Faculty Bibliography

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery¹. 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 workforce⁴. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)^5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)². In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, 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 complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

BACKGROUND:Niemann-Pick disease type C is a fatal and progressive neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomes and lysosomes. We sought to develop new therapeutics for this disorder by harnessing the body's endogenous cholesterol scavenging particle, high-density lipoprotein (HDL). METHODS:Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles. RESULTS:We demonstrate a dose-dependent rescue of cholesterol storage that is sensitive to sHDL lipid and peptide composition, enabling the identification of compounds with a range of therapeutic potency. Peripheral administration of sHDL to Npc1 I1061T homozygous mice mobilizes cholesterol, reduces serum bilirubin, reduces liver macrophage size, and corrects body weight deficits. Additionally, a single intraventricular injection into adult Npc1 I1061T brains significantly reduces cholesterol storage in Purkinje neurons. Since endogenous HDL is also a carrier of sphingomyelin, we tested the same sHDL formulation in the sphingomyelin storage disease Niemann-Pick type A. Utilizing stimulated Raman scattering microscopy to detect endogenous unlabeled lipids, we show significant rescue of Niemann-Pick type A lipid storage. CONCLUSIONS:Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases.

Background/UNASSIGNED:Cognitive and language dysfunction is common among patients with glioma and has a significant impact on survival and health-related quality of life (HRQOL). Little is known about the factors that make individual patients more or less susceptible to the cognitive sequelae of the disease. A better understanding of the individual and population characteristics related to cognitive function in glioma patients is required to appropriately stratify patients, prognosticate, and develop more efficacious treatment regimens. There is evidence that allelic variation among genes involved in neurotransmission and synaptic plasticity are related to neurocognitive performance in states of health and neurologic disease. Methods/UNASSIGNED:, rs4680) with neurocognitive function and ability to return to work in glioma patients at diagnosis and at 3 months. We developed a functional score based on the number of high-performance alleles that correlates with the capacity for patients to return to work. Results/UNASSIGNED:Patients with higher-performing alleles have better scores on neurocognitive testing with the Repeatable Battery for the Assessment of Neuropsychological Status and Stroop test, but not the Trail Making Test. Conclusions/UNASSIGNED:A better understanding of the genetic contributors to neurocognitive performance in glioma patients and capacity for functional recovery is necessary to develop improved treatment strategies based on patient-specific factors.

In low-grade glioma surgery, depicting tumor margins is challenging. 7 - Bowden 2018 - Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue.pdf Several tools have emerged to assist surgical decision-making. Intraoperative MRI, albeit expensive and time-consuming, can provide useful information during surgery. Fluorescence-guidance with 5-aminolevulinic acid (5-ALA) helps provide real-time information during surgery regardless of brain-shift, assists in finding anaplastic foci in low-grade tumors, and enables diagnosis of malignant tissue. Raman histology has potential for detecting viable tumor in biopsied tissue and for identifying tumor infiltration in vivo. This article analyzes and discusses these surgical adjuncts.

BACKGROUND AND PURPOSE/OBJECTIVE:We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. MATERIALS AND METHODS/METHODS:Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. RESULTS:Median follow-up was 23 months (95% CI 4-124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3-11.0) and OS was 18.7 months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. CONCLUSION/CONCLUSIONS:Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

BACKGROUND AND IMPORTANCE/BACKGROUND:Neurocysticercosis (NCC) is an infectious helminthic disease often presenting in patients who have immigration or travel history from areas where NCC is endemic. Fourth ventricle cysts from NCC pose a unique treatment challenge, as there is little consensus on the best treatment. This case study describes the treatment of a patient with fourth ventricle neurocysticercosis (FVNCC), examines the therapeutic decision-making, and provides a video of a posterior fossa craniotomy (PFC) resection of a degenerative cyst. CLINICAL PRESENTATION/METHODS:The patient presented with headache, dizziness, nausea, and memory difficulties. A fourth ventricle cyst consistent with NCC was found on magnetic resonance imaging, and serum enzyme-linked immunosorbent assay (ELISA) confirmed the diagnosis. The cyst was removed utilizing an open PFC followed by antihelminthic therapy and corticosteroids. There was resolution of symptoms at 9 mo postoperatively. CONCLUSION/CONCLUSIONS:Several treatment modalities have been proposed for isolated cysts in the fourth ventricle, including medication, ventriculoperitoneal shunt, endoscopic removal, and PFC. The treatment decision is complex, and there is little guidance on the best treatment choices. In this article, we describe treatment via PFC for an adherent FVNCC cyst.

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

OBJECTIVES:The postoperative management of patients who undergo brain tumor resection frequently occurs in an ICU. However, the routine admission of all patients to an ICU following surgery is controversial. This study seeks to identify the frequency with which patients undergoing elective supratentorial tumor resection require care, aside from frequent neurologic checks, that is specific to an ICU and to determine the frequency of new complications during ICU admission. Additionally, clinical predictors of ICU-specific care are identified, and a scoring system to discriminate patients most likely to require ICU-specific treatment is validated. DESIGN:Retrospective observational cohort study. SETTING:Academic neurosurgical center. PATIENTS:Two-hundred consecutive adult patients who underwent supratentorial brain tumor surgery. An additional 100 consecutive patients were used to validate the prediction score. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Univariate statistics and multivariable logistic regression were used to identify clinical characteristics associated with ICU-specific treatment. Eighteen patients (9%) received ICU-specific care, and 19 (9.5%) experienced new complications or underwent emergent imaging while in the ICU. Factors significantly associated with ICU-specific care included nonelective admission, preoperative Glasgow Coma Scale, and volume of IV fluids. A simple clinical scoring system that included Karnofsky Performance Status less than 70 (1 point), general endotracheal anesthesia (1 point), and any early postoperative complications (2 points) demonstrated excellent ability to discriminate patients who required ICU-specific care in both the derivation and validation cohorts. CONCLUSIONS:Less than 10% of patients required ICU-specific care following supratentorial tumor resection. A simple clinical scoring system may aid clinicians in stratifying the risk of requiring ICU care and could inform triage decisions when ICU bed availability is limited.

Primary melanocytic disease of the central nervous system is a rarely encountered condition currently without consensus on treatment and lacking major guidelines for management. Understanding the nature of the disease and differentiating primary melanocytic disease from the much more commonly encountered secondary (metastatic) melanoma is important in identifying the condition and pursuing appropriate treatment.