Faculty Bibliography

The detection and tracking of metastatic cancer over the lifetime of a patient remains a major challenge in clinical trials and real-world care. Advances in deep learning combined with massive datasets may enable the development of tools that can address this challenge. We present NYUMets-Brain, the world's largest, longitudinal, real-world dataset of cancer consisting of the imaging, clinical follow-up, and medical management of 1,429 patients. Using this dataset we developed Segmentation-Through-Time, a deep neural network which explicitly utilizes the longitudinal structure of the data and obtained state-of-the-art results at small (<10 mm³) metastases detection and segmentation. We also demonstrate that the monthly rate of change of brain metastases over time are strongly predictive of overall survival (HR 1.27, 95%CI 1.18-1.38). We are releasing the dataset, codebase, and model weights for other cancer researchers to build upon these results and to serve as a public benchmark.

It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.

PURPOSE/OBJECTIVE:The IC Profiler (ICP) manufactured by Sun Nuclear Corporation (SNC) is an ionization chamber (IC) array used for linear accelerator dosimetry measurements. Previous work characterized response of the ICP under various conditions, but there is limited work of its implementation into monthly QA measurement procedures. This work quantifies ICP accuracy and variables that affect accuracy for beam output measurements, and demonstrates feasibility of using the ICP for all recommended monthly dosimetry measurements. METHODS:A total of 1985 output measurements on six Varian TrueBeam and Edge linear accelerators were performed using three ICP with quad wedges (QWs) and were compared with conventional IC measurements. The accuracy of the ICP for beam output was characterized as the difference between the ICP and IC. Variables that affect ICP accuracy, including gain settings, calibrations, and template baselining as well as machine or energy-specific bias were investigated. Measurements of profile constancy, energy, dose rate constancy, wedge factors, and gating were performed. RESULTS:The initially observed mean output difference between the ICP and IC was 0.16% (0.61%). When gain settings were optimized, the output difference accuracy improved to -0.02% (0.38%). The output accuracy of the ICP was not dependent on array, dose, temperature and pressure calibrations, or template baselining. Statistically, ICP output accuracy was dependent on machine and beam energy, but clinically, all measurements fell within 0.5% of unity. ICP measurements of energy, dose rate constancy, and wedge factors matched passing results with conventional IC in water measurements. Gating and beam profile constancy measurements demonstrated good stability using the ICP. Finally, monthly dosimetry QA using ICP was completed in an average of 33 min compared to 66 min using the IC. CONCLUSION/CONCLUSIONS:This work demonstrated the feasibility and efficiency of using the ICP, with specific considerations, as a measurement device for dosimetric linear accelerator monthly QA.

Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from nonplatelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with nonplatelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.

Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally^1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic^3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues⁷. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion^8-10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.

PURPOSE/OBJECTIVE:Whole brain radiotherapy (WBRT) is a common treatment for brain metastases (BM) and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer's disease, and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset-time or extent of NCF impairment in patients with BM treated with WBRT. METHODS AND MATERIALS/METHODS:NRG/RTOG 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. RESULTS:APOE results were available for 45% (n=227/508) of patients. NCF did not differ by APOE e4 carrier status at baseline. Mixed effects modeling showed that APOE e4 carriers had worse memory after WBRT compared to APOE e4 non-carriers (HVLT-R Total Recall [least square (LS) mean difference = 0.63, p=0.0074], Delayed Recognition [LS mean difference= 0.75, p=0.023]). However, APOE e4 carrier status was not associated with time to NCF failure (HR=0.86, 95% CI: 0.60-1.23, p=0.40). Memantine delayed the time to NCF failure, regardless of carrier status (HR=0.72, 95% CI: 0.52-1.01, p=0.054). CONCLUSIONS:APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/- memantine), without acceleration of onset of difference in time to NCF failure.

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.

BACKGROUND:Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS:We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS:There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS:The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

PURPOSE/OBJECTIVE:Radiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex. METHODS AND MATERIALS/METHODS:We conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity. RESULTS:Of 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P = .04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P = .03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events. CONCLUSIONS:This report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal.

Radiation therapy is part of a multimodality treatment approach to lung cancer. The radiologist must be aware of both the expected and the unexpected imaging findings of the post-radiation therapy patient, including the time course for development of post- radiation therapy pneumonitis and fibrosis. In this review, a brief discussion of radiation therapy techniques and indications is presented, followed by an image-heavy differential diagnostic approach. The review focuses on computed tomography imaging examples to help distinguish normal postradiation pneumonitis and fibrosis from alternative complications, such as infection, local recurrence, or radiation-induced malignancy.