Successful treatment of a TSC2-mutant glioblastoma with everolimus.

A 14-year-old boy with familial Li-Fraumeni syndrome presented with diplopia. Brain MRI revealed a right temporoparietal rim-enhancing mass. Following surgical resection and diagnosis of a gigantocellular-type glioblastoma multiforme (GBM), his family wished to avoid cytotoxic chemotherapy given the amplified risk of secondary malignancy. As such, we performed whole exome and transcriptome sequencing, which revealed germline TP53 and somatic TSC2 mutations. On completion of adjuvant radiotherapy, he was started on maintenance therapy with everolimus per recommendations from our multi-institutional brain tumour precision medicine tumour board. He has achieved a complete remission with resolution of visual symptoms and remains on everolimus therapy with concurrent electromagnetic field therapy, now 33 months from diagnosis. Our data highlight the benefit of precision medicine in children with GBM and offer insight into a targetable pathway that may be involved in similar cases.

Pediatric Thalamic Gliomas: An Updated Review.

CONTEXT: - Neoplasms originating in the thalamus are rare overall (1% of all brain tumors); however, they comprise approximately 5% of pediatric intracranial tumors and approach 15% of all malignant pediatric intracranial tumors in some series. OBJECTIVE: - To update readers about the current understanding of the diverse histology, biology, and behavior of pediatric thalamic tumors. Histologic verification is now thought to be critical for planning treatment, and, as a result, biopsy and total/subtotal resections are much more common today than in the past. DATA SOURCES: - A PubMed search using the keywords "pediatric + thalamic + glioma" yielded 45 publications with a total of 445 cases of thalamic gliomas in patients less than 18 years of age. We found only 9 substantial institutional series tabulating all encountered thalamic histologic types in children. This survey confirmed a high proportion of astrocytomas, 81% (214 of 265), of which approximately two-thirds were diffuse astrocytomas (146 of 214) and one-third were pilocytic astrocytomas (68 of 214). Of the diffuse astrocytomas, 34% (49 of 146) were low grade (World Health Organization grade II) and 55% (81 of 146) were high grade (World Health Organization grade III or IV), making the latter subgroup the largest single category of all pediatric thalamic tumors. Oligodendrogliomas and ependymomas (mostly anaplastic in both cases) comprised 10% and 3% of all pediatric thalamic tumors, respectively. CONCLUSIONS: - Tissue diagnosis is now thought crucial for prognostication and treatment, particularly as more potentially therapeutic molecular targets are discovered. Secure diagnosis allows identification of tumors for which resection is more feasible and beneficial.

Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy.

Conventional methods for intraoperative histopathologic diagnosis are labour- and time-intensive, and may delay decision-making during brain-tumour surgery. Stimulated Raman scattering (SRS) microscopy, a label-free optical process, has been shown to rapidly detect brain-tumour infiltration in fresh, unprocessed human tissues. Here, we demonstrate the first application of SRS microscopy in the operating room by using a portable fibre-laser-based microscope and unprocessed specimens from 101 neurosurgical patients. We also introduce an image-processing method - stimulated Raman histology (SRH) - which leverages SRS images to create virtual haematoxylin-and-eosin-stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, we found a remarkable concordance of SRH and conventional histology for predicting diagnosis (Cohen's kappa, κ > 0.89), with accuracy exceeding 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain-tumour subtype with 90% accuracy. Our findings provide insight into how SRH can now be used to improve the surgical care of brain tumour patients.

Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.

DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics.

BACKGROUND: De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. METHODS: To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. RESULTS: Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. CONCLUSIONS: Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders.

Management of symptomatic intrathecal catheter-associated inflammatory masses.

OBJECTIVE: Intrathecal catheter-associated inflammatory masses (CIMs) are a serious complication of implanted drug pumps. The goal of this study was to review our experience with CIMs, including the pathology of all resected CIMs, and identify objective data which may guide management. METHODS: We performed a retrospective review of 13 patients who developed symptomatic CIMs during continuous intrathecal opioid therapy for chronic pain. Eight patients presented with pain plus neurologic deficit and 5 patients presented with pain alone. RESULTS: CIM resection via laminectomy and intradural exploration was ultimately performed in 8 patients, 3 of whom were initially treated with a non-resective surgical approach (catheter repositioning or pump removal) that failed. All 3 patients who experienced a failure with non-resective surgery had CIMs located in the thoracic spine with a maximum diameter≥13 mm and 2 of these patients had neurologic deficits on presentation. CONCLUSIONS: Our experience, with the largest reported single-surgeon series of patients harboring CIMs, favors early resection, especially in patients with neurologic deficit. Resection may also be a prudent first-line strategy for patients with larger thoracic masses (≥13 mm) regardless of neurologic status. Neurologic deficits engendered by CIM usually improve after resection and the majority of patients in our series would have still elected to have an intrathecal pump for pain control knowing a CIM would have developed.