Noninvasive Autopsy-Validated Tumor Probability Maps Identify Glioma Invasion Beyond Contrast Enhancement.

BACKGROUND AND OBJECTIVES: This study identified a clinically significant subset of patients with glioma with tumor outside of contrast enhancement present at autopsy and subsequently developed a method for detecting nonenhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to noninvasively identify areas of infiltrative tumor beyond traditional imaging signatures. METHODS: A total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this retrospective 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, and cytoplasm density as input (6 train/3 test subjects). A second level of ensemble algorithms was used to predict voxelwise Cell, extracellular fluid, and cytoplasm on the full data set (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1 + C, fluid-attenuated inversion recovery, and apparent diffusion coefficient as input. The models were then combined to generate noninvasive whole brain maps of tumor probability. RESULTS: Tumor outside of contrast was identified in 41.5% of patients, who showed worse survival outcomes (hazard ratio = 3.90, P < .001). Tumor probability maps reliably tracked nonenhancing tumor on a range of local and external unseen data, identifying tumor outside of contrast in 69% of presurgical cases that also showed reduced survival outcomes (hazard ratio = 1.67, P = .027). CONCLUSION: This study developed a multistage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

BACKGROUND: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. METHODS: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. RESULTS: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). CONCLUSION: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

Background: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. Methods: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. Results: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). Conclusion: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Quantitative Histomorphometric Features of Prostate Cancer Predict Patients Who Biochemically Recur Following Prostatectomy.

Prostate cancer is the most commonly diagnosed cancer in men, accounting for 27% of the new male cancer diagnoses in 2022. If organ-confined, removal of the prostate through radical prostatectomy is considered curative; however, distant metastases may occur, resulting in a poor patient prognosis. This study sought to determine whether quantitative pathomic features of prostate cancer differ in patients who biochemically experience biological recurrence after surgery. Whole-mount prostate histology from 78 patients was analyzed for this study. In total, 614 slides were hematoxylin and eosin stained and digitized to produce whole slide images (WSI). Regions of differing Gleason patterns were digitally annotated by a genitourinary fellowship-trained pathologist, and high-resolution tiles were extracted from each annotated region of interest for further analysis. Individual glands within the prostate were identified using automated image processing algorithms, and histomorphometric features were calculated on a per-tile basis and across WSI and averaged by patients. Tiles were organized into cancer and benign tissues. Logistic regression models were fit to assess the predictive value of the calculated pathomic features across tile groups and WSI; additionally, models using clinical information were used for comparisons. Logistic regression classified each pathomic feature model at accuracies >80% with areas under the curve of 0.82, 0.76, 0.75, and 0.72 for all tiles, cancer only, noncancer only, and across WSI. This was comparable with standard clinical information, Gleason Grade Groups, and CAPRA score, which achieved similar accuracies but areas under the curve of 0.80, 0.77, and 0.70, respectively. This study demonstrates that the use of quantitative pathomic features calculated from digital histology of prostate cancer may provide clinicians with additional information beyond the traditional qualitative pathologist assessment. Further research is warranted to determine possible inclusion in treatment guidance.

T2-Weighted MRI Radiomic Features Predict Prostate Cancer Presence and Eventual Biochemical Recurrence.

Prostate cancer (PCa) is the most diagnosed non-cutaneous cancer in men. Despite therapies such as radical prostatectomy, which is considered curative, distant metastases may form, resulting in biochemical recurrence (BCR). This study used radiomic features calculated from multi-parametric magnetic resonance imaging (MP-MRI) to evaluate their ability to predict BCR and PCa presence. Data from a total of 279 patients, of which 46 experienced BCR, undergoing MP-MRI prior to surgery were assessed for this study. After surgery, the prostate was sectioned using patient-specific 3D-printed slicing jigs modeled using the T2-weighted imaging (T2WI). Sectioned tissue was stained, digitized, and annotated by a GU-fellowship trained pathologist for cancer presence. Digitized slides and annotations were co-registered to the T2WI and radiomic features were calculated across the whole prostate and cancerous lesions. A tree regression model was fitted to assess the ability of radiomic features to predict BCR, and a tree classification model was fitted with the same radiomic features to classify regions of cancer. We found that 10 radiomic features predicted eventual BCR with an AUC of 0.97 and classified cancer at an accuracy of 89.9%. This study showcases the application of a radiomic feature-based tool to screen for the presence of prostate cancer and assess patient prognosis, as determined by biochemical recurrence.

Whole slide imaging (WSI) scanner differences influence optical and computed properties of digitized prostate cancer histology.

Purpose: Digital pathology is becoming an increasingly popular area of advancement in both research and clinically. Pathologists are now able to manage and interpret slides digitally, as well as collaborate with external pathologists with digital copies of slides. Differences in slide scanners include variation in resolution, image contrast, and optical properties, which may influence downstream image processing. This study tested the hypothesis that varying slide scanners would result in differences in computed pathomic features on prostate cancer whole mount slides. Design: This study collected 192 unique tissue slides from 30 patients following prostatectomy. Tissue samples were paraffin-embedded, stained for hematoxylin and eosin (H&E), and digitized using 3 different scanning microscopes at the highest available magnification rate, for a total of 3 digitized slides per tissue slide. These scanners included a (S1) Nikon microscope equipped with an automated sliding stage, an (S2) Olympus VS120 slide scanner, and a (S3) Huron TissueScope LE scanner. A color deconvolution algorithm was then used to optimize contrast by projecting the RGB image into color channels representing optical stain density. The resulting intensity standardized images were then computationally processed to segment tissue and calculate pathomic features including lumen, stroma, epithelium, and epithelial cell density, as well as second-order features including lumen area and roundness; epithelial area, roundness, and wall thickness; and cell fraction. For each tested feature, mean values of that feature per digitized slide were collected and compared across slide scanners using mixed effect models, fit to compare differences in the tested feature associated with all slide scanners for each slide, including a random effect of subject with a nested random effect of slide to account for repeated measures. Similar models were also computed for tissue densities to examine how differences in scanner impact downstream processing. Results: Each mean color channel intensity (i.e., Red, Green, Blue) differed between slide scanners (all P<.001). Of the color deconvolved images, only the hematoxylin channel was similar in all 3 scanners (all P>.05). Lumen and stroma densities between S3 and S1 slides, and epithelial cell density between S3 and S2 (P>.05) were comparable but all other comparisons were significantly different (P<.05). The second-order features were found to be comparable for all scanner comparisons, except for lumen area and epithelium area. Conclusion: This study demonstrates that both optical and computed properties of digitized histological samples are impacted by slide scanner differences. Future research is warranted to better understand which scanner properties influence the tissue segmentation process and to develop harmonization techniques for comparing data across multiple slide scanners.

Comparison of a machine and deep learning model for automated tumor annotation on digitized whole slide prostate cancer histology.

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.

Synthesis and Different Effects of Biotinylated PAMAM G3 Dendrimer Substituted with Nimesulide in Human Normal Fibroblasts and Squamous Carcinoma Cells.

Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in cancer cell proliferation, and its inhibition become a target for control of cancer development, particularly in the view of recognized additive or synergic action of COX-2 inhibitors with other forms of therapy. Nimesulide (N), the selective COX-2 inhibitor, inhibits growth and proliferation of various types of cancer cells by COX-2 dependent and independent mechanisms. In the presented study, the conjugates of biotinylated third generation poly(amidoamine) dendrimer (PAMAM) with covalently linked 18 (G3B18N) and 31 (G3B31N) nimesulide residues were synthesized and characterized by NMR spectroscopy. Biological properties of conjugates were evaluated, including cytotoxicity, proliferation, and caspase 3/7 activities in relation to COX-2/PGE2 axis signaling in human normal fibroblast (BJ) and squamous cell carcinoma (SCC-15). Both conjugates exerted a selective cytotoxicity against SCC-15 as compared with BJ cells at low 1.25-10 µM concentration range and their action in cancer cells was over 250-fold stronger than nimesulide alone. Conjugates overcome apoptosis resistance and sensitized SCC-15 cells to the apoptotic death independently of COX-2/PGE2 axis. In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2.