Chandana A. Reddy

PURPOSE: Artificial intelligence (AI) tools that identify pathologic features from digitized whole-slide images (WSIs) of prostate cancer (CaP) generate data to predict outcomes. The objective of this study was to evaluate the clinical validity of an AI-enabled prognostic test, PATHOMIQ_PRAD, using a clinical cohort from the Cleveland Clinic. METHODS: We conducted a retrospective analysis of PATHOMIQ_PRAD using CaP WSIs from patients who underwent radical prostatectomy (RP) between 2009 and 2022 and did not receive adjuvant therapy. Patients also had Decipher genomic testing available. WSIs were deidentified, anonymized, and outcomes were blinded. Patients were stratified into high-risk and low-risk categories on the basis of predetermined thresholds for PATHOMIQ_PRAD scores (0.45 for biochemical recurrence [BCR] and 0.55 for distant metastasis [DM]). RESULTS: The study included 344 patients who underwent RP with a median follow-up of 4.3 years. Both PathomIQ and Decipher scores were associated with rates of biochemical recurrence-free survival (BCRFS; PathomIQ score >0.45 v ≤0.45, P <.001; Decipher score >0.6 v ≤0.6, P = .002). There were 16 patients who had DM, and 15 were in the high-risk PathomIQ group (Mets Score >0.55). Both PathomIQ and Decipher scores were associated with rates of metastasis-free survival (PathomIQ score >0.55 v ≤0.55, P <.001; Decipher score >0.6 v ≤0.6, P = .0052). Despite the low event rates for metastasis, multivariable regression demonstrated that high PathomIQ score was significantly associated with DM (>0.55 v ≤0.55, hazard ratio, 10.10 [95% CI, 1.28 to 76.92], P = .0284). CONCLUSION: These findings independently validate PATHOMIQ_PRAD as a reliable predictor of clinical risk in the postprostatectomy setting. PATHOMIQ_PRAD therefore merits prospective evaluation as a risk stratification tool to select patients for adjuvant or early salvage interventions.

Purpose/objective: Radiation necrosis (RN) is a potential complication after stereotactic radiosurgery (SRS) for brain metastases. This study develops a recursive partitioning analysis (RPA) to identify patients at risk for RN following SRS. Methods: Patients who underwent single-fraction SRS for intact brain metastases at a single institution from 2017 to 2021 were identified. Cox regression identified factors associated with RN, and variables with p < 0.1 were included in the RPA. Patients with staged SRS, incomplete records, or less than 3 months of follow-up were excluded. Results: The study included 170 patients with 919 lesions, with median follow-up of 9 months. Primary disease sites were non-small cell lung cancer (NSCLC, 49%), breast cancer (12%), melanoma (11%), renal cancer (6%), and others (22%). Median prescription dose was 24 Gy, and median maximum lesion dimension (MLD) was 0.7 cm. RN occurred in 110 (12.2%) lesions, of which 32 (3.5%) were symptomatic, at median of 4.9 months after SRS. Variables for RPA included primary disease site, tumor location, MLD, prior SRS, number of SRS targets, dosimetry, prior hemorrhage, and concurrent systemic therapy. RPA identified four groups: Group 1 (MLD ≤ 0.8 cm, non-breast/NSCLC/renal), Group 2 (MLD ≤ 0.8 cm, breast/NSCLC/renal), Group 3 (MLD > 0.8 cm, no post-SRS hemorrhage), and Group 4 (MLD > 0.8 cm, post-SRS hemorrhage). Two-year RN free survival was 99% (Group 1), 89% (Group 2), 70% (Group 3), and 52% (Group 4). Conclusion: This is the first RPA model for RN after single-fraction SRS, which may aid in risk assessment and distinguishing RN from tumor progression.

Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.