Can MRI Help Inform Which Men With a History of Multifocal High-Grade Prostatic Intraepithelial Neoplasia or Atypical Small Acinar Proliferation Remain at an Elevated Risk for Clinically Significant Prostate Cancer?

PURPOSE: We investigated the association of MRI findings in men with a previous diagnosis of atypical small acinar proliferation (ASAP) or multifocal high-grade intraepithelial neoplasia (HGPIN) with pathologic findings on repeat biopsy. MATERIALS AND METHODS: We retrospectively reviewed patients with ASAP/multifocal HGPIN undergoing a repeat biopsy in the Michigan Urological Surgery Improvement Collaborative registry. We included men with and without an MRI after the index biopsy demonstrating ASAP/multifocal HGPIN but before the repeat biopsy. Men with an MRI prior to the index biopsy were excluded. We compared the proportion of men with ≥ GG2 CaP (Grade Group 2 prostate cancer) on repeat biopsy among the following groups with the χ2 test: no MRI, PIRADS (Prostate Imaging-Reporting and Data System) ≥ 4, and PIRADS ≤ 3. Multivariable models were used to estimate the adjusted association between MRI findings and ≥ GG2 CaP on repeat biopsy. RESULTS: Among the 207 men with a previous diagnosis of ASAP/multifocal HGPIN that underwent a repeat biopsy, men with a PIRADS ≥ 4 lesion had a higher proportion of ≥ GG2 CaP (56%) compared with men without an MRI (12%, P < .001). A lower proportion of men with PIRADS ≤ 3 lesions had ≥ GG2 CaP (3.0%) compared with men without an MRI (12%, P = .13). In the adjusted model, men with a PIRADS 4 to 5 lesion had higher odds (OR: 11.4, P < .001) of ≥ GG2 CaP on repeat biopsy. CONCLUSIONS: MRI is a valuable diagnostic tool to triage which men with a history of ASAP or multifocal HGPIN on initial biopsy should undergo or avoid repeat biopsy without missing clinically significant CaP.

MyProstateScore in men considering repeat biopsy: validation of a simple testing approach.

BACKGROUND: Men with persistent risk of Grade Group (GG) ≥ 2 cancer after a negative biopsy present a unique clinical challenge. The validated MyProstateScore test is clinically-available for pre-biopsy risk stratification. In biopsy-naïve patients, we recently validated a straightforward testing approach to rule-out GG ≥ 2 cancer with 98% negative predictive value (NPV) and 97% sensitivity. In the current study, we established a practical MPS-based testing approach in men with a previous negative biopsy being considered for repeat biopsy. METHODS: Patients provided post-digital rectal examination urine prior to repeat biopsy. MyProstateScore was calculated using the validated, locked model including urinary PCA3 and TMPRSS2:ERG scores with serum PSA. In a clinically-appropriate primary (i.e., training) cohort, we identified a lower (rule-out) threshold approximating 90% sensitivity and an upper (rule-in) threshold approximating 80% specificity for GG ≥ 2 cancer. These thresholds were applied to an external validation cohort, and performance measures and clinical outcomes associated with their use were calculated. RESULTS: MyProstateScore thresholds of 15 and 40 met pre-defined performance criteria in the primary cohort (422 patients; median PSA 6.4, IQR 4.3-9.1). In the 268-patient validation cohort, 25 men (9.3%) had GG ≥ 2 cancer on repeat biopsy. The rule-out threshold of 15 provided 100% NPV and sensitivity for GG ≥ 2 cancer and would have prevented 23% of unnecessary biopsies. Use of MyProstateScore >40 to rule-in biopsy would have prevented 67% of biopsies while maintaining 95% NPV. In the validation cohort, the prevalence of GG ≥ 2 cancer was 0% for MyProstateScore 0-15, 6.5% for MyProstateScore 15-40, and 19% for MyProstateScore >40. CONCLUSIONS: In patients who previously underwent a negative prostate biopsy, the MyProstateScore values of 15 and 40 yielded clinically-actionable rule-in and rule-out risk groups. Using this straightforward testing approach, MyProstateScore can meaningfully inform patients and physicians weighing the need for repeat biopsy.

Urinary MyProstateScore (MPS) to Rule out Clinically-Significant Cancer in Men with Equivocal (PI-RADS 3) Multiparametric MRI: Addressing an Unmet Clinical Need.

OBJECTIVE: To evaluate the complementary value of urinary MyProstateScore (MPS) testing and multiparametric MRI (mpMRI) and assess outcomes in patients with equivocal mpMRI. MATERIALS AND METHODS: Included patients underwent mpMRI followed by urine collection and prostate biopsy at the University of Michigan between 2015 -2019. MPS values were calculated from urine specimens using the validated model based on serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. In the PI-RADS 3 population, the discriminative accuracy of PSA, PSAD, and MPS for GG≥2 cancer was quantified by the AUC curve. Decision curve analysis was used to assess net benefit of MPS relative to PSAD. RESULTS: There were 540 patients that underwent mpMRI and biopsy with MPS available. The prevalence of GG≥2 cancer was 13% for PI-RADS 3, 56% for PI-RADS 4, and 87% for PI-RADS 5. MPS was significantly higher in men with GG≥2 cancer [median 44.9, IQR (29.4 -57.5)] than those with negative or GG1 biopsy [median 29.2, IQR (14.8 -44.2); P <.001] in the overall population and when stratified by PI-RADS score. In the PI-RADS 3 population (n = 121), the AUC for predicting GG≥2 cancer was 0.55 for PSA, 0.62 for PSAD, and 0.73 for MPS. MPS provided the highest net clinical benefit across all pertinent threshold probabilities. CONCLUSION: In patients that underwent mpMRI and biopsy, MPS was significantly associated with GG≥2 cancer across all PI-RADS scores. In the PI-RADS 3 population, MPS significantly outperformed PSAD in ruling out GG≥2 cancer. These findings suggest a complementary role of MPS testing in patients that have undergone mpMRI.

Initial Findings from a High Genetic Risk Prostate Cancer Clinic.

OBJECTIVE: To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. METHODS: We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. RESULTS: Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. CONCLUSION: These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Reframing Financial Incentives Around Reducing Readmission After Radical Cystectomy.

OBJECTIVE: To better understand the financial implications of readmission after radical cystectomy, an expensive surgery coupled with a high readmission rate. Currently, whether hospitals benefit financially from readmissions after radical cystectomy remains unclear, and potentially obscures incentives to invest in readmission reduction efforts. MATERIALS AND METHODS: Using a 20% sample of national Medicare beneficiaries, we identified 3544 patients undergoing radical cystectomy from January 2010 to November 2014. We compared price-standardized Medicare payments for index admissions and readmissions after surgery. We also examined the variable financial impact of length of stay and the proportion of Medicare payments coming from readmissions based on overall readmission rate. RESULTS: Medicare patients readmitted after cystectomy had higher index hospitalization payments ($19,164 readmitted vs $18,146 non-readmitted, P = .03) and an average readmission payment of $7356. Adjusted average Medicare readmission payments and length of stay varied significantly across hospitals, ranging from $2854 to $15,605, and 2.0 to 17.1 days, respectively (both P <.01), with longer length of stay associated with increased payments. After hospitals were divided into quartiles based on overall readmission rates, the percent of payments coming from readmissions ranged from 5% to 13%. CONCLUSION: Readmissions following radical cystectomy were associated with increased Medicare payments for the index hospitalization, and the readmission payment, potentially limiting incentives for readmission reduction programs. Our findings highlight opportunities to reframe efforts to support patients, caregivers, and providers through improving the discharge and readmission processes to create a patient-centered experience, rather than for fear of financial penalties.

Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium.

Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi-lineage differentiation and can form glands with tubal-type epithelium. We used double transgenic Ovgp1-iCreERT2 ;R26RLSL-eYFP mice, which express an eYFP reporter protein in OVGP1-positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post-TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM-treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post-TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM-treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre-pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

High-grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease.

Recent studies have suggested that the most common and lethal type of 'ovarian' cancer, i.e. high-grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human fallopian tube epithelium (FTE). We employed Ovgp1-iCreERT2 mice to show that FTE-specific inactivation of several different combinations of tumour suppressor genes that are recurrently mutated in human HGSCs - namely Brca1, Trp53, Rb1, and Nf1 - results in serous tubal intraepithelial carcinomas (STICs) that progress to HGSC or carcinosarcoma, and to widespread metastatic disease in a subset of mice. The cancer phenotype is highly penetrant and more rapid in mice carrying engineered alleles of all four tumour suppressor genes. Brca1, Trp53 and Pten inactivation in the oviduct also results in STICs and HGSCs, and is associated with diffuse epithelial hyperplasia and mucinous metaplasia, which are not observed in mice with intact Pten. Oviductal tumours arise earlier in these mice than in those with Brca1, Trp53, Rb1 and Nf1 inactivation. Tumour initiation and/or progression in mice lacking conditional Pten alleles probably require the acquisition of additional defects, a notion supported by our identification of loss of the wild-type Rb1 allele in the tumours of mice carrying only one floxed Rb1 allele. Collectively, the models closely recapitulate the heterogeneity and histological, genetic and biological features of human HGSC. These models should prove useful for studying the pathobiology and genetics of HGSC in vivo, and for testing new approaches for prevention, early detection, and treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.