complication of both primary central nervous system (CNS) tumors and other oncologic processes with CNS involvement. They occur most frequently during induction or consolidation therapy, but there is a growing body of evidence that they can also develop later in life. Refractory epilepsy can develop as a late complication for survivors of pediatric cancer with CNS involvement who undergo chemoradiation therapy. PATIENT DESCRIPTIONS: We report three patients who presented with atypical nonconvulsive seizures (behavioral arrest, falls, nonsensical speech) up to 14 years after cancer diagnosis. All underwent whole-brain radiation in addition to chemotherapy. None had a prior epilepsy diagnosis or known prior seizures. One patient suddenly passed away of unclear causes five months after diagnosis, and the other two continued to have EEG findings consistent with cerebral dysfunction and epileptogenicity years after diagnosis. CONCLUSION: We hypothesize that the development of refractory epilepsy may be a late effect of radiation treatment. Given the high morbidity and mortality associated with epilepsy, early identification is crucial to improve outcomes and quality of life for this vulnerable population. This is especially true for patients with medication-refractory epilepsy as there is an increasing breadth of effective surgical options.

Therapy-related myeloid neoplasms resembling juvenile myelomonocytic leukemia: a case series and review of the literature.

Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.

IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma.

Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559-73. ©2018 AACR.

IDO1 in cancer: a Gemini of immune checkpoints.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.

The Kynurenine/Tryptophan Ratio and Glioblastoma Patients Treated with Hsppc-96 Vaccine.

The discovery that immunotherapy is a clinically-relevant approach for the treatment of malignant tumors is revolutionizing patient care. In adults diagnosed with glioblastoma (GBM), an aggressive and incurable primary brain tumor, autologous HSPPC-96 vaccination provides a significant increase in overall survival. However, all GBM patients eventually succumb to their disease, providing rationale for discovering new methods that proactively identify individuals that will respond, optimally. Of the immunosuppressive mediators that contribute to the inhibition of productive tumor immunity, indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn), has been demonstrated to be expressed at elevated levels in patients with malignant glioma. Recently, our group determined that a correlation exists between peripheral blood Trp and Kyn levels in GBM patients and the association with overall survival after HSPPC-96 treatment. Our findings indicate that the Kyn/Trp ratio may be a useful benchmark for identifying GBM patients with a higher likelihood to survive longer after vaccination. The relevance to future clinical trials, the limitations of brain tumor models to address these findings and the role of IDO1 versus tryptophan dioxygenase (TDO) in the maintenance of peripheral Trp and Kyn levels, is discussed.

Improving vaccine efficacy against malignant glioma.

The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.

Use of allogeneic stem cell transplantation for moderate-severe Glanzmann thrombasthenia.

Glanzmann thrombasthenia (GT) is a rare, autosomal recessive coagulopathy characterized by either qualitative or quantitative abnormalities of the membrane glycoprotein αIIbß3 complex leading to bleeding tendencies, ranging from purpura to life-threatening hemorrhage. Although patients can be managed with supportive measures including platelet transfusions, complications such as alloimmunization are possible. Allogeneic stem cell transplantation (ASCT) can be indicated in severe cases of GT. We report the case of an eight-month-old girl diagnosed with moderate-severe GT, who was successfully treated with a reduced-intensity, human leukocyte antigen (HLA)-identical ASCT.