Organoid cultures derived from patients with advanced prostate cancer.

The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.

Do Phosphodiesterase Type 5 Inhibitors Increase the Risk of Biochemical Recurrence After Radical Prostatectomy?

PURPOSE: There have been conflicting studies on the association between phosphodiesterase type 5 inhibitor (PDE5i) use and biochemical recurrence (BCR) following radical prostatectomy (RP). Our aim was to determine whether PDE5i drug exposure after RP increases the risk of BCR in patients undergoing RP. MATERIALS AND METHODS: An institutional database of prostate cancer patients treated between January 2009 and December 2020 was reviewed. BCR was defined as 2 PSA measurements greater than 0.1 ng/mL. PDE5i exposure was defined using a 0 to 3 scale, with 0 representing never use, 1 sometimes use, 2 regularly use, and 3 routinely use. The risk of BCR with any PDE5i exposure, the quantity of exposure, and the duration of PDE5i exposure were assessed by multivariable Cox proportional hazards models. RESULTS: The sample size included 4630 patients to be analyzed, with 776 patients having BCR. The median follow-up for patients without BCR was 27 (IQR 12, 49) months. Eighty-nine percent reported taking a PDE5i at any time during the first 12 months after RP, and 60% reported doing so for 6 or more months during the year after RP. There was no evidence of an increase in the risk of BCR associated with any PDE5i use (HR 1.05, 95% CI 0.84, 1.31, P = .7) or duration of PDE5i use in the first year (HR 0.98 per 1 month duration, 95% CI 0.96, 1.00, P = .055). Baseline oncologic risk was lower in patients using PDE5i, but differences between groups were small, suggesting that residual confounding is unlikely to obscure any causal association with BCR. CONCLUSIONS: Prescription of PDE5i to men after RP can be based exclusively on quality of life considerations. Patients receiving PDE5is can be reassured that their use does not increase the risk of BCR.

The oncologic risk of magnetic resonance imaging-targeted and systematic cores in patients treated with radical prostatectomy.

BACKGROUND: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-biopsy) detects high-Grade Group (GG) prostate cancers not identified by systematic biopsy (S-biopsy). However, questions have been raised whether cancers detected by MRI-biopsy and S-biopsy, grade-for-grade, are of equivalent oncologic risk. The authors evaluated the relative oncologic risk of GG diagnosed by S-biopsy and MRI-biopsy. METHODS: This was a retrospective analysis of all patients who had both MRI-biopsy and S-biopsy and underwent with prostatectomy (2014-2022) at Memorial Sloan Kettering Cancer Center. Three logistic regression models were used with adverse pathology as the primary outcome (primary pattern 4, any pattern 5, seminal vesicle invasion, or lymph node involvement). The first model included the presurgery prostate-specific antigen level, the number of positive and negative S-biopsy cores, S-biopsy GG, and MRI-biopsy GG. The second model excluded MRI-biopsy GG to obtain the average risk based on S-biopsy GG. The third model excluded S-biopsy GG to obtain the risk based on MRI-biopsy GG. A secondary analysis using Cox regression evaluated the 12-month risk of biochemical recurrence. RESULTS: In total, 991 patients were identified, including 359 (36%) who had adverse pathology. MRI-biopsy GG influenced oncologic risk compared with S-biopsy GG alone (p < .001). However, if grade was discordant between biopsies, then the risk was intermediate between grades. For example, the average risk of advanced pathology for patients who had GG2 and GG3 on S-biopsy was 19% and 66%, respectively, but the average risk was 47% for patients who had GG2 on S-biopsy and patients who had GG3 on MRI-biopsy. The equivalent estimates for 12-month biochemical recurrence were 5.8%, 15%, and 10%, respectively. CONCLUSIONS: The current findings cast doubt on the practice of defining risk group based on the highest GG. Because treatment algorithms depend fundamentally on GG, further research is urgently required to assess the oncologic risk of prostate tumors depending on detection technique. PLAIN LANGUAGE SUMMARY: Using magnetic resonance imaging (MRI) to help diagnose prostate cancer can help identify more high-grade cancers than using a systematic template biopsy alone. However, we do not know if high-grade cancers diagnosed with the help of an MRI are as dangerous to the patient as high-grade cancers diagnosed with a systematic biopsy. We examined all of our patients who had an MRI biopsy and a systematic biopsy and then had their prostates removed to find out if these patients had risk factors and signs of aggressive cancer (cancer that spread outside the prostate or was very high grade). We found that, if there was a difference in grade between the systematic biopsy and the MRI-targeted biopsy, the risk of aggressive cancer was between the two grades.

Predictive value of kallikrein forms and ß-microseminoprotein in blood from patients with evidence of detectable levels of PSA after radical prostatectomy.

PURPOSE: To determine whether ß-microseminoprotein or any of the kallikrein forms in blood-free, total or intact PSA or total hK2-predict metastasis in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. METHOD: We determined marker concentrations in blood from 173 men treated with radical prostatectomy and evidence of detectable levels of PSA in the blood (PSA ≥ 0.05) after surgery between 2014 and 2015 and at least 1 year after any adjuvant therapy. We used Cox regression to determine whether any marker was associated with metastasis using both univariate and multivariable models that included standard clinical predictors. RESULTS: Overall, 42 patients had metastasis, with a median follow-up of 67 months among patients without an event. The levels of intact and free PSA and free-to-total PSA ratio were significantly associated with metastasis. Discrimination was highest for free PSA (c-index: 0.645) and free-to-total PSA ratio (0.625). Only free-to-total PSA ratio remained associated with overall metastasis (either regional or distant) after including standard clinical predictors (p = 0.025) and increased discrimination from 0.686 to 0.697. Similar results were found using distant metastasis as an outcome (p = 0.011; c-index increased from 0.658 to 0.723). CONCLUSION: Our results provide evidence that free-to-total PSA ratio can risk stratifying patients with evidence of detectable levels of PSA in blood after RP. Further research is warranted on the biology of prostate cancer markers in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. Our findings on the free-to-total ratio for predicting adverse oncologic outcomes need to be validated in other cohorts.

MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study.

BACKGROUND: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer. METHODS: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting. FINDINGS: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths. INTERPRETATION: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term. FUNDING: Insightec and the National Cancer Institute.

Have urinary function outcomes after radical prostatectomy improved over the past decade?

BACKGROUND: Changes in surgical technique and postoperative care that target improvements in functional outcomes are widespread in the literature. Radical prostatectomy (RP) is one such procedure that has seen multiple advances over the past decade. The objective of this study was to leverage RP as an index case to determine whether practice changes over time produced observable improvements in patient-reported outcomes. METHODS: This study analyzed patients undergoing RP by experienced surgeons at a tertiary care center with prospectively maintained patient-reported outcome data from 2008 to 2019. Four patient-reported urinary function outcomes at 6 and 12 months after RP were defined with a validated instrument: good urinary function (domain score ≥ 17), no incontinence (0 pads per day), social continence (≤1 pad per day), and severe incontinence (≥3 pads per day). Multivariable logistic regressions evaluated changes in outcomes based on the surgical date. RESULTS: Among 3945 patients meeting the inclusion criteria, excellent urinary outcomes were reported throughout the decade but without consistent observable improvements over time. Specifically, there were no improvements in good urinary function at 12 months (P = .087) based on the surgical date, and there were countervailing effects on no incontinence (worsening; P = .005) versus severe incontinence (improving; P = .003). Neither approach (open, laparoscopic, or robotic), nor nerve sparing, nor membranous urethral length mediated changes in outcomes. CONCLUSIONS: In a decade with multiple advances in surgical and postoperative care, there was evidence of improvements in severe incontinence, but no measurable improvements across 3 other urinary outcomes. Although worsening disease factors could contribute to the stable observed outcomes, a more systematic approach to evaluating techniques and implementing patient selection and postoperative care advances is needed. LAY SUMMARY: Although there have been advances in radical prostatectomy over the past decade, consistent observable improvements in postoperative incontinence were not reported by patients. To improve urinary function outcomes beyond the current high standard, the approach to studying innovations in surgical technique needs to be changed, and further development of other aspects of prostatectomy care is needed.

Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence.

BACKGROUND: Accurate markers for prostate cancer (PC) risk stratification could aid decision-making for initial management strategies. The 4Kscore has an undefined role in predicting outcomes after radical prostatectomy (RP). METHODS: We included 1476 patients with 4Kscore measured prior to RP at two institutions. The 4Kscore was assessed for prediction of adverse pathology at RP and biochemical recurrence (BCR) relative to a clinical model. We pre-specified that all analyses would be assessed in biopsy Grade Group 1 (GG1) or 2 (GG2) PC patients, separately. RESULTS: The 4Kscore increased discrimination for adverse pathology in all patients (delta area under the receiver operative curve (AUC) 0.009, 95% confidence interval (CI) 0.002, 0.016; clinical model AUC 0.767), driven by GG1 (delta AUC 0.040, 95% CI 0.006, 0.073) rather than GG2 patients (delta AUC 0.005, 95% CI -0.012, 0.021). Adding 4Kscore improved prediction of BCR in all patients (delta C-index 0.014, 95% CI 0.007, 0.021; preop-BCR nomogram C-index 0.738), again with larger changes in GG1 than in GG2. CONCLUSIONS: This study validates prior investigations on the use of 4Kscore in men with biopsy-confirmed PC. Men with GG1 PC and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC.

Oncologic Outcomes of Total Length Gleason Pattern 4 on Biopsy in Men with Grade Group 2 Prostate Cancer.

PURPOSE: Gleason Score 7 prostate cancer comprises a wide spectrum of disease risk, and precise substratification is paramount. Our group previously demonstrated that the total length of Gleason pattern (GP) 4 is a better predictor than %GP4 for adverse pathological outcomes at radical prostatectomy. We aimed to determine the association of GP4 length on prostate biopsy with post-prostatectomy oncologic outcomes. MATERIALS AND METHODS: We compared 4 GP4 quantification methods-including maximum %GP4 in any single core, overall %GP4, total length GP4 (mm) across all cores and length GP4 (mm) in the highest volume core-for prediction of biochemical recurrence-free survival after radical prostatectomy using multivariable Cox proportional hazards regression. RESULTS: A total of 457 men with grade group 2 prostate cancer on biopsy subsequently underwent radical prostatectomy. The 3-year biochemical recurrence-free survival probability was 85% (95% CI 81-88). On multivariable analysis, all 4 GP4 quantification methods were associated with biochemical recurrence-maximum %GP4 (HR=1.30; 95% CI 1.07-1.59; p=0.009), overall %GP4 (HR=1.61; 95% CI 1.21-2.15; p=0.001), total length GP4 (HR=2.48; 95% CI 1.36-4.52; p=0.003) and length GP4 in highest core (HR=1.32; 95% CI 1.11-1.57; p=0.001). However, we were unable to identify differences between methods of quantification with a relatively low event rate. CONCLUSIONS: These findings support further studies on GP4 quantification in addition to the ratio of GP3 and GP4 to classify prostate cancer risk. Research should also be conducted on whether GP4 quantification could provide a surrogate endpoint for disease progression for trials in active surveillance.

Association of Family History of Cancer with Clinical and Pathological Outcomes for Prostate Cancer Patients on Active Surveillance.

PURPOSE: The impact of germline mutations associated with hereditary cancer syndromes in patients on active surveillance (AS) for prostate cancer is poorly defined. We examined the association between family history of prostate cancer (FHP) or family history of cancer (FHC) and risk of progression or adverse pathology at radical prostatectomy (RP) in patients on AS. MATERIALS AND METHODS: Patients on AS at a single tertiary-care center between 2000-2019 were categorized by family history. Disease progression was defined as an increase in Gleason grade on biopsy. Adverse pathology was defined as upgrading/upstaging at RP. Multivariable Cox and logistic regression models were used to assess association between family history and time to progression or adverse pathology, respectively. RESULTS: Among 3,211 evaluable patients, 669 (21%) had FHP, 34 (1%) had FHC and 95 (3%) had both; 753 progressed on AS and 481 underwent RP. FHP was associated with increased risk of progression (HR 1.31; 95% CI, 1.11-1.55; p=0.002) but FHC (HR 0.67; 95% CI, 0.30-1.50; p=0.3) or family history of both (HR 1.22; 95% CI, 0.81-1.85; p=0.3) were not. FHP, FHC or both were not associated with adverse pathology at RP (p >0.4). CONCLUSIONS: While FHP was associated with an increased risk of progression on AS, wide confidence intervals render this outcome of unclear clinical significance. FHC was not associated with risk of progression on AS. In the absence of known genetically defined hereditary cancer syndrome, we suggest FHP and/or FHC should not be used as a sole trigger to preclude patients from enrolling on AS.

Characterization of Symptoms after Radical Prostatectomy and Their Relation to Postoperative Complications.

PURPOSE: Many patients will experience symptoms in the initial days after radical prostatectomy (RP), but early patient-reported symptoms have not been well characterized. Our objective was to illustrate the pattern of symptoms experienced after RP and the relation of severe symptoms to postoperative complications. MATERIALS AND METHODS: In 2016, electronic patient-reported symptom monitoring began at our institution's ambulatory surgery center. We retrospectively reviewed patients treated with minimally invasive RP who were sent a daily questionnaire completed using a web interface until postoperative day 10. Severe symptoms automatically generate a "yellow alert," which messages the clinic, while very severe symptoms generate a "red alert," additionally prompting the patient to call. We summarized rates of moderate-to-very severe symptoms and fit local polynomial regressions. We compared rates of 30-day or 90-day complications (grade ≥2) based on the presence of alert symptoms. RESULTS: Of 2,266 men undergoing RP, 1,942 (86%) completed surveys. Among moderate-to-very severe symptom levels, pain (72%) and dyspnea (11%) were most common. Pain, nausea and dyspnea consistently decreased over time; fever and vomiting had a flat pattern. In patients experiencing red-alert symptoms, we observed a higher risk of 30-day complications, but rates were low and differences between groups were nonsignificant (2.9% vs 1.9%; difference 1.1%; 95% CI -1.3-3.5; p=0.3). Results were similar examining 90-day complications. CONCLUSIONS: While symptoms are common after RP, substantial improvements occur over the first 10 days. Severe or very severe symptoms conferred at most a small absolute increase in complication risk, which should be reassuring to patients and clinicians.

Clinical utility of subclassifying positive surgical margins at radical prostatectomy.

OBJECTIVE: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision-making in patients undergoing radical prostatectomy. PATIENTS AND METHODS: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate-specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy. RESULTS: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c-index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs - alone or with maximum Gleason grade at the margin (c-index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters. CONCLUSIONS: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision-making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design.

Morbidity of salvage radical prostatectomy: limited impact of the minimally invasive approach.

PURPOSE: We aimed to report the morbidity profile of salvage radical prostatectomy (SRP) after radiotherapy failure and assess the impact of minimally invasive surgery (MIS) on postoperative complications and functional outcomes. MATERIALS AND METHODS: Between 1985 and 2019, a total of 293 patients underwent SRP; 232 underwent open SRP; and 61 underwent laparoscopic SRP with or without robotic assistance. Complications were recorded and classified into standardized categories per the Clavien-Dindo classification. RESULTS: Twenty-nine patients (10%) experienced grade 3 complications within 30 days, 22 (9.5%) after open and 7 (11%) after MIS (p = 0.6). Between 30 and 90 days after surgery, 7.3% of patients in the open group and 10% in the MIS group had grade 3 complications (p = 0.5). The most common complication was bladder neck contracture (BNC), representing 40% of the 30-90 day complications. Within one year of SRP, 81 patients (31%, 95% CI 25%, 37%) developed BNC; we saw non-significant lower rates in MIS (25 vs 32%; p = 0.4). Functional outcomes were poor after SRP and showed no difference between open and MIS groups for urinary continence (16 vs 18%, p = 0.7) and erectile function (7 vs 13%, p = 0.4). 5 year cancer-specific survival and overall survival was 95% and 88% for the entire cohort, respectively. CONCLUSIONS: Our outcomes suggest poor functional recovery after SRP, regardless of the operative approach. Currently there is no evidence favoring the use of open or MIS approach. Further studies are required to ensure comparable outcomes between these approaches.

The Duration of Antibiotics Prophylaxis at the Time of Catheter Removal after Radical Prostatectomy: Clinically Integrated, Cluster, Randomized Trial.

PURPOSE: Prophylactic antibiotics are routinely given at the time of catheter removal post-radical prostatectomy (RP). The low rate of infectious complications entails that large sample sizes are required for randomized controlled trials, a challenge given the cost of standard randomized controlled trials. We evaluated infectious complications associated with 1 vs 3 days of prophylactic antibiotics at the time of catheter removal post-RP using a novel, clinically integrated trial with randomization at the surgeon level. MATERIALS AND METHODS: Surgeons were cluster randomized for periods of 3 months to prescribe 1-day vs 3-day regimen of prophylactic antibiotics at the time of catheter removal. The primary end point was an infectious complication as routinely captured by nursing phone call within 10 days of catheter removal and defined as positive urine cultures (≥105 CFU) and at least 1 of the following symptoms: fever (>38°C), urgency, frequency, dysuria or suprapubic tenderness. RESULTS: A total of 824 patients were consented and underwent RP with, respectively, 389 and 435 allocated to 1-day and 3-day antibiotics, predominantly ciprofloxacin. Accrual was achieved within 3 years: 95% vs 88% of patients received the allocated 3-day vs 1-day antibiotic regimen. There were 0 urinary tract infections (0%) in the 1-day regimen and 3 urinary tract infections (0.7%) in the 3-day regimen, meeting our prespecified criterion for declaring the 1-day regimen to be noninferior. CONCLUSIONS: A clinically integrated trial using cluster randomization accrued rapidly with no important logistical problems and negligible burden on surgeons. If surgeons choose to prescribe empiric prophylactic antibiotics after catheter removal following RP, then the duration should not exceed 1 day.

Oncologic Outcomes after Localized Prostate Cancer Treatment: Associations with Pretreatment Prostate Magnetic Resonance Imaging Findings.

PURPOSE: We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival. MATERIALS AND METHODS: For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively. RESULTS: The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all). CONCLUSION: Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.

A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy.

BACKGROUND: A pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and variation in pathology reporting may miss aggressive disease. METHODS: The 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4. RESULTS: Adjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67; p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26; p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630-0.660) within GG 3 + 3, but not GG 3 + 4. CONCLUSIONS: The 4Kscore can help guide the clinical decision whether additional risk assessment-such as confirmatory biopsy-is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.

Risk of Metastasis in Men with Grade Group 2 Prostate Cancer Managed with Active Surveillance at a Tertiary Cancer Center.

PURPOSE: We studied the risk of metastatic prostate cancer development in men with Grade Group 2 disease managed with active surveillance at Memorial Sloan Kettering Cancer Center. MATERIALS AND METHODS: A total of 219 men with Grade Group 2 prostate cancer had disease managed with active surveillance between 2000 and 2017. Biopsy was performed every 2 to 3 years, or upon changes in magnetic resonance imaging, prostate specific antigen level or digital rectal examination. The primary outcome was development of distant metastasis. The Kaplan-Meier method was used to estimate treatment-free survival. RESULTS: Median age at diagnosis was 67 years (IQR 61-72), median prostate specific antigen was 5 ng/ml (IQR 4-7) and most patients (69%) had nonpalpable disease. During followup 64 men received treatment, including radical prostatectomy in 36 (56%), radiotherapy in 20 (31%), hormone therapy in 3 (5%) and focal therapy in 5 (8%). Of the 36 patients who underwent radical prostatectomy 32 (89%) had Grade Group 2 disease on pathology and 4 (11%) had Grade Group 3 disease. Treatment-free survival was 61% (95% CI 52-70) at 5 years and 49% (95% CI 37-60) at 10 years. Three men experienced biochemical recurrence, no men had distant metastasis and no men died of prostate cancer during the followup. Median followup was 3.1 years (IQR 1.9-4.9). CONCLUSIONS: Active surveillance appears to be a safe initial management strategy in the short term for carefully selected and closely monitored men with Grade Group 2 prostate cancer treated at a tertiary cancer center. Definitive conclusions await further followup.

Long-Term Outcomes of Active Surveillance for Prostate Cancer: The Memorial Sloan Kettering Cancer Center Experience.

PURPOSE: We report oncologic outcomes for men with Grade Group 1 prostate cancer managed with active surveillance at a tertiary cancer center. MATERIALS AND METHODS: A total of 2,907 patients were managed with active surveillance between 2000 and 2017, of whom 2,664 had Grade Group 1 disease. Patients were recommended confirmatory biopsy to verify eligibility and were followed semiannually with prostate specific antigen, digital rectal examination and review of symptoms. Magnetic resonance imaging was increasingly used in recent years. Biopsy was repeated every 2 to 3 years or after a sustained prostate specific antigen increase or changes in magnetic resonance imaging/digital rectal examination. The Kaplan-Meier method was used to estimate probabilities of treatment, progression and development of metastasis. RESULTS: Median patient age at diagnosis was 62 years. For men with Grade Group 1 prostate cancer the treatment-free probability at 5, 10 and 15 years was 76% (95% CI 74-78), 64% (95% CI 61-68) and 58% (95% CI 51-64), respectively. At 5, 10 and 15 years there were 1,146, 220 and 25 men at risk for metastasis, respectively. Median followup for those without metastasis was 4.3 years (95% CI 2.3-6.9). Distant metastasis developed in 5 men. Upon case note review only 2 of these men were deemed to have disease that could have been cured on immediate treatment. The risk of distant metastasis was 0.6% (95% CI 0.2-2.0) at 10 years. CONCLUSIONS: Active surveillance is a safe strategy over longer followup for appropriately selected patients with Grade Group 1 disease following a well-defined monitoring plan.

Complex Cancer Surgery in the Outpatient Setting: The Josie Robertson Surgery Center.

Minimally invasive operative techniques and enhanced recovery after surgery (ERAS) protocols have transformed clinical practice and made it possible to perform increasingly complex oncologic procedures in the ambulatory setting, with recovery at home after a single overnight stay. Capitalizing on these changes, Memorial Sloan Kettering Cancer Center's Josie Robertson Surgery Center (JRSC), a freestanding ambulatory surgery facility, was established to provide both outpatient procedures and several surgeries that had previously been performed in the inpatient setting, newly transitioned to this ambulatory extended recovery (AXR) model. However, the JRSC core mission goes beyond rapid recovery, aiming to be an innovation center with a focus on superlative patient experience and engagement, efficiency, and data-driven continuous improvement. Here, we describe the JRSC genesis, design, care model, and outcome tracking and quality improvement efforts to provide an example of successful, patient-centered surgical care for select patients undergoing relatively complex procedures in an ambulatory setting.

Extensive disease among potential candidates for hemi-ablative focal therapy for prostate cancer.

OBJECTIVE: To examine a set of proposed eligibility factors for hemi-ablative focal therapy in prostate cancer and to determine the likelihood of residual extensive disease. METHODS: We retrospectively analyzed data from 98 patients with unilateral prostate cancer on biopsy with detailed tumor maps from whole-mount slides and preoperative magnetic resonance imaging data. These patients met the focal therapy consensus meeting inclusion criteria (prostate-specific antigen <15 ng/mL, clinical stage T1c-T2a and Gleason score 3 + 3 or 3 + 4 on needle biopsy), and underwent radical prostatectomy between 2000 and 2014. Extensive disease was defined as having Gleason pattern 4/5 in bilateral lobes, any extraprostatic extension, seminal vesicle invasion or lymph node invasion. Both lobes of the prostate were scored on magnetic resonance imaging. Preoperative characteristics including biopsy and magnetic resonance imaging data were used to predict extensive disease. RESULTS: Among our cohort of 98 patients, 40% (95% CI 30-50%) had extensive disease. A total of 33% (95% CI 24-43%) had Gleason pattern 4/5 in both lobes with a median Gleason pattern 4/5 tumor volume in the biopsy negative lobe of 0.06 cm3 , 17 patients had pathological tumor stage ≥3 and one patient had lymph node invasion. CONCLUSIONS: An important number of patients meeting the focal therapy consensus meeting inclusion criteria can present extensive disease. Further studies using targeted biopsies might provide more accurate information about the selection of focal therapy candidates.

Ki-67 is an independent predictor of prostate cancer death in routine needle biopsy samples: proving utility for routine assessments.

Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ12 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ12 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ12 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.