Explore the vast range of titles available.

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. Cancers of the brain and spine are the second most common kind of tumor in children, after cancers of the blood and bone marrow. Yet brain and spine tumors kill more children than any other cancer, in part because many become resistant to treatment. Like in other cancers, cells in brain and spine tumors often use a process called autophagy to survive the treatments that are used to try and kill them. This process allows cells to recycle proteins and other things inside the cell and use them for energy when the cell is under stress. In 2014, researchers reported that brain tumors carrying a mutation called BRAFV600E rely on autophagy to survive treatment with medications that target this mutation. These findings suggested that blocking autophagy might make the medications more effective against BRAFV600Emutant tumors and overcome the resistance. Now, Mulcahy Levy et al. – who include most of the researchers involved in the 2014 study – report that blocking autophagy does indeed overcome this kind of resistance in multiple types of tumor. The experiments made use of human brain tumor cells that can be grown in the laboratory and have been widely studied, as well as samples collected from patients. Mulcahy Levy et al. were able to block autophagy in the tumor cells by using genetic methods and, importantly, by using an approved and inexpensive drug that could be rapidly translated into clinical trials. Together these findings suggest that blocking autophagy in patients might be a safe and effective strategy to improve their response to existing therapies that target the BRAFV600E mutation. Future clinical trials are now needed to test more patients and verify if this treatment plan can be broadly effective in patients with these types of brain cancers.

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.

Deep learning (DL) is a widely applied mathematical modeling technique. Classically, DL models utilize large volumes of training data, which are not available in many healthcare contexts. For patients with brain tumors, non-invasive diagnosis would represent a substantial clinical advance, potentially sparing patients from the risks associated with surgical intervention on the brain. Such an approach will depend upon highly accurate models built using the limited datasets that are available. Herein, we present a novel genetic algorithm (GA) that identifies optimal architecture parameters using feature embeddings from state-of-the-art image classification networks to identify the pediatric brain tumor, adamantinomatous craniopharyngioma (ACP). We optimized classification models for preoperative Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and combined CT and MRI datasets with demonstrated test accuracies of 85.3%, 83.3%, and 87.8%, respectively. Notably, our GA improved baseline model performance by up to 38%. This work advances DL and its applications within healthcare by identifying optimized networks in small-scale data contexts. The proposed system is easily implementable and scalable for non-invasive computer-aided diagnosis, even for uncommon diseases.

Background Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 ( PLK1 ) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy. Methods We examined the expression of PLK1 mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting PLK1 mRNA on tumor-initiating cells was evaluated using tumor sphere assays. Results Analysis of gene expression in two independent cohorts revealed that PLK1 mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 ( SOX2 ) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells. Conclusions Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation.

MRI showed an avidly enhancing, dural-based mass from C2 to C4 causing spinal cord compression (figure). Specimen review by the parasitology division of the US Centers for Disease Control and Prevention confirmed the diagnosis.

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.

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.

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution, with peaks occurring in children and older adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other pediatric brain tumors and normal tissue. We now present the results of a transcriptome analysis comparing pediatric to adult ACP to identify biological differences between these groups that may provide novel therapeutic insights or support the assertion that potential therapies identified through the study of pediatric ACP may also have a role in adult ACP. Using our compiled transcriptome dataset of 27 pediatric and 9 adult ACPs, obtained through the Advancing Treatment for Pediatric Craniopharyngioma Consortium, we interrogated potential age-related transcriptional differences using several rigorous mathematical analyses. These included: canonical differential expression analysis; divisive, agglomerative, and probabilistic based hierarchical clustering; information theory based characterizations; and the deep learning approach, HD Spot. Our work indicates that there is no therapeutically relevant difference in ACP gene expression based on age. As such, potential therapeutic targets identified in pediatric ACP are also likely to have relvance for adult patients.

Abstract Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions.

Abstract BACKGROUND: Low-grade gangliogliomas/gangliocytomas (GGs) are rare tumors of the central nervous system that occur mostly in young people. Because of their rarity, large-scale, population-based studies focusing on epidemiology and outcomes are lacking. OBJECTIVE: To use the Surveillance, Epidemiology, and End Results (SEER) data sets of the National Cancer Institute to study demographics, tumor location, initial treatment, and outcome data on low-grade GGs in children. METHODS: SEER-STAT v8.1.2 identified all patients aged 0 to 19 years in the SEER data sets with low-grade GGs. Using the Kaplan-Meier method and Cox proportional hazard regression, we examined associations between these characteristics and survival. RESULTS: There were 348 children with low-grade GGs diagnosed from 2004 to 2010, with a median follow-up of 37 months. Tumors were more prevalent in males (n = 208, 59.8%) than females (n = 140, 40.2%) (P < .001). Almost 63% occurred in children >10 years, whereas only 3.5% were found in those <1 year old. Approximately 50% were located in the temporal lobes, and only 3.7% and 3.5% were located in the brainstem and spinal cord, respectively. Surgery was performed on 91.6% of cases, with gross total resection achieved in 68.3%. Radiation was used in 3.2%. Young age (<1 year) and brainstem location were associated with worse overall survival. CONCLUSION: This study shows that low-grade GGs occur in older children with a male preference. Gross total resection is achieved in the majority of cases, and radiation is rarely used. Although the majority of patients have an excellent prognosis, infants and patients with brainstem tumors have worse survival rates.