Association of Genomic Prostate Score at positive margin with recurrence after radical prostatectomy.

Objectives: To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR).

Patients And Methods: We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk.

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 regrade initial prostate biopsies in 2 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.

Semi-Supervised, Attention-Based Deep Learning for Predicting TMPRSS2:ERG Fusion Status in Prostate Cancer Using Whole Slide Images.

Our study illuminates the potential of deep learning in effectively inferring key prostate cancer genetic alterations from the tissue morphology depicted in routinely available histology slides, offering a cost-effective method that could revolutionize diagnostic strategies in oncology.

Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers.

Background: Several studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown.

Patients And Methods: To ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN.

ERG Status at the Margin Is Associated With Biochemical Recurrence After Radical Prostatectomy With Positive Surgical Margins.

Positive surgical margins at radical prostatectomy are associated with an increased risk of biochemical recurrence (BCR). However, there is considerable variability in outcomes, suggesting that molecular biomarkers-when assessed specifically at the margin tumor tissue-may be useful to stratify prognosis in this group. We used a case-cohort design for the outcome of BCR, selecting 215 patients from a cohort of 813 patients undergoing prostatectomy treated at the Johns Hopkins from 2008 to 2017 with positive margins and available clinical data.

Clonal relationships of adjacent Gleason pattern 3 and Gleason pattern 5 lesions in Gleason Scores 3+5=8 and 5+3=8.

Genomic studies have demonstrated a high level of intra-tumoral heterogeneity in prostate cancer. There is strong evidence suggesting that individual tumor foci can arise as genetically distinct, clonally independent lesions. However, recent studies have also demonstrated that adjacent Gleason pattern (GP) 3 and GP4 lesions can originate from the same clone but follow divergent genetic and morphologic evolution.

GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms.

GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2-associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR-Cas9 genome editing as well as in a mouse model of Tsc2 inactivation-driven renal tumorigenesis.

Association between pathogenic germline mutations in BRCA2 and ATM and tumor-infiltrating lymphocytes in primary prostate cancer.

Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort.

Mismatch repair-deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade.

Parenchymal brain metastases from prostate cancer are unusual and are associated with poor prognosis. Given the rarity of this entity, little is known about its molecular and histologic characteristics. Here we describe a patient with metastatic castration-resistant, mismatch repair-deficient (dMMR) prostate cancer with parenchymal brain metastases.

Assessment of MYC/PTEN Status by Gene-Protein Assay in Grade Group 2 Prostate Biopsies.

This study leveraged a gene-protein assay to assess MYC and PTEN status at prostate cancer biopsy and examined the association with adverse outcomes after surgery. MYC gain and PTEN loss were simultaneously assessed by chromogenic in situ hybridization and immunohistochemistry, respectively, using 277 Grade Group 2 needle biopsies that were followed by prostatectomy. The maximal size of cribriform Gleason pattern 4 carcinoma (CRIB), the presence of intraductal carcinoma (IDC), and percentage of Gleason pattern 4 carcinoma at biopsy were also annotated.

Neoadjuvant Nivolumab in Patients with High-risk Nonmetastatic Renal Cell Carcinoma.

Neoadjuvant immune checkpoint blockade represents a novel approach for potentially decreasing the risk of recurrence in patients with nonmetastatic renal cell carcinoma (RCC). In this early phase clincal tiral, we evaluated the safety and tolerability of neoadjuvant treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab in patients with nonmetastatic high-risk RCC. Nonprimary endpoints included objective radiographic tumor response rate, immune-related pathologic response rate, quality of life alterations, and metastasis-free and overall survival.

Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.

Background: Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.

Association between BRCA2 alterations and intraductal and cribriform histologies in prostate cancer.

Background: Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of genetic testing for patients with IDC in the primary tumour.

Patients And Methods: To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case-control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status.

Plasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression.

Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer.

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102).

Well-differentiated neuroendocrine tumors of the lower urinary tract: biologic behavior of a rare entity.

The spectrum of neuroendocrine (NE) tumors in the genitourinary tract ranges from the aggressive large and small cell carcinomas to the often benign paraganglioma and well-differentiated neuroendocrine tumor (WD-NET). At least 15 pure lower urinary tract (LUT) WD-NETs have been described. Owing to the rarity of WD-NET in the LUT and the limited number of reported cases, a better definition of their biologic long-term behavior is warranted.

PIN-like ductal carcinoma of the prostate has frequent activating RAS/RAF mutations.

Aims: Prostatic intraepithelial neoplasia-like (PIN-like) ductal carcinoma is a rare tumour characterised by often cystically dilated glands architecturally resembling high-grade PIN, but lacking basal cells. These tumours are frequently accompanied by grade group 1 acinar cancer and behave relatively indolently. In contrast, conventional ductal adenocarcinoma of the prostate is an aggressive variant comparable to grade group 4 acinar cancer.

Genomic and Clinicopathologic Characterization of -deficient Prostate Cancer.

Purpose: The (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.

Experimental Design: We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes.

Significance of Paneth cell-like differentiation in prostatic adenocarcinoma: a retrospective cohort study of 80 cases.

The grading and prognosis of prostatic adenocarcinoma with Paneth cell-like differentiation (PanEC) is controversial with limited available data. We identified 80 cases, not previously published, of PanEC first identified on biopsy (n = 69), transurethral resection of the prostate (n = 1), and radical prostatectomy (RP) (n = 10). Of 69 biopsies, 22 did not have a grade assigned.

Gleason pattern 4 with cribriform morphology on biopsy is associated with adverse clinicopathological findings in a prospective radical prostatectomy cohort.

The prognostic significance of the Gleason grading system has been well established. However, individual Gleason patterns comprise heterogeneous morphologies which might add additional prognostic information. Recent evidence suggests that Gleason pattern 4 with cribriform growth pattern is associated with an adverse prognosis.

Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer.

Purpose: The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population.

Experimental Design: Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA).

Clinical significance of urothelial carcinoma ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor.

Purpose: To evaluate the clinical significance of invasive urothelial carcinoma that is ambiguous for muscularis propria invasion on initial transurethral resection of bladder tumor (TURBT).

Methods: All consecutive in-house TURBTs with invasive urothelial carcinoma from 1999 to 2017 that underwent radical cystectomy (RC) were grouped as follows: invasion of the lamina propria (INLP; n = 102; 24%), invasion of muscularis propria (INMP; n = 296; 69%) and ambiguous for muscularis propria invasion (AMP; n = 30; 7%). AMP was defined as extensive invasive carcinoma displaying thin muscle bundles where it is difficult to determine with certainty if those muscle bundles represent muscularis mucosae or muscularis propria (detrusor).

Incidence and distribution of UroSEEK gene panel in a multi-institutional cohort of bladder urothelial carcinoma.

Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer.