Faculty Bibliography

Active nematic liquid crystals are the main structural phase of gliomas, promoting collective migration and aggression. We establish the existence of nematic order and topological defect lines and loops in 3D in vivo mouse and human glioma brain tumors. As predicted by theory, sections through the disclination lines in 3D appear as ±1/2 topological defects in 2D. In 3D, these defects either persist along disclination lines or twist as they interconvert from -1/2 to +1/2. Cell alignment exhibits quasi-long-range order, spreading throughout the tumor over distances between 300-3000 μm. In vitro -1/2 and +1/2 defects display changes in apoptosis levels, suggesting topological defects regulate glioma cell density. The large scale order of gliomas correlates with tumors' aggressive behavior. The organization of gliomas as active nematic liquid crystals provides a novel physical foundation of complex solid tumors; their deconstruction signposts potential treatments for deadly cancers.

A critical challenge in glioma treatment is detecting tumour infiltration during surgery to achieve safe maximal resection^1-3. Unfortunately, safely resectable residual tumour is found in the majority of patients with glioma after surgery, causing early recurrence and decreased survival^4-6. Here we present FastGlioma, a visual foundation model for fast (<10 s) and accurate detection of glioma infiltration in fresh, unprocessed surgical tissue. FastGlioma was pretrained using large-scale self-supervision (around 4 million images) on rapid, label-free optical microscopy, and fine-tuned to output a normalized score that indicates the degree of tumour infiltration within whole-slide optical images. In a prospective, multicentre, international testing cohort of patients with diffuse glioma (n = 220), FastGlioma was able to detect and quantify the degree of tumour infiltration with an average area under the receiver operating characteristic curve of 92.1 ± 0.9%. FastGlioma outperformed image-guided and fluorescence-guided adjuncts for detecting tumour infiltration during surgery by a wide margin in a head-to-head, prospective study (n = 129). The performance of FastGlioma remained high across diverse patient demographics, medical centres and diffuse glioma molecular subtypes as defined by the World Health Organization. FastGlioma shows zero-shot generalization to other adult and paediatric brain tumour diagnoses, demonstrating the potential for our foundation model to be used as a general-purpose adjunct for guiding brain tumour surgeries. These findings represent the transformative potential of medical foundation models to unlock the role of artificial intelligence in the care of patients with cancer.

BACKGROUND:High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS:Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS:Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION:The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING:Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid (<90 seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma (n = 153) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of 93.3 ± 1.6%. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.

Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.

OBJECTIVE: To formally test whether insulin sensitivity mediates the relationship between fitness and brain integrity. METHODS: Eighty-four middle-aged participants without diabetes received a 6-min walk test from which maximal oxygen uptake (VO2 max) was derived, a structural magnetic resonance scan, and a medical evaluation including fasting glucose and insulin levels. RESULTS: This study showed significant associations between fitness, abdominal obesity, and insulin sensitivity and anterior cingulate cortex (ACC) volume as well as between ACC thickness and quantitative insulin-sensitivity check index (QUICKI). The relationship between ACC volume and VO2 max was completely mediated through QUICKI. Further, this strong association was confirmed by a single and very significant cluster on the ACC linking gray matter volume and QUICKI in a voxel-based morphometry analysis. CONCLUSIONS: As expected, increased abdominal obesity was associated with reductions in fitness, ACC volumes, and insulin sensitivity. Importantly, this study demonstrated a significant mediation of the relationship between VO2 max and ACC volume by QUICKI. This suggests that the links between impaired insulin sensitivity and brain abnormalities in adults carrying excess weight could be alleviated through increased physical activity and fitness.

BACKGROUND: The prevalence of metabolic syndrome (MetS) parallels the rise in childhood obesity. MetS is associated with neurocognitive impairments in adults, but this is thought to be a long-term effect of poor metabolism. It would be important to ascertain whether these brain complications are also present among adolescents with MetS, a group without clinically manifest vascular disease and relatively short duration of poor metabolism. METHODS: Forty-nine adolescents with and 62 without MetS, matched on age, socioeconomic status, school grade, gender, and ethnicity, received endocrine, MRI, and neuropsychological evaluations. RESULTS: Adolescents with MetS showed significantly lower arithmetic, spelling, attention, and mental flexibility and a trend for lower overall intelligence. They also had, in a MetS-dose-related fashion, smaller hippocampal volumes, increased brain cerebrospinal fluid, and reductions of microstructural integrity in major white matter tracts. CONCLUSIONS: We document lower cognitive performance and reductions in brain structural integrity among adolescents with MetS, thus suggesting that even relatively short-term impairments in metabolism, in the absence of clinically manifest vascular disease, may give rise to brain complications. In view of these alarming results, it is plausible that obesity-associated metabolic disease, short of type 2 diabetes mellitus, may be mechanistically linked to lower the academic and professional potential of adolescents. Although obesity may not be enough to stir clinicians or even parents into action, these results in adolescents strongly argue for an early and comprehensive intervention. We propose that brain function be introduced among the parameters that need to be evaluated when considering early treatment of childhood obesity.