Predicting prostate cancer grade reclassification on active surveillance using a deep Learning-Based grading algorithm.

Deep learning (DL)-based algorithms to determine prostate cancer (PCa) Grade Group (GG) on biopsy slides have not been validated by comparison to clinical outcomes. We used a DL-based algorithm, AIRAProstate, to re-grade initial prostate biopsies in two independent PCa active surveillance (AS) cohorts. In a cohort initially diagnosed with GG1 PCa using only systematic biopsies (n = 138), upgrading of the initial biopsy to ≥GG2 by AIRAProstate was associated with rapid or extreme grade reclassification on AS (odds ratio 3.3, p = .04), whereas upgrading of the initial biopsy by contemporary uropathologist reviews was not associated with this outcome. In a contemporary validation cohort that underwent prostate magnetic resonance imaging before initial biopsy (n = 169), upgrading of the initial biopsy (all contemporary GG1 by uropathologist grading) by AIRAProstate was associated with grade reclassification on AS (hazard ratio 1.7, p = .03). These results demonstrate the utility of a DL-based grading algorithm in PCa risk stratification for AS.

Mesothelioma of Uncertain Malignant Potential (MUMP) of the Tunica Vaginalis: Proposal for Reclassification as "Complex Mesothelial Tumor of the Tunica Vaginalis".

A well-differentiated papillary mesothelial tumor (WDPMT) and malignant mesothelioma are 2 well-recognized entities arising from the testis tunica vaginalis. Another mesothelial lesion exclusively seen at this site is mesothelioma of uncertain malignant potential (MUMP)-a lesion reminiscent of WDPMT yet demonstrating variable proportions of more complex architectural patterns that could be confused with invasion. MUMP was first described in 2010 with a total of 11 cases reported to date. Herein, we describe 19 additional patients who underwent hydrocelectomy, excision, and/or orchiectomy. Novel morphologic patterns found in addition to the 2010 series include spindle cells, keloidal-type collagen, and multicystic architecture lined by bland mesothelial cells. Clinical follow-up in 9 patients for more than 1 year (1.5 to 22.5 y, median 4.5 y) revealed no evidence of disease recurrence or metastases. Despite greater architectural complexity, MUMP has (1) bland cytology; (2) merging in with WDPMT areas; (3) low mitotic rate and Ki-67 nuclear labeling index; (4) retention of MTAP and BAP1 expression; and (5) benign clinical follow-up. If these cases were malignant mesotheliomas, one would have expected at least some of the patients to demonstrate disease recurrence/progression without adjuvant therapy within the available follow-up time, particularly with limited resection in most patients. Thus, we propose that "mesothelioma of uncertain malignant potential" be renamed as "complex mesothelial tumor of the tunica vaginalis." Using the term "complex" draws a contrast with the simple cuboidal lining and simple papillary architecture seen in WDPMT. Also, labeling the lesion as "tumor" removes the stigmata of "uncertain malignant potential" and "mesothelioma" that are alarming to patients and clinicians, and potentially could unduly lead to more extensive surgery in an attempt at "complete" resection. At the same time, not definitively labeling the lesion as benign allows recommendations for follow-up.

Prostate Cancer in Male-to-Female Transgender Individuals: Histopathologic Findings and Association With Gender-affirming Hormonal Therapy.

Male-to-female (MtF) transgender individuals are at risk for prostate cancer, although guidelines for screening and management in this population are not well established. We describe a series of 9 MtF transgender patients who underwent prostate tissue sampling and highlight histopathologic features and challenges related to pathologic interpretation of prostate tissue in this patient population. Seven of 9 total patients were diagnosed with prostate cancer and all had elevated prostate-specific antigen at the time of diagnosis. Three of the 7 patients diagnosed with prostate cancer had received different types of hormone therapy for gender affirmation before the diagnosis of prostate cancer, and in all 3 of these patients, there was histologic evidence of hormone therapy effect in both benign prostate tissue and/or the adenocarcinoma. The 2 patients with benign prostate tissue underwent transurethral resection for lower urinary tract symptoms and were previously on hormone therapy for gender affirmation. Both of these specimens showed diffuse glandular atrophy and basal cell hyperplasia, indicative of hormone therapy effect on benign prostatic tissue. In the patients diagnosed with prostate cancer, a spectrum of grades was observed, ranging from Grade Group 1 to Grade Group 5. Four patients underwent radical prostatectomy, with 2 cases showing extraprostatic extension and Grade Group 5 prostatic adenocarcinoma, and 2 showing Grade Group 2 prostatic adenocarcinoma. Three of the 4 patients who underwent radical prostatectomy had received gender-affirming hormone therapy before surgery, and all 3 of these specimens showed hormone therapy effect in non-neoplastic prostate tissue and focal hormone therapy effect in prostatic adenocarcinoma. The presence of areas of viable carcinoma without hormone therapy effect enabled the assignment of a Gleason score and Grade Group in these 3 cases. Hormone therapy administered for gender identity affirmation induces histopathologic changes to both benign prostate tissue (nonkeratinizing squamous metaplasia, diffuse atrophy, basal cell hyperplasia, and stromal dominance with decreased numbers of glands) and prostatic adenocarcinoma (nuclear pyknosis, atrophy, cytoplasmic vacuolization, and architectural patterns that would qualify for Gleason 4 and 5 in the absence of hormone therapy effect) that have been traditionally seen in cis-male prostate cancer patients receiving hormone therapy. In the absence of hormone therapy, the morphology of prostatic adenocarcinoma in transgender patients shows classic morphologic features similar to those seen in cis-male patients not on hormone therapy. Prostate cancer with hormone therapy effect may not only be histologically quite subtle and may be overlooked if not suspected, but also should not be assigned a Gleason score because the Gleason score would substantially overstate its biologic potential. Therefore, similar to cis-male patients who have received androgen deprivation therapy for prostate cancer, transgender patients on hormone therapy for gender affirmation may be at risk for both underrecognition and over-grading of prostate cancer, particularly if the pathologist is not aware of the clinical history.

A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer.

Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we performed nutrigenetic screens on a panel of clear cell and serous ovarian cancer cells and identified cystine addiction and vulnerability to ferroptosis, a novel form of regulated cell death. Our results may have therapeutic potential, but little is known about the determinants of ferroptosis susceptibility in ovarian cancer. We found that vulnerability to ferroptosis in ovarian cancer cells is enhanced by lower cell confluency. Because the Hippo pathway effectors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are recognized as sensors of cell density, and TAZ is the predominant effector in the tested ovarian cancer cell lines, we investigated the role of TAZ in ferroptosis of ovarian cancer. TAZ removal confers ferroptosis resistance, while TAZS89A overexpression sensitizes cells to ferroptosis. In addition, we found that lower TAZ level in chemo-resistant recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility. The integrative genomic analysis identified ANGPTL4 as a direct TAZ-regulated target gene that sensitizes ferroptosis by activating NOX2. Collectively, cell density-regulated ferroptosis in ovarian cancer is mediated by TAZ through the regulation of the ANGPTL4-NOX2 axis, suggesting therapeutic potentials for ovarian cancers and other TAZ-activated tumors. IMPLICATIONS: This study reveals that TAZ promotes ferroptosis in ovarian cancers by regulating ANGPTL4 and NOX, offering a novel therapeutic potential for ovarian tumors with TAZ activation.

Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.

BACKGROUND: Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population. METHODS: A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively. RESULTS: All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits. CONCLUSIONS: Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.