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PURPOSE: During the COVID-19 surge months of March and April 2020, our New York multicenter health system experienced an influx of cases with COVID-19. We sought to study the impact of the surge period on patients with cancer prescribed radiation treatment (RT). METHODS: We reviewed our secure departmental quality assurance database for all patients who underwent RT planning simulations from March 6, 2020, through April 30, 2020. A priority level between 1 and 3 was prospectively assigned to each case based on faculty consensus to determine which patients required immediate RT. In May 2020, each faculty physician again retrospectively reviewed their patients from the database and provided additional commentary on how the COVID-19 pandemic had affected each patient's care. All statistics are descriptive. RESULTS: A total of 412 RT courses in 406 unique patients were simulated for linear accelerator–based external beam RT. The median age was 66 years. Treatment intent was curative in 70.6% and palliative in 29.4%. Of the 412 cases, 66.7% were priority 1, 25% priority 2, and 7.8% priority 3. Two hundred thirty-nine cases (58%) underwent standard-of-care diagnosis, workup, and treatment plan. Seventeen patients (4.1%) electively canceled their RT, and 17 others (4.1%) electively delayed RT start. Thirty-four (8.3%) were prescribed hypofractionation to shorten their RT course, and 22 (5.3%) had a change in modality. Incomplete or delayed workup was identified in 19 cases (4.6%). CONCLUSION: The COVID-19 pandemic surge resulted in 42% of our patients having a non–standard-of-care pathway. This outcome demonstrates a significant impact of the COVID-19 crisis on routine cancer care.

Background Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown. Methods We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018. Results Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) (P = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, P = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate (P = .004) in response to radiation. Conclusions Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.

OBJECTIVES: Quantitative radiologic and radiomic features can identify brain tumors at risk for poor outcomes. Here, we investigate prognostic models for meningioma grade, local failure (LF) and overall survival (OS) based on demographic, radiologic, radiomic and therapeutic data. METHODS: We developed a database that was enriched for high grade meningiomas from 219 patients who underwent surgery for 229 meningiomas from 1990 to 2015 who had comprehensive clinical, pathologic and radiologic information available for retrospective review. The median imaging follow up was 4.3 years, and there were 112 WHO grade I (49%), 93 grade II (41%) and 24 grade III (10%) meningiomas. Two neuro-radiologists independently annotated 17 radiologic features, and 154 radiomic features were extracted from preoperative post-contrast 3D SPGR MR images for each meningioma. Random forest models were trained using nested resampling, and the performance of each model was assessed by calculating feature importance, mean balanced accuracy (BA) and area under the curve (AUC). RESULTS: Models restricted to preoperative demographic information and quantitative imaging features had superior BA (0.60–0.67) and AUC (0.60–0.76) for LF or OS as compared to models based on meningioma grade and extent of resection (BA 0.65, AUC 0.64). Integrated models incorporating all available data provided the most accurate estimates of LF and OS (BA 0.67, AUC 0.76). Radiomic features alone or in combination with other variables showed moderate and marginal predictive value for grade (BA 0.63, AUC 0.72) and LF (BA 0.61, AUC 0.65), respectively. Among radiologic features, meningioma diffusion characteristics significantly strengthened prognostication of grade and LF (RR 25.6, P = 0.001). Recursive partitioning analysis identified tumor size, primary versus recurrent presentation, grade, sphericity, apparent diffusion coefficient, location, extent of resection and T2 signal as the most important features for LF. CONCLUSIONS: Models using clinical and quantitative imaging data can accurately predict meningioma outcomes.

INTRODUCTION: Bevacizumab responsiveness in glioblastoma is transient. The time course and upstream regulators of resistance still remain undefined. There is also conflicting evidence as to whether the resistance is driven by upregulated VEGF-independent angiogenic pathways or adaptation to treatment-induced hypoxia involving perivascular invasion. METHODS: We analyzed paired patient specimens before and after bevacizumab-resistance and two xenograft models of bevacizumab-resistance: (1) a multigenerational model that replicates the lengthy treatment duration in patients and (2) PDXs replicating patient tumor resistance. Transcriptional changes were studied using microarray and qPCR. Morphological changes were assessed by immunostaining; invasion was assessed by bioengineered 3D models of perivascular vs. parenchymal invasion. Stem cell enrichment was confirmed by stem cell reformation assays. RESULTS: Despite upregulated VEGF-independent pro-angiogenic genes, immunostaining revealed increased hypoxia and decreased vessel density in resistant xenografts and patient specimens, suggesting tumor growth despite effective bevacizumab-induced devascularization. Microarrays revealed overexpression of the mesenchymal subtype gene signature across resistant xenograft generations and in resistant PDXs, replicating patient specimens whose elevated mesenchymal gene signature correlated with bevacizumab treatment duration. Single-cell sequencing of bevacizumab-resistant patient specimens revealed these mesenchymal changes to arise in early cell clones with fewer mutations. Xenograft and patient specimen microarray analysis implicated ZEB1, a key mediator of mesenchymal transition and glioma-stemness, as a potential regulator of this change, with ZEB1 increasing across xenograft generations (P< 0.001). Late-generation resistant-xenografts revealed lower form factor (p< 0.001), increased perivascular and parenchymal invasion in 3D bioengineered models (p< 0.001 and p< 0.05), and larger neurospheres (p= 0.002) with higher stem cell counts (p< 0.001) versus to early-generations. CRISPR targeting of ZEB1 reversed the morphology, stem cell neurosphere formation, and mesenchymal gene expression changes defining resistance to that of bevacizumab-sensitive tumors. CONCLUSION: We identified ZEB1 as a targetable regulator of the mesenchymal change and associated perivascular invasion and stem cell enrichment defining bevacizumab resistance.

OBJECTIVES: Chordoid meningiomas are a rare histologic variant that follow an aggressive clinical course. Here, we examine histopathologic and radiologic features of chordoid meningiomas to identify risk factors for recurrence. METHODS: Retrospective chart reviews were performed on 11 patients with chordoid meningioma and 15 patients with meningioma with focal chordoid features (

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Received: June 10, 2010 , Accepted: July 29, 2010 , Published: August 8, 2010 // The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

Aggregation is a social behavior that varies between and within species, providing a model to study the genetic basis of behavioral diversity. In the nematode Caenorhabditis elegans, aggregation is regulated by environmental context and by two neuromodulatory pathways, one dependent on the neuropeptide receptor NPR-1 and one dependent on the TGF-β family protein DAF-7. To gain further insight into the genetic regulation of aggregation, we characterize natural variation underlying behavioral differences between two wild-type C. elegans strains, N2 and CB4856. Using quantitative genetic techniques, including a survey of chromosome substitution strains and QTL analysis of recombinant inbred lines, we identify three new QTLs affecting aggregation in addition to the two known N2 mutations in npr-1 and glb-5. Fine-mapping with near-isogenic lines localized one QTL, accounting for 5%–8% of the behavioral variance between N2 and CB4856, 3′ to the transcript of the GABA neurotransmitter receptor gene exp-1. Quantitative complementation tests demonstrated that this QTL affects exp-1, identifying exp-1 and GABA signaling as new regulators of aggregation. exp-1 interacts genetically with the daf-7 TGF-β pathway, which integrates food availability and population density, and exp-1 mutations affect the level of daf-7 expression. Our results add to growing evidence that genetic variation affecting neurotransmitter receptor genes is a source of natural behavioral variation., Author Summary In both animals and humans, normal individuals can behave differently in the same environment. Natural variation in behavior is partly due to genetic differences between individuals and partly due to experience. Mapping studies have demonstrated that the genetic component of natural behavioral variation is complex, with many genes that each contribute a small amount to the observed behavior. This complexity has made it difficult to identify the causative genes for individual differences. Here we use the nematode worm C. elegans to dissect a social behavioral trait, the propensity to aggregate with other animals in the presence of food. We find that the behavioral differences between two wild-type worm strains result from at least five genetic differences between the strains, two of which were previously known. One of the three new loci affects a receptor for the neurotransmitter GABA, which regulates excitability in the brain. In the context of previous work, we suggest that a significant number of genes that generate behavioral variation encode neurotransmitter receptors. This analysis in a model animal may help guide discoveries of the genetic variants that affect common human behavioral traits by suggesting classes of genes to examine closely.

Ethanol-induced neuro-developmental abnormalities are associated with impaired insulin and IGF signaling, and increased oxidative stress in CNS neurons. We examined the roles of ethanol and its principal toxic metabolite, acetaldehyde, as mediators of impaired insulin/IGF signaling and oxidative injury in immature cerebellar neurons. Cultures were exposed to 3.5 mM acetaldehyde or 50 mM ethanol ± 4-methylpyrazole (4-MP), an inhibitor of ethanol metabolism, and viability, mitochondrial function, oxidative stress, DNA damage, and insulin responsiveness were measured 48 hours later. Acetaldehyde or ethanol increased neuronal death and levels of 8-OHdG and 4-HNE, and reduced mitochondrial function. Ethanol inhibited insulin responsiveness, whereas acetaldehyde did not. 4-MP abated ethanol-induced oxidative stress and mitochondrial dysfunction, but failed to restore insulin responsiveness. Furthermore, alcohol and aldehyde metabolizing enzyme genes were inhibited by prenatal ethanol exposure; this effect was mediated by acetaldehyde and not ethanol + 4MP. These findings suggest that brain insulin resistance in prenatal alcohol exposure is caused by direct effects of ethanol, whereas oxidative stress induced neuronal injury is likely mediated by ethanol and its toxic metabolites. Moreover, the adverse effects of prenatal ethanol exposure on brain development may be exacerbated by down-regulation of genes needed for metabolism and detoxification of alcohol in the brain.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.