Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children's Oncology Group study ANBL0531.

BACKGROUND: We previously reported excellent three-year overall survival (OS) for patients with newly diagnosed intermediate-risk neuroblastoma treated with a biology- and response-based algorithm on the Children's Oncology Group study ANBL0531. We now present the long-term follow-up results. METHODS: All patients who met the age, stage, and tumor biology criteria for intermediate-risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event-free survival (EFS) and OS were estimated by the Kaplan-Meier method. RESULTS: The 10-year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%-86.9%) and 94.7% (95% CI, 91.8%-97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non-stage 4 patients (n = 271; 10-year OS: 90.8% [95% CI, 84.5%-97.0%] vs 96.6% [95% CI, 93.9%-99.4%], p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10-year EFS: 66.8% [95% CI, 50.4%-83.3%] vs 86.9% [95% CI, 76.0%-97.8%], p = .02); OS did not differ (10-year OS: 84.4% [95% CI, 71.8%-97.0%] vs 95.0% [95% CI, 87.7%-100.0%], p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10-year EFS: 68.4% [95% CI, 44.5%-92.2%] vs 83.9% [95% CI, 78.7%-89.2%], p = .03; 10-year OS: 88.0% [95% CI, 72.0%-100.0%] vs 95.7% [95% CI, 92.8%-98.6%], p = .09). CONCLUSIONS: The ANBL0531 trial treatment algorithm resulted in excellent long-term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.

Technical evolution of pediatric neurosurgery: the evolution of intraoperative imaging.

Imaging has always been fundamental to neurosurgery, and its evolution over the last century has made a dramatic transformation in the ability of neurosurgeons to define pathology and preserve normal tissue during their operations. In the mid-70 s, the development of computerized cross-sectional imaging with CT scan and subsequently MRI have revolutionized the practice of neurosurgery. Later, further advances in computer technology and medical engineering have allowed the combination of many modalities to bring them into the operating theater. This evolution has allowed real-time intraoperative imaging, in the hope of helping neurosurgeons achieve accuracy, maximal safe resection, and the implementation of minimally invasive techniques in brain and spine pathologies. Augmented reality and robotic technologies are also being applied as useful intra-operative techniques that will improve surgical planning and outcomes in the future. In this article, we will review imaging modalities and provide our institutional perspective on how we have integrated them into our practice.

Pediatric pineal region masses: a single-center experience over 25 years.

PURPOSE: Pineal region tumors (PRT) represent less than 1% of brain neoplasms. The rare and heterogeneous nature of these tumors is reflected in the variety of treatment modalities employed. METHODS: A single-center retrospective review of all pediatric patients with pineal region tumors between November 1996 and June 2021 was performed. Fifty-six cases of pineal tumors were reviewed for age and symptoms upon presentation, diagnostic methods, imaging characteristics, histological classification, treatment modalities, recurrence, and mortality rates. RESULTS: The average age at diagnosis was 11.3 years. The majority of patients were male (82.1%) and Caucasian (73.2%). The most common presenting symptoms were headache (n = 38, 67.9%) and visual problems (n = 34, 60.7%). Hydrocephalus was present in 49 patients (87.5%). Germinoma (n = 20, 35.7%) and non-germinomatous germ cell tumor (NGGCT) (n = 17, 30.4%) were the most common tumors. Chemotherapy was employed for 54 patients (96.4%), radiation for 49 (87.5%), and surgical resection for 14 (25.0%). The average duration of treatment was 5.9 months. Progression-free survival was 74.4% at 5 years and 72.0% at 10 years. Overall survival was 85.7% at 5 years and 77.1% at 10 years. CONCLUSION: Treatment of pineal region tumors must be targeted to each patient based on presentation, subtype, presence of hydrocephalus, and extent of disease. Upfront surgical resection is usually not indicated. As advances in oncological care proceed, treatment modalities may continue to improve in efficacy.

Pediatric versus adult meningioma: comparison of epidemiology, treatments, and outcomes using the Surveillance, Epidemiology, and End Results database.

Pediatric meningiomas, which account for < 1% of all meningiomas, are thought to have unique features, including being more aggressive than their adult counterparts. The goal of this investigation was to compare pediatric and adult meningiomas in a large head-to-head comparison. We used the Surveillance, Epidemiology, and End Result (SEER) datasets to compare meningioma demographics, first treatments, and outcomes among children/adolescents (0-21 years), young adults (22-45 years), and older adults (> 45 years). During 2004-2012, SEER contained 59148 patients age 0-107 years diagnosed with meningioma, with children/adolescents accounting for 381 (0.64%) patients. Unlike older and young adults, children/adolescents with meningioma did not demonstrate female predominance, and had an equal 1:1 male-to-female ratio. Children/adolescents also had almost three-times as many spinal tumors (13.1%) than young adults (4.2%) and older adults (4.4%). Both children/adolescents and young adults had undergone more gross total resections (both 43%) versus older adults (25%), and were treated more with radiation (14.6%, and 12.0% respectively) than their older counterparts (8.5%). In addition, both children/adolescents and young adults had significantly lower all-cause mortality (4.5% in both) than older adults (24.6%), during median 35-month follow-up. Inherent limitations of the SEER datasets restrict our ability to answer important questions regarding comparisons of tumor grading, histological diagnosis, cause-specific mortality, and neurofibromatosis status. Pediatric meningiomas appear distinct from their adult counterparts as they do not display the typical female predominance and include more clinically relevant spinal tumors. More extensive surgeries, greater use of radiation therapy, and lower all-cause mortality were seen in both children/adolescents and young adults, which raises questions regarding the perceived uniquely aggressive nature of pediatric meningiomas. However, due to the significant limitations of the SEER datasets, our results must be interpreted cautiously and stand only to foster novel questions, which would be better answered in well-designed, prospective studies.

Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy.

BACKGROUND: A desperate need for novel therapies in pediatric ependymoma (EPN) exists, as chemotherapy remains ineffective and radiotherapy often fails. EPN have significant infiltration of immune cells, which correlates with outcome. Immune checkpoint inhibitors provide an avenue for new treatments. This study characterizes tumor-infiltrating immune cells in EPN and aims at predicting candidates for clinical trials using checkpoint inhibitors targeting PD-L1/PD-1 (programmed death ligand 1/programmed death 1). METHODS: The transcriptomic profiles of the primary study cohort of EPN and other pediatric brain tumors were interrogated to identify PD-L1 expression levels. Transcriptomic findings were validated using the western blotting, immunohistochemistry and flow cytometry. RESULTS: We evaluated PD-L1 mRNA expression across four intracranial subtypes of EPN in two independent cohorts and found supratentorial RELA fusion (ST-RELA) tumors to have significantly higher levels. There was a correlation between high gene expression and protein PD-L1 levels in ST-RELA tumors by both the western blot and immunohistochemisty. The investigation of EPN cell populations revealed PD-L1 was expressed on both tumor and myeloid cells in ST-RELA. Other subtypes had little PD-L1 in either tumor or myeloid cell compartments. Lastly, we measured PD-1 levels on tumor-infiltrating T cells and found ST-RELA tumors express PD-1 in both CD4 and CD8 T cells. A functional T-cell exhaustion assay found ST-RELA T cells to be exhausted and unable to secrete IFNγ on stimulation. CONCLUSIONS: These findings in ST-RELA suggest tumor evasion and immunsuppression due to PD-L1/PD-1-mediated T-cell exhaustion. Trials of checkpoint inhibitors in EPN should be enriched for ST-RELA tumors.

Intracranial Ewing sarcoma: four pediatric examples.

BACKGROUND: Ewing sarcoma typically arises in bone and is unrelated to intraparenchymal small blue cell embryonal central nervous system (CNS) tumors previously designated primitive neuroectodermal tumors (PNETs). When the CNS is impacted, it is usually secondary to local extension from either the epidural space, skull, or intracranial or spinal metastases. Primary examples within the cranial vault are rare, usually dural-based, and are largely case reports in the literature. We detail four pediatric patients with solitary, primary intracranial Ewing sarcoma, all manifesting the archetypal EWRS1 gene rearrangement that confirms diagnosis. PROCEDURE: Neurosurgical Department records, spanning 21 years (1995-2016), were reviewed to identify patients. Demographics, clinical history, pathological/genetic features, and clinical course were retrieved from the medical record and personal files of the authors. RESULTS: Four patients, one male and three females, age 5 to 16 years, were identified. One presented in extremis from a large lesion, two with soft tissue masses, and the fourth as an incidental finding after being involved in a motor vehicle collision. Three had clear bony involvement: a 10-year-old girl with a large left temporal lesion had clear origin in the skull, with spiculated calcified striations throughout the mass; a 9-year-old girl presented with a bony left petrous apex mass; and a 16-year-old girl presented with a left temporal mass with extension to the dura and underlying bone erosion. Only the 5-year-old boy had a large left frontoparietal mass traversing the falx with no bony contact. All four tumors manifested the diagnostic EWSR1 mutation and were treated with an Ewing sarcoma regimen. Outcomes were variable, with one patient showing progressive metastatic disease and death 3 years after presentation, one patient with disease-free survival 10.5 years after completion of therapy, and one alive and well at the completion of therapy 1 year after diagnosis. One patient completed therapy recently with post-therapy scans showing no evidence of disease. CONCLUSION: Testing for the EWSR1 mutation confirms the diagnosis of Ewing sarcoma and excludes other types of embryonal CNS tumors. Long-term disease-free survival is possible with adherence to the appropriate therapeutic regimen after gross surgical resection.

Insular epilepsy surgery.

Since it was originally described nearly 70 years ago, insular epilepsy has been increasingly recognized and may explain failures after apparently well-planned operations. We review the history of awareness of the phenomenon, techniques for its assessment, and its surgical management. Insular epilepsy can mimic features of frontal, parietal, or temporal seizures. It should be considered when a combination of somatosensory, visceral, and motor symptoms is observed early in a seizure. Extraoperative intracranial recordings are required to accurately diagnose insular seizures. Stereo-electroencephalography (EEG) or craniotomy with implantation of surface and depth electrodes have been used successfully to identify insular onset of seizures. Surgical resection of an insular focus may be performed with good success and acceptable risk.

The Emergence of Zoonotic Onchocerca lupi Infection in the United States--A Case-Series.

This case-series describes the 6 human infections with Onchocerca lupi, a parasite known to infect cats and dogs, that have been identified in the United States since 2013. Unlike cases reported outside the country, the American patients have not had subconjunctival nodules but have manifested more invasive disease (eg, spinal, orbital, and subdermal nodules). Diagnosis remains challenging in the absence of a serologic test. Treatment should be guided by what is done for Onchocerca volvulus as there are no data for O. lupi. Available evidence suggests that there may be transmission in southwestern United States, but the risk of transmission to humans is not known. Research is needed to better define the burden of disease in the United States and develop appropriately-targeted prevention strategies.

Pediatric choroid plexus tumors: epidemiology, treatments, and outcome analysis on 202 children from the SEER database.

Choroid plexus papillomas (CPPs) and carcinomas (CPCs) are rare neoplasms that affect mostly children. Due to their rarity, their epidemiology and outcomes are incompletely understood. The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program is a well-established population-based group of registries that collects and publishes cancer incidence and survival data representing approximately 28 % of the US population. SEER-STAT v8.1.2 was used to identify patients with ICD-O-3 codes for choroid plexus tumors in patients aged 0-19. Demographics, initial treatment, and follow-up data were collected. Statistical methods including Kaplan-Meier curves, log rank tests, and Cox proportional hazards regression were used to estimate associations between independent variables and survival. The SEER registries contained 107 CPPs (2004-2010) and 95 CPCs (1978-2010). Median follow-up was 38 and 40 months, respectively. More than 75 % of CPCs were diagnosed before the age of 5 years, versus 48 % for CPPs. Sixty-five percent of CPCs and 57 % of CPPs occurred in males. In both groups at least 90 % of children underwent surgical resection. Gross total resection (GTR) was achieved in 67.0 % of CPCs and 63.6 % of CPPs. Almost 17 % of CPCs were treated with radiation versus only 0.9 % of CPPs. More than 98 % of patients with CPP were alive at the last follow-up, versus 62 % of CPC patients. For CPC, surgery was significantly associated with increased overall survival, but contrary to previous reports, extent of surgical resection was not associated with survival. Age, sex, race, and radiation treatment also had no effect on survival. This report, using the SEER datasets, corroborates many findings of previous smaller studies on CPTs. CPC occurs in younger children, with a male predominance, and a much worse prognosis than CPP. As such, these tumors have been treated aggressively with high rates of GTR and radiation treatment. Despite these treatments, overall survival for CPC remains poor.

Characterization of distinct immunophenotypes across pediatric brain tumor types.

Despite increasing evidence that antitumor immune control exists in the pediatric brain, these findings have yet to be exploited successfully in the clinic. A barrier to development of immunotherapeutic strategies in pediatric brain tumors is that the immunophenotype of these tumors' microenvironment has not been defined. To address this, the current study used multicolor FACS of disaggregated tumor to systematically characterize the frequency and phenotype of infiltrating immune cells in the most common pediatric brain tumor types. The initial study cohort consisted of 7 pilocytic astrocytoma (PA), 19 ependymoma (EPN), 5 glioblastoma (GBM), 6 medulloblastoma (MED), and 5 nontumor brain (NT) control samples obtained from epilepsy surgery. Immune cell types analyzed included both myeloid and T cell lineages and respective markers of activated or suppressed functional phenotypes. Immune parameters that distinguished each of the tumor types were identified. PA and EPN demonstrated significantly higher infiltrating myeloid and lymphoid cells compared with GBM, MED, or NT. Additionally, PA and EPN conveyed a comparatively activated/classically activated myeloid cell-skewed functional phenotype denoted in particular by HLA-DR and CD64 expression. In contrast, GBM and MED contained progressively fewer infiltrating leukocytes and more muted functional phenotypes similar to that of NT. These findings were recapitulated using whole tumor expression of corresponding immune marker genes in a large gene expression microarray cohort of pediatric brain tumors. The results of this cross-tumor comparative analysis demonstrate that different pediatric brain tumor types exhibit distinct immunophenotypes, implying that specific immunotherapeutic approaches may be most effective for each tumor type.

Surgery for infants with catastrophic epilepsy: an analysis of complications and efficacy.

PURPOSE: Infants with epilepsy often have a catastrophic course. There is a reluctance to operate in the very young, due to the perception of an unacceptable risk of morbidity with early operations. The purpose of this investigation was to better characterize the efficacy and safety of epilepsy surgery in infants. METHODS: Epilepsy operations performed on children under 1 year old, between 2002 and 2013, were reviewed for demographic information, epilepsy characteristics, surgical approach, outcomes, and surgical complications. RESULTS: Twenty-five patients, ages 11 days to 11.5 months (mean 4.7) at operation, were identified. All had daily seizures. Twenty-two (88%) had an abnormal magnetic resonance imaging (MRI). Sixteen (64%) patients underwent hemispherotomy at initial operation. Seven (28%) infants had grid placement followed by focal resection. Focal cortical dysplasia was the most common pathology (40%) followed by hemimegalencephaly (32%). Complications occurred in 36% of patients. These included hydrocephalus in five patients (20%). Two patients had significant intra-operative complications which required unplanned staging of their operations. Both recovered without permanent injury. Mean follow-up was 62.4 months. Twenty patients (80%) are seizure-free, and 10 (40%) are off anticonvulsant medication. Two patients are Engel class 2, and the remaining three patients were Engel class 4, one of whom died with status epilepticus from the contralateral hemisphere. CONCLUSION: Infants with localization-related catastrophic epilepsy can have excellent outcomes from early epilepsy surgery. Complications are common in this patient group and proper diagnosis can be challenging. Young age should not exclude infants with catastrophic epilepsy from consideration for early surgical intervention.

MicroRNA 218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma.

Aberrant expression of microRNAs has been implicated in many cancers. We recently demonstrated differential expression of several microRNAs in medulloblastoma. In this study, the regulation and function of microRNA 218 (miR-218), which is significantly underexpressed in medulloblastoma, was evaluated. Re-expression of miR-218 resulted in a significant decrease in medulloblastoma cell growth, cell colony formation, cell migration, invasion, and tumor sphere size. We used C17.2 neural stem cells as a model to show that increased miR-218 expression results in increased cell differentiation and also decreased malignant transformation when transfected with the oncogene REST. These results suggest that miR-218 acts as a tumor suppressor in medulloblastoma. MicroRNAs function by down-regulating translation of target mRNAs. Targets are determined by imperfect base pairing of the microRNA to the 3'-UTR of the mRNA. To comprehensively identify actual miR-218 targets, medulloblastoma cells overexpressing miR-218 and control cells were subjected to high throughput sequencing of RNA isolated by cross-linking immunoprecipitation, a technique that identifies the mRNAs bound to the RNA-induced silencing complex component protein Argonaute 2. High throughput sequencing of mRNAs identified 618 genes as targets of miR-218 and included both previously validated targets and many targets not predicted computationally. Additional work further confirmed CDK6, RICTOR, and CTSB (cathepsin B) as targets of miR-218 and examined the functional role of one of these targets, CDK6, in medulloblastoma.

Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma.

Better understanding of ependymoma (EPN) biology at relapse is needed to improve therapy at this critical event. Convincing data exist defining transcriptionally distinct posterior fossa (PF) sub-groups A and B at diagnosis. The clinical and biological consequence of these sub-groups at recurrence has not yet been defined. Genome and transcriptome microarray profiles and clinical variables of matched primary and first recurrent PF EPN pairs were used to identify biologically distinct patterns of progression between EPN sub-groups at recurrence. Key findings were validated by histology and immune function assays. Transcriptomic profiles were partially conserved at recurrence. However, 4 of 14 paired samples changed sub-groups at recurrence, and significant sub-group-specific transcriptomic changes between primary and recurrent tumors were identified, which were predominantly immune-related. Further examination revealed that Group A primary tumors harbor an immune gene signature and cellular functionality consistent with an immunosuppressive phenotype associated with tissue remodeling and wound healing. Conversely, Group B tumors develop an adaptive, antigen-specific immune response signature and increased T-cell infiltration at recurrence. Clinical distinctions between sub-groups become more apparent after first recurrence. Group A tumors were more often sub-totally resected and had a significantly shorter time to subsequent progression and worse overall survival. Minimal tumor-specific genomic changes were observed for either PF Groups A or B at recurrence. Molecular sub-groups of PF EPN convey distinct immunobiologic signatures at diagnosis and recurrence, providing potential biologic rationale to their disparate clinical outcomes. Immunotherapeutic approaches may be warranted, particularly in Group A PF EPN.

Fractionated stereotactic radiosurgery for recurrent ependymoma in children.

Outcomes for children with relapsed ependymoma are poor. Re-irradiation is a potentially viable salvage option in these patients. Data were reviewed for 12 patients (median age 5.6 years) with relapsed ependymoma who received fractionated stereotactic radiosurgery (fSRS) following maximal surgical resection from 1995 to 2012. Four patients experienced a second recurrence, including 2 in-field and 2 distant failures. Median time to second recurrence (32 months) was significantly longer than time to first recurrence (24 months) (p = 0.008). Three-year local control was 89 %, and median event free survival from fSRS was 3.4 years. Radiation necrosis was observed in 6 patients, 3 who were symptomatic. In conclusion, fSRS offers durable response with a tolerable toxicity profile in children with recurrent EPN.

Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors.

Survival in the majority of high-grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and survival prediction. Factors associated with long-term survival have not been extensively studied using unbiased genome-wide expression analyses. In the current study, gene expression microarray profiles of HGA from long-term survivors were interrogated for discovery of survival-associated biological factors. Ontology analyses revealed that increased expression of immune function-related genes was the predominant biological factor that positively correlated with longer survival. A notable T cell signature was present within this prognostic immune gene set. Using immune cell-specific gene classifiers, both T cell-associated and myeloid linage-associated genes were shown to be enriched in HGA from long-term versus short-term survivors. Association of immune function and cell-specific genes with survival was confirmed independently in a larger publicly available glioblastoma gene expression microarray data set. Histology was used to validate the results of microarray analyses in a larger cohort of long-term survivors of HGA. Multivariate analyses demonstrated that increased immune cell infiltration was a significant independent variable contributing to longer survival, as was Karnofsky/Lansky performance score. These data provide evidence of a prognostic anti-tumor adaptive immune response and rationale for future development of immunotherapy in HGA.

Maintaining Survival While Improving Quality of Life: An Advanced Practitioner-Led Pilot Feasibility Study to Reduce Radiation Dose in Children With Brain Tumors.

Purpose: Oncology advanced practitioners (APs) are on the front line in treating adverse effects. Among children with brain tumors, treatments such as craniospinal irradiation (CSI) cause neurocognitive injury, endocrinopathies, and ototoxicity. High-dose CSI with concurrent chemotherapy allows high-risk embryonal tumors (non-anaplastic) good survival (70%), but significant distressing effects are commonly treated by APs in multidisciplinary long-term follow-up. The aim of this study was to test feasibility of reducing radiation dose with an AP-led protocol. Methods: An interdisciplinary team developed this pilot study with the primary outcome of fewer than two deaths in 10 patients (80% survival). Secondary outcomes were feasibility of an AP-led treatment protocol and acute/late effects of treatment. The AP held a pioneering role as principal investigator of a tumor treatment study. Exclusion criteria included age less than 3 years and anaplasia. The CSI was reduced from 36 to 24 Gy. All other treatment was standard. Results: Survival rate exceeded the primary outcome threshold (88%); the accrual rate (80%) and follow-up neurocognitive testing rate (75%) were acceptable. Eight children ages 3 to 19 years (M = 8) with tumors of varied molecular subtyping were enrolled. The single death occurred 2.5 years from diagnosis of multiorgan failure (without evidence of tumor). The mean survival is 11 years, with two college and one graduate degrees. Acute and late effects were decreased compared with the higher-dose CSI. Conclusion: APs who treat cancer adverse effects can also conduct clinical prospective studies to maintain survival rates and improve quality-of life-outcomes.

B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a brain cancer with a median survival of only 1 year. Lack of molecular characterization of this tumor impedes the development of novel therapies. Membrane protein B7-H3, aka CD276, involved in interactions with host defenses in certain cancers, has been shown to be over-expressed in the majority of malignant neuroectodermal tumors including adult high-grade glioma. Targeting B7-H3 with a monoclonal antibody has demonstrated safety and efficacy in the salvage treatment of stage IV childhood neuroblastoma, another neuroectodermal tumor. It thus stands to reason that B7-H3 might serve as a therapeutic target in DIPG. B7-H3 immunoreactivity was determined in DIPG and non-diffuse brainstem glioma specimens with immunohistochemistry. In addition, B7-H3 mRNA expression was evaluated with microarrays in another set of specimens. All of the nine (100 %) DIPG specimens were shown to be B7-H3 immunoreactive. In the non-diffuse brainstem glioma group, none of the eight WHO grade I specimens showed B7-H3 immunoreactivity and nine of the 24 WHO grade II specimens (37.5 %) showed B7-H3 immunoreactivity. The association between histological grade and B7-H3 immunoreactivity was statistically highly significant. B7-H3 mRNA expression was also significantly higher in DIPG samples than in normal brain and juvenile pilocytic astrocytoma (WHO grade I) specimens. In summary, B7-H3 is over-expressed in DIPG. Given the need for novel treatment in this disease, antibody-based immunotherapy against B7-H3 in DIPG warrants further investigation.

Pediatric rhabdoid tumors of kidney and brain show many differences in gene expression but share dysregulation of cell cycle and epigenetic effector genes.

BACKGROUND: Rhabdoid tumors (RTs) are aggressive tumors of early childhood that occur most often in brain (AT/RTs) or kidney (KRTs). Regardless of location, they are characterized by loss of functional SMARCB1 protein, a component of the SWI/SNF chromatin remodeling complex. The aim of this study was to determine genes and biological process dysregulated in common to both AT/RTs and KRTs. PROCEDURE: Gene expression for AT/RTs was compared to that of other brain tumors and normal brain using microarray data from our lab. Similar analysis was performed for KRTs and other kidney tumors and normal kidney using data from GEO. Dysregulated genes common to both analyses were analyzed for functional significance. RESULTS: Unsupervised hierarchical clustering of RTs identified three major subsets: two comprised of AT/RTs, and one of KRTs. Compared to other tumors, 1,187, 663, and 539 genes were dysregulated in each subset, respectively. Only 14 dysregulated genes were common to all three subsets. Compared to normal tissue, 5,209, 4,275, and 2,841 genes were dysregulated in each subset, with an overlap of 610 dysregulated genes. Among these genes, processes associated with cell proliferation, MYC activation, and epigenetic dysregulation were common to all three RT subsets. CONCLUSIONS: The low overlap of dysregulated genes in AT/RTs and KRTs suggests that factors in addition to SMARCB1 loss play a role in determining subsequent gene expression. Drugs which target cell cycle or epigenetic genes may be useful in all RTs. Additionally, targeted therapies tailored to specific RT subset molecular profiles should be considered.

Patterns of care for craniopharyngioma: survey of members of the american association of neurological surgeons.

BACKGROUND: Initial therapy for craniopharyngioma remains controversial. Population-based datasets indicate that traditional algorithms [gross total resection (GTR) vs. subtotal resection (STR) +/- radiation therapy (XRT)] are often not employed. We investigated neurosurgical practice patterns. METHODS: A ten-question survey was electronically distributed to members of the American Association of Neurological Surgeons. Responses were analyzed using standard statistical techniques. RESULTS: 102 responses were collected, with a median of 25 craniopharyngiomas managed per respondent. 36% estimated that their practice included ≥75% pediatric patients and 61% had an academic practice. 36% would recommend observation or XRT for a suspected craniopharyngioma in the absence of a tissue diagnosis, with 46% of these indicating this recommendation in ≥10% of the cases. Following STR, 35% always recommend XRT and 59% recommend it in over half of the cases. However, following STR or biopsy alone, 18 and 11% never recommend XRT. There was no association between the type of practice (i.e. academic or ≥75% pediatric patients) and practice patterns. CONCLUSIONS: This survey verifies that a deviation from established algorithms is common, underscoring the clinical complexity of these patients and recent secondary data analyses. This should influence clinical researchers to investigate outcomes for patients treated using alternative methods. It will lend insight into appropriate treatment options and contribute to quality of life outcomes studies for craniopharyngioma.