Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery 1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin-staining of processed tissue is time-, resource-, and labor-intensive 2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed pathology workforce 4. Here, we report a parallel workflow that combines stimulated Raman histology (SRH) 5-7 , a label-free optical imaging method, and deep convolutional neural networks (CNN) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNN, trained on over 2.5 million SRH images, predicts brain tumor diagnosis in the operating room in under 150 seconds, an order of magnitude faster than conventional techniques (e.g., 20-30 minutes) 2. In a multicenter, prospective clinical trial (n = 278) we demonstrated that CNN-based diagnosis of SRH images was non-inferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% vs. 93.9%). Our CNN learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. Additionally, we implemented a semantic segmentation method to identify tumor infiltrated, diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complimentary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. Despite surgical resection followed by radiotherapy and chemotherapy, the median survival rate is approximately 14 months. Although experimental therapies are in clinical trials for GBM, there is an urgent need for a peripheral GBM biomarker for measuring treatment response. As we have previously demonstrated that the long noncoding RNA HOX Transcript Antisense Intergenic RNA, or HOTAIR, is dysregulated in GBM and required for GBM cell proliferation, we hypothesized that HOTAIR expression may be utilized as a peripheral biomarker for GBM. HOTAIR expression was measured in serum from 43 GBM and 40 controls using quantitative real-time PCR (qRT-PCR). The PCR products were subsequently subcloned into pCR™4-TOPO®TA vectors for DNA sequencing. A ROC curve was also generated to examine HOTAIR’s prognostic value. The amount of HOTAIR in serum exosomes and exosome-depleted supernatant was calculated by qRT-PCR. The relative HOTAIR expression was also investigated in 15 pairs of GBM serum and tumors. We detected HOTAIR in serum from GBM patients. HOTAIR levels in serum samples from GBM patients was significantly higher than in the corresponding controls (P < 0.0001). The area under the ROC curve distinguishing GBM patients from controls was 0.913 (95% CI: 0.845–0.982, P < 0.0001), with 86.1% sensitivity and 87.5% specificity at the cut-off value of 10.8. HOTAIR expression was significantly correlated with high grade brain tumors. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r = 0.734, P < 0.01). We confirmed via sequencing that the amplified HOTAIR from serum contained the HOTAIR sequence and maps to the known HOTAIR locus at 12q13. The serum-derived exosomes contain HOTAIR and the purified exosomes were validated by western blot and nanoparticle tracking analysis. Importantly, our results demonstrate that serum HOTAIR can be used as a novel prognostic and diagnostic biomarker for GBM.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0822-0) contains supplementary material, which is available to authorized users.

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Bevacizumab has been used in patients with GBM as a salvage therapy since its approval in the United States for recurrent GBM in 2009. In order to review the therapeutic effect of bevacizumab in the primary and recurrent clinical setting we have performed a systematic analysis of data from the published literature. Weighted median progression free survival and overall survival were calculated and compared to standard therapy or other experimental therapies. A qualitative analysis of the limited studies on health related quality of life and effects on steroid requirements was also undertaken. We found that the available literature supports the use of bevacizumab for prolonging PFS and OS in the recurrent setting either alone or in combination with a cytotoxic agent (P < 0.05), but does not support its use in the primary setting (P > 0.05). The survival advantage of bevacizumab compared to experimental therapy at recurrence is limited to 4 months. There is no additional benefit reported to date in health-related quality of life with the use of bevacizumab, although it may reduce steroid requirements. On average there is one side-effect event per patient and 74% of these events are grade 3 toxicity or higher. Further studies investigating the role of bevacizumab in combination with cytotoxic agents at recurrence are awaited.

Object Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. Methods The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. Results There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). Conclusions Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

SUMMARY:Minimally invasive stereotactic tumor ablation is a viable option for the treatment of benign and malignant intracranial lesions. Although surgical excision constitutes first-line therapy for various brain pathologies, it can cause irreversible neurologic deficits. Additionally, many patients who may benefit from surgery do not qualify as surgical candidates due to multiple comorbidities. Recent advancements in laser interstitial thermal therapy, namely the ability to monitor ablation in real-time under MR imaging, have improved the safety and efficacy of the procedure. MRI-guided laser interstitial thermal therapy is currently used as a minimally invasive treatment for brain metastases, radiation necrosis, glioma, and epilepsy. This article will discuss the principles, suggested indications, complications, and imaging characteristics of MRI-guided laser interstitial thermal therapy as they pertain to the treatment of brain pathology. ABBREVIATIONS:GBM ϭ glioblastoma multiforme; LITT ϭ laser interstitial thermal therapy; MRgLITT ϭ MRI-guided laser interstitial thermal therapy; MRTI ϭ MRI thermal imaging; RN ϭ delayed radiation necrosis; SRS ϭ stereotactic radiosurgery