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BackgroundOne in eight men will be affected by prostate cancer (PCa) in their lives. While the current clinical standard prognostic marker for PCa is the Gleason score, it is subject to interreviewer variability. This study compares two machine learning methods for discriminating between high- and low-grade PCa on histology from 47 PCa patients.MethodsDigitized slides were annotated by a GU fellowship-trained pathologist. High-resolution tiles were extracted from annotated and unlabeled tissue. Glands were segmented and pathomic features were calculated and averaged across each patient. Patients were separated into a training set of 31 patients (Cohort A, n=9345 tiles) and a testing cohort of 16 patients (Cohort B, n=4375 tiles). Tiles from Cohort A were used to train a compact classification ensemble model and a ResNet model to discriminate tumor and were compared to pathologist annotations.ResultsThe ensemble and ResNet models had overall accuracies of 89% and 88%, respectively. The ResNet model was additionally able to differentiate Gleason patterns on data from Cohort B while the ensemble model was not.ConclusionsOur results suggest that quantitative pathomic features calculated from PCa histology can distinguish regions of cancer; how-ever, texture features captured by deep learning frameworks better differentiate unique Gleason patterns.

Local paracrine versions of the renin-angiotensin (ANG) system within the brain have been implicated in aspects of cardiovascular and metabolic control, including fluid and electrolyte homeostasis, blood pressure, and energy expenditure, and these effects are often mediated via the ANG type 1 (AT1) receptor. Previous radiographic studies of human brain support ligand binding to AT1 within the hypothalamic arcuate nucleus (ARC), but its localization to individual cell types remains unresolved. Studies of rodent brain demonstrate expression of the rodent AT1 homolog AT1A within the murine ARC almost exclusively within a subset of cells that also express Agouti-related peptide (AgRP) and neuropeptide-Y (NPY). Rodent studies also demonstrate a major role for AT1A within AgRP/NPY neurons in integrative control of energy expenditure, autonomic function, and possibly blood pressure. Thus, we hypothesized that AgRP/NPY neurons of the human ARC would express AT1. ARC sections were obtained after autopsy from a 74 year old male subject diagnosed with Amyotrophic Lateral Sclerosis, body mass index of 34, with self-reported occasional use of over the counter fluticasone propionate, fexofenadine, and topical hydrocortisone. Formalin-fixed, paraffin-embedded ARC was sectioned at 4 microns. RNAscope in situ hybridization methods were used to localize mRNA for AT1 (ACDBio catalog 602841-C2) and AgRP (557451), and nuclei were visualized using DAPI. A similar 4 micron section, obtained within 12 microns of the first section, was analyzed as a negative control (AT1 control: 310043-C2, AgRP control: 310043). As expected, robust expression of AgRP was observed within the ARC (51/106 cells), but not in regions lateral to the ARC (4/114 cells). AT1 expression was observed in cells both within (49/106 cells) and outside the ARC (26/114 cells). Within the ARC, AT1 expression was detected in approximately 40% of AgRP neurons (double-positive n=21, AgRP-only n=30, AT1-only n=28, total cells n=106 in a 95,000 μm 2 region). Only a very small number of signal artifacts (AgRP 0.13; AT1 0.01 % total area) were detected in the negative control. These findings indicate that within the human ARC, and similar to rodents, AT1 is expressed within a unique subset of AgRP/NPY neurons.

BackgroundThis study identified a clinically significant subset of glioma patients with tumor outside of contrast-enhancement present at autopsy, and subsequently developed a method for detecting non-enhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to non-invasively identify areas of infiltrative tumor beyond traditional imaging signatures.MethodsA total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this study. Demographic and survival characteristics for patients with and without tumor beyond the contrast-enhancing margin were computed. An ensemble algorithm was used to predict pixelwise tumor presence from pathological annotations using segmented cellularity (Cell), extracellular fluid (ECF), and cytoplasm (Cyt) density as input (6 train/3 test subjects). A second level of ensemble algorithms were used to predict voxel-wise Cell, ECF, and Cyt on the full dataset (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1+C, FLAIR, and ADC as input. The models were then combined to generate non-invasive whole brain maps of tumor probability.ResultsTumor outside of contrast was identified in 41.5 percent of patients, who showed worse survival outcomes (HR=3.90, p<0.001). Tumor probability maps reliably tracked non-enhancing tumor in the test set, external data collected pre-surgery, and longitudinal data to identify treatment-related changes and anticipate recurrence.ConclusionsThis study developed a multi-1 stage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

One in eight men will be affected by prostate cancer (PCa) in their lives. While the current clinical standard prognostic marker for PCa is the Gleason score, it is subject to inter-reviewer variability. This study compares two machine learning methods for discriminating between cancerous regions on digitized histology from 47 PCa patients. Whole-slide images were annotated by a GU fellowship-trained pathologist for each Gleason pattern. High-resolution tiles were extracted from annotated and unlabeled tissue. Patients were separated into a training set of 31 patients (Cohort A, n = 9345 tiles) and a testing cohort of 16 patients (Cohort B, n = 4375 tiles). Tiles from Cohort A were used to train a ResNet model, and glands from these tiles were segmented to calculate pathomic features to train a bagged ensemble model to discriminate tumors as (1) cancer and noncancer, (2) high- and low-grade cancer from noncancer, and (3) all Gleason patterns. The outputs of these models were compared to ground-truth pathologist annotations. The ensemble and ResNet models had overall accuracies of 89% and 88%, respectively, at predicting cancer from noncancer. The ResNet model was additionally able to differentiate Gleason patterns on data from Cohort B while the ensemble model was not. Our results suggest that quantitative pathomic features calculated from PCa histology can distinguish regions of cancer; however, texture features captured by deep learning frameworks better differentiate unique Gleason patterns.

BACKGROUND Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE Prospective. POPULATION Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST Levene's test, P