Citations

Epstein-Barr virus–associated smooth-muscle tumors are rare tumors seen in immunocompromised patients. Most cases occur in the context of AIDS and organ transplantation, and very rarely in the setting of congenital immunodeficiency, with only 5 case reports of the latter published so far in the literature. The authors report the case of a previously healthy 8-year-old girl with headaches and precocious puberty who was found to have a large skull base lesion. There was a synchronous left adrenal lesion. She underwent resection of the skull base lesion and a left adrenalectomy. Thorough evaluation for immunodeficiency was negative for a known congenital immunodeficiency syndrome. She had a short course of intravenous immunoglobulin and has had no recurrence of disease or new lesions in the 17 months since presentation. Continued surveillance for the development of opportunistic infections and new or recurrent lesions is warranted in this case. Repeat surgery for surgically accessible tumors or chemoradiation would be recommended for any additional lesions.

Abstract Pediatric craniopharyngioma is a rare sellar-region epithelial tumor that, in spite of its typically benign pathology, has the potential to be clinically devastating, and presents a host of formidable management challenges for the skull base surgeon. Strategies in craniopharyngioma care have been the cause of considerable controversy, with respect to both philosophical and technical issues. Key questions remain unresolved, and include optimizing extent-of-resection goals; the ideal radiation modality and its role as an alternative, adjuvant, or salvage treatment; appropriate indications for expanded endoscopic endonasal surgery as an alternative to transcranial microsurgery; risks and benefits of skull base techniques in a pediatric population; benefits of and indications for intracavitary therapies; and the preferred management of common treatment complications. Correspondingly, we sought to review the preceding basic science and clinical outcomes literature on pediatric craniopharyngioma, so as to synthesize overarching recommendations, highlight major points of evidence and their conflicts, and assemble a general algorithm for skull base surgeons to use in tailoring treatment plans to the individual patient, tumor, and clinical course. In general terms, we concluded that safe, maximal, hypothalamic-sparing resection provides very good tumor control while minimizing severe deficits. Endoscopic endonasal, intraventricular, and transcranial skull base technique all have clear roles in the armamentarium, alongside standard craniotomies; these roles frequently overlap, and may be further optimized by using the approaches in adaptive combinations. Where aggressive subtotal resection is achieved, patients should be closely followed, with radiation initiated at the time of progression or recurrence—ideally via proton beam therapy, although three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic radiosurgery are very appropriate in a range of circumstances, governed by access, patient age, disease architecture, and character of the recurrence. Perhaps most importantly, outcomes appear to be optimized by consolidated, multidisciplinary care. As such, we recommend treatment in highly experienced centers wherever possible, and emphasize the importance of longitudinal follow-up—particularly given the high incidence of recurrences and complications in a benign disease that effects a young patient population at risk of severe morbidity from hypothalamic or pituitary injury in childhood.

OBJECTIVESurgery is the definitive treatment of Chiari malformation Type I (CM-I). It involves posterior fossa decompression, which can be performed along with C-1 laminectomy, reconstructive duraplasty, or tonsil shrinkage. The aim of this study was to provide an updated systematic review and meta-analysis of the latest available evidence regarding posterior fossa decompression only (PFDO) versus posterior fossa decompression with duraplasty (PFDD) in the treatment of CM-I in children.METHODSA literature search was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for article identification, screening, eligibility, and inclusion. Relevant articles were identified from 6 electronic databases from their inception to April 2016. These articles were screened against established criteria for inclusion into this study.RESULTSFrom 12 relevant studies identified, 1492 pediatric patients treated via PFDD were compared with 1963 pediatric patients treated by PFDO for CM-I. PFDD was associated with greater overall clinical improvement (p = 0.009), along with longer length of stay (p < 0.0001) and more postoperative complications (p = 0.0001) compared with PFDO. No difference was observed between PFDD and PFDO in terms of revision surgery incidence (p = 0.13), estimated blood loss (p = 0.14), syrinx improvement (p = 0.09), or scoliosis improvement (p = 0.95).CONCLUSIONSIt appears that the addition of duraplasty to posterior decompression in the definitive treatment of CM-I in children may alter surgical and performance outcomes. In particular, parameters of overall clinical improvement, length of stay, and postoperative complication may differ between children undergoing PFDD and those undergoing PFDO. Current evidence in the literature is of low to very low quality that, as of yet, has not been able to completely control for inherent selection bias both in study design and surgeon preference. Future, large prospective registries and randomized controlled trials are warranted to validate the findings of this study.

Abstract Medulloblastoma (MB) is a pediatric brain tumor comprising of four molecular subgroups, with Group 3 and 4 tumors characterized by particularly poor prognosis. While research has advanced our understanding of MB, there is still a pressing need for new knowledge of the functional processes underlying its progression due to a scarcity of therapeutics. Recent studies have identified Orthodenticle homeobox 2 (Otx2), a cerebellar transcription factor, to be highly expressed in MB Group 3/4 subtypes. Datamining studies from Northcott and Robinson datasets revealed co-expression of Otx2 and c-Myc in Group 3/4 tumors. DAB staining conducted in human MB specimens showed increased expression of Otx2 and c-Myc. Colocalization studies confirmed datamining results. Next, we used a clinical Otx2 inhibitor, all-trans retinoic acid (ATRA), in a PDX cell line, P9, and in UW228 cells. Western blot analysis demonstrated reduced levels of c-Myc along with Otx2. In another experiment, we used the c-Myc/Max inhibitor 10058-F4 and observed comparable results to Otx2 inhibition. Real time PCR and immunocytochemistry experiments confirmed the aforementioned results. Further, treatment with ATRA and 10058-F4 showed reduced proliferation and migratory abilities in p9 and UW228 when compared to their respective controls. Mass spectrometry conducted on immune-precipitated Otx2 in P9 cells revealed a plethora of novel interaction partners that drive tumor growth and progression. In addition, western blot analysis in ATRA treated cells showed reduced expression of Max, suggestive of the existence of a feedback loop that link with Otx2 and c-Myc. Collectively our studies highlight Otx2 as a potential contributor to the malignant phenotype and describe its role in mediating the aggressiveness of Group 3/4 medulloblastoma. Citation Format: Yining Lu, Maheedhara R. Guda, Swapna Asuthkar, Ian Purvis, Collin M. Labak, Neha Jain, David J. Daniels, Sarah E. Martin, Andrew J. Tsung, Kiran K. Velpula. Otx2 and c-Myc association drives tumor progression in medulloblastoma molecular subtypes 3/4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2017-3537

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for 20% of pediatric CNS tumors. Following surgery and treatment with chemotherapy and radiation, MBs recur in a significant proportion of patients. Moreover, survivors experience comorbidities related to the tumor and/or its treatment. New insights into MB tumor pathogenesis are needed for improving the survivorship and outcome of MB. Epigenetic silencing, including histone modification and DNA methylation, is an important tumorigenic mechanism in MB. However, its role in cancer immunopathology is poorly understood. Using datamining and immunohistochemistry analysis, we show that B7-H3 (CD276), an important immune checkpoint member of the B7 and CD28 families, is highly upregulated in all four molecular subtypes of MB compared to normal tissue. Based on the clinical success of inhibitory immune checkpoint blockades (CTLA-4, PD-1, and PD-L1), CD276 appears to be a promising therapeutic target for cancer immunotherapy. Moreover, we observed that increased expression of CD276 correlates significantly with the expression of Enhancer of Zeste Homologue 2 (EZH2), a histone H3-methylating (H3K27me3) catalytic subunit in the human MB specimens. We hypothesize that combined targeting of CD276 and EZH2 may have greater impact on tumor progression and immune cell response in MB. Simultaneously, we performed LC/MS analysis to identify novel interaction partners of CD276 in MB tumor. These findings taken together suggest that CD276 is strongly associated with several epigenetic markers, indicating a strong relationship between cancer immune evasion and epigenetic mechanisms. Citation Format: Maheedhara R. Guda, Jose R. Castellanos, Collin M. Labak, Ramadevi Sanam, David J. Daniels, Sarah E. Martin, Julian J. Lin, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar. Epigenetic targeting of CD276 expression in medullolbastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2004. doi:10.1158/1538-7445.AM2017-2004

AbstractPurposeTo evaluate patterns of failure after multimodality treatment of nongerminomatous germ cell tumors (NGGCTs).Materials and methodsWe retrospectively reviewed records of 34 patients diagnosed with primary intracranial NGGCT between 1988 and 2014.ResultsThirty‐four patients received induction chemotherapy followed by radiation with or without surgery. Median follow‐up was 11.1 years (0.8–23.3). Outcomes were significantly improved in these 34 patients (5‐year overall survival [OS]: 88% versus 50%, P = 0.0092), so analysis is restricted to that subset. Disease‐free survival (DFS) was 67, 60, and 54% at 5, 10, and 15 years, respectively. Elevated cerebrospinal fluid–α‐fetoprotein (CSF–AFP) at diagnosis was associated with poorer DFS (37 vs. 89% at 10 years; P = 0.01). There was no statistically significant difference in OS, or DFS, or patterns of failure for limited radiotherapy volumes versus larger volumes; however, patients receiving initial local radiotherapy had 32% distant central nervous system (CNS) recurrence at 10 years compared to 0% for those receiving initial larger field irradiation (P = 0.09). Fifteen patients recurred. All four patients who relapsed in the spine had received local radiotherapy and had elevated serum and CSF‐AFP at baseline. All three patients with ventricular relapse received local radiation therapy.ConclusionsNGGCT patients continue to relapse beyond 5 years. Late ventricular relapse occurred even in patients without clear evidence of germinoma component. Elevated CSF‐AFP at diagnosis is associated with poor DFS and risk for distant CNS relapse. Patients with residual radiographic disease after chemotherapy or residual malignant histologies after second‐look surgery have inferior outcomes. Our data support consideration of treatment intensification for these patients.

OBJECT Nonpowder guns, defined as spring- or gas-powered BB or pellet guns, can be dangerous weapons that are often marketed to children. In recent decades, advances in compressed-gas technology have led to a significant increase in the power and muzzle velocity of these weapons. The risk of intracranial injury in children due to nonpowder weapons is poorly documented. METHODS A retrospective review was conducted at 3 institutions studying children 16 years or younger who had intracranial injuries secondary to nonpowder guns. RESULTS The authors reviewed 14 cases of intracranial injury in children from 3 institutions. Eleven (79%) of the 14 children were injured by BB guns, while 3 (21%) were injured by pellet guns. In 10 (71%) children, the injury was accidental. There was 1 recognized assault, but there were no suicide attempts; in the remaining 3 patients, the intention was indeterminate. There were no mortalities among the patients in this series. Ten (71%) of the children required operative intervention, and 6 (43%) were left with permanent neurological injuries, including epilepsy, cognitive deficits, hydrocephalus, diplopia, visual field cut, and blindness. CONCLUSIONS Nonpowder guns are weapons with the ability to penetrate a child’s skull and brain. Awareness should be raised among parents, children, and policy makers as to the risk posed by these weapons.