Clinical Epidemiology and Risk Factors for Critical Outcomes Among Vaccinated and Unvaccinated Adults Hospitalized With COVID-19-VISION Network, 10 States, June 2021-March 2023.

BACKGROUND: The epidemiology of coronavirus disease 2019 (COVID-19) continues to develop with emerging variants, expanding population-level immunity, and advances in clinical care. We describe changes in the clinical epidemiology of COVID-19 hospitalizations and risk factors for critical outcomes over time. METHODS: We included adults aged ≥18 years from 10 states hospitalized with COVID-19 June 2021-March 2023. We evaluated changes in demographics, clinical characteristics, and critical outcomes (intensive care unit admission and/or death) and evaluated critical outcomes risk factors (risk ratios [RRs]), stratified by COVID-19 vaccination status. RESULTS: A total of 60 488 COVID-19-associated hospitalizations were included in the analysis. Among those hospitalized, median age increased from 60 to 75 years, proportion vaccinated increased from 18.2% to 70.1%, and critical outcomes declined from 24.8% to 19.4% (all P < .001) between the Delta (June-December, 2021) and post-BA.4/BA.5 (September 2022-March 2023) periods. Hospitalization events with critical outcomes had a higher proportion of ≥4 categories of medical condition categories assessed (32.8%) compared to all hospitalizations (23.0%). Critical outcome risk factors were similar for unvaccinated and vaccinated populations; presence of ≥4 medical condition categories was most strongly associated with risk of critical outcomes regardless of vaccine status (unvaccinated: adjusted RR, 2.27 [95% confidence interval {CI}, 2.14-2.41]; vaccinated: adjusted RR, 1.73 [95% CI, 1.56-1.92]) across periods. CONCLUSIONS: The proportion of adults hospitalized with COVID-19 who experienced critical outcomes decreased with time, and median patient age increased with time. Multimorbidity was most strongly associated with critical outcomes.

Cumulative cancer locations on prostate biopsy and active surveillance outcomes in the MRI era.

BACKGROUND: To validate the use of a cumulative cancer locations (CCLO) score, a measurement of tumor volume on biopsy, and to develop a novel magnetic resonance imaging (MRI)-informed CCLO (mCCLO) score to predict clinical outcomes on active surveillance (AS). METHODS: The CCLO score is a sum of uniquely involved sextants with prostate cancer on diagnostic + confirmatory biopsy. The mCCLO score incorporates MRI findings into the CCLO score. Participants included 1284 individuals enrolled on AS between 1994 and 2022, 343 of whom underwent prostate MRI. The primary outcome was grade reclassification (GR) to grade group ≥2 disease; the secondary outcome was receipt of definitive treatment. RESULTS: Increasing CCLO and mCCLO risk groups were associated with higher risk of GR and undergoing definitive treatment (both p < 0.001). On multivariable analysis, increasing mCCLO score was associated with higher risk of GR and receipt of definitive treatment (hazard ratios [HRs] per 1-unit increase: 1.26 [95% confidence interval [CI]: 1.12-1.41] and 1.21 [95% CI: 1.07-1.36], respectively). The model using mCCLO score to predict GR (c-index: 0.671; 95% CI: 0.621-0.721) performed at least as well as models using the number of cores positive for cancer (0.664 [0.613-0.715]; p = 0.7) and the maximum percentage of cancer in a core (0.641 [0.585-0.696]; p = 0.14). CONCLUSIONS: The CCLO score is a valid, objective metric to predict GR and receipt of treatment in a large AS cohort. The ability of the MRI-informed mCCLO to predict GR is on par with traditional metrics of tumor volume but is more descriptive and may benefit from greater reproducibility. The mCCLO score can be implemented as a shorthand, informative tool for counseling patients about whether to remain on AS.

Protection From COVID-19 mRNA Vaccination and Prior SARS-CoV-2 Infection Against COVID-19-Associated Encounters in Adults During Delta and Omicron Predominance.

BACKGROUND: Data assessing protection conferred from COVID-19 mRNA vaccination and/or prior SARS-CoV-2 infection during Delta and Omicron predominance periods in the United States are limited. METHODS: This cohort study included persons ≥18 years who had ≥1 health care encounter across 4 health systems and had been tested for SARS-CoV-2 before 26 August 2021. COVID-19 mRNA vaccination and prior SARS-CoV-2 infection defined the exposure. Cox regression estimated hazard ratios (HRs) for the Delta and Omicron periods; protection was calculated as (1-HR)×100%. RESULTS: Compared to unvaccinated and previously uninfected persons, during Delta predominance, protection against COVID-19-associated hospitalizations was high for those 2- or 3-dose vaccinated and previously infected, 3-dose vaccinated alone, and prior infection alone (range, 91%-97%, with overlapping 95% confidence intervals [CIs]); during Omicron predominance, estimates were lower (range, 77%-90%). Protection against COVID-19-associated emergency department/urgent care (ED/UC) encounters during Delta predominance was high for those exposure groups (range, 86%-93%); during Omicron predominance, protection remained high for those 3-dose vaccinated with or without a prior infection (76%; 95% CI = 67%-83% and 71%; 95% CI = 67%-73%, respectively). CONCLUSIONS: COVID-19 mRNA vaccination and/or prior SARS-CoV-2 infection provided protection against COVID-19-associated hospitalizations and ED/UC encounters regardless of variant. Staying up-to-date with COVID-19 vaccination still provides protection against severe COVID-19 disease, regardless of prior infection.

Protection of Two and Three mRNA Vaccine Doses Against Severe Outcomes Among Adults Hospitalized With COVID-19-VISION Network, August 2021 to March 2022.

BACKGROUND: We assessed coronavirus disease 2019 (COVID-19) vaccination impact on illness severity among adults hospitalized with COVID-19, August 2021-March 2022. METHODS: We evaluated differences in intensive care unit (ICU) admission, in-hospital death, and length of stay among vaccinated (2 or 3 mRNA vaccine doses) versus unvaccinated patients aged ≥18 years hospitalized for ≥24 hours with COVID-19-like illness and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing. We calculated odds ratios (ORs) for ICU admission and death and subdistribution hazard ratios (SHR) for time to hospital discharge adjusted for age, geographic region, calendar time, and local virus circulation. RESULTS: We included 27 149 SARS-CoV-2-positive hospitalizations. During both Delta- and Omicron-predominant periods, protection against ICU admission was strongest among 3-dose vaccinees compared with unvaccinated patients (Delta OR, 0.52 [95% CI, .28-.96]; Omicron OR, 0.69 [95% CI, .54-.87]). During both periods, risk of in-hospital death was lower among vaccinated compared with unvaccinated patients but ORs overlapped across vaccination strata. We observed SHR >1 across all vaccination strata in both periods indicating faster discharge for vaccinated patients. CONCLUSIONS: COVID-19 vaccination was associated with lower rates of ICU admission and in-hospital death in both Delta and Omicron periods compared with being unvaccinated.

Positive surgical margins after breast-conserving surgery for ductal carcinoma in-situ: does histologic grade or estrogen receptor status matter?

PURPOSE: DCIS has been shown to have a higher rate of positive margins following breast-conserving surgery (BCS) than invasive breast cancer. We aim to analyze certain factors of DCIS, specifically histologic grade and estrogen receptor (ER) status, in patients with positive surgical margins following BCS to determine if there is an association. METHODS: A retrospective review of our institutional patient registry was performed to identify women with DCIS and microinvasive DCIS who underwent BCS by a single surgeon from 1999 to 2021. Demographics and clinicopathologic characteristics between patients with and without positive surgical margins were compared using chi-square or Student's t-test. We assessed factors associated with positive margins using univariate and multivariable logistic regression. RESULTS: Of the 615 patients evaluated, there was no significant difference in demographics between the patients with and without positive surgical margins. Increasing tumor size was an independent risk factor for margin positivity (P = < 0.001). On univariate analysis both high histologic grade (P = 0.009) and negative ER status (P = < 0.001) were significantly associated with positive surgical margins. However, when adjusted in multivariable analysis, only negative ER status remained significantly associated with margin positivity (OR = 0.39 [95% CI 0.20-0.77]; P = 0.006). CONCLUSION: The study confirms increased tumor size as a risk factor for positive surgical margins. We also demonstrated that ER negative DCIS was independently associated with a higher rate of positive margins after BCS. Given this information, we can modify our surgical approach to reduce rate of positive margins in patients with large-sized ER negative DCIS.

Clinical Significance of Perineural Invasion in Men With Grade Group 1 Prostate Cancer on Active Surveillance.

PURPOSE: We aimed to evaluate the clinical significance of perineural invasion in men on active surveillance for Grade Group 1 prostate cancer. MATERIALS AND METHODS: We identified 1,969 men with Grade Group 1 prostate cancer and at least 1 follow-up biopsy. A time-dependent Cox model and a logistic regression model were used to assess the association between biopsy-detected perineural invasion and grade reclassification (defined as the detection of Grade Group ≥2 prostate cancer on a surveillance biopsy), and adverse pathology (defined as Grade Group ≥3 ± seminal vesicle invasion ± lymph node involvement) at radical prostatectomy, respectively. RESULTS: The 198 men with perineural invasion detected during active surveillance had lower rates of grade reclassification-free survival than those without perineural invasion (P < .001). On multivariable analysis perineural invasion was significantly associated with grade reclassification (HR 3.25, 95% CI 2.54-4.16, P < .001); an association that persisted in the multiparametric magnetic resonance imaging subset. At radical prostatectomy, men with biopsy-detected perineural invasion had more extraprostatic extension than men without perineural invasion (Relative Risk 1.71, 95% CI 1.15-2.56). However, on multivariable analysis biopsy-detected perineural invasion was not associated with adverse pathology (OR 0.68, 95% CI 0.27-1.68, P = .40) and these patients did not exhibit more biochemical recurrence at 5 years (P > .05). CONCLUSIONS: Perineural invasion during active surveillance was associated with grade reclassification. At radical prostatectomy biopsy-detected perineural invasion patients exhibited more extraprostatic extension but biopsy-detected perineural invasion was not independently associated with more adverse pathology. In addition, these patients did not have more biochemical recurrence during follow-up. Perineural invasion should not preclude Grade Group 1 patients from active surveillance but they may warrant more stringent monitoring.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults - VISION Network, 10 States, December 2021-March 2022.

CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [Johnson & Johnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome† (1), and clinical trial data indicating similar or higher neutralizing antibody response following heterologous boosting compared with homologous boosting (2). Data on real-world vaccine effectiveness (VE) of different booster strategies following a primary Janssen vaccine dose are limited, particularly during the period of Omicron variant predominance. The VISION Network§ determined real-world VE of 1 Janssen vaccine dose and 2 alternative booster dose strategies: 1) a homologous booster (i.e., 2 Janssen doses) and 2) a heterologous mRNA booster (i.e., 1 Janssen dose/1 mRNA dose). In addition, VE of these booster strategies was compared with VE of a homologous booster following mRNA primary series vaccination (i.e., 3 mRNA doses). The study examined 80,287 emergency department/urgent care (ED/UC) visits¶ and 25,244 hospitalizations across 10 states during December 16, 2021-March 7, 2022, when Omicron was the predominant circulating variant.** VE against laboratory-confirmed COVID-19-associated ED/UC encounters was 24% after 1 Janssen dose, 54% after 2 Janssen doses, 79% after 1 Janssen/1 mRNA dose, and 83% after 3 mRNA doses. VE for the same vaccination strategies against laboratory-confirmed COVID-19-associated hospitalizations were 31%, 67%, 78%, and 90%, respectively. All booster strategies provided higher protection than a single Janssen dose against ED/UC visits and hospitalizations during Omicron variant predominance. Vaccination with 1 Janssen/1 mRNA dose provided higher protection than did 2 Janssen doses against COVID-19-associated ED/UC visits and was comparable to protection provided by 3 mRNA doses during the first 120 days after a booster dose. However, 3 mRNA doses provided higher protection against COVID-19-associated hospitalizations than did other booster strategies during the same time interval since booster dose. All adults who have received mRNA vaccines for their COVID-19 primary series vaccination should receive an mRNA booster dose when eligible. Adults who received a primary Janssen vaccine dose should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later, or a homologous Janssen vaccine booster dose if mRNA vaccine is contraindicated or unavailable. Further investigation of the durability of protection afforded by different booster strategies is warranted.

Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance - VISION Network, 10 States, December 2021-August 2022.

Persons with moderate-to-severe immunocompromising conditions might have reduced protection after COVID-19 vaccination, compared with persons without immunocompromising conditions (1-3). On August 13, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended that adults with immunocompromising conditions receive an expanded primary series of 3 doses of an mRNA COVID-19 vaccine. ACIP followed with recommendations on September 23, 2021, for a fourth (booster) dose and on September 1, 2022, for a new bivalent mRNA COVID-19 vaccine booster dose, containing components of the BA.4 and BA.5 sublineages of the Omicron (B.1.1.529) variant (4). Data on vaccine effectiveness (VE) of monovalent COVID-19 vaccines among persons with immunocompromising conditions since the emergence of the Omicron variant in December 2021 are limited. In the multistate VISION Network,§ monovalent 2-, 3-, and 4-dose mRNA VE against COVID-19-related hospitalization were estimated among adults with immunocompromising conditions¶ hospitalized with COVID-19-like illness,** using a test-negative design comparing odds of previous vaccination among persons with a positive or negative molecular test result (case-patients and control-patients) for SARS-CoV-2 (the virus that causes COVID-19). During December 16, 2021-August 20, 2022, among SARS-CoV-2 test-positive case-patients, 1,815 (36.3%), 1,387 (27.7%), 1,552 (31.0%), and 251 (5.0%) received 0, 2, 3, and 4 mRNA COVID-19 vaccine doses, respectively. Among test-negative control-patients during this period, 6,928 (23.7%), 7,411 (25.4%), 12,734 (43.6%), and 2,142 (7.3%) received these respective doses. Overall, VE against COVID-19-related hospitalization among adults with immunocompromising conditions hospitalized for COVID-like illness during Omicron predominance was 36% ≥14 days after dose 2, 69% 7-89 days after dose 3, and 44% ≥90 days after dose 3. Restricting the analysis to later periods when Omicron sublineages BA.2/BA.2.12.1 and BA.4/BA.5 were predominant and 3-dose recipients were eligible to receive a fourth dose, VE was 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. Protection offered by vaccination among persons with immunocompromising conditions during Omicron predominance was moderate even after a 3-dose monovalent primary series or booster dose. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent vaccine booster doses that target recently circulating Omicron sublineages, in line with ACIP recommendations. Further, additional protective recommendations for persons with immunocompromising conditions, including the use of prophylactic antibody therapy, early access to and use of antivirals, and enhanced nonpharmaceutical interventions such as well-fitting masks or respirators, should also be considered.

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

BACKGROUND: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients. METHODS: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy. RESULTS: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05). CONCLUSIONS: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors.

Transperineal Prostate Biopsy Improves the Detection of Clinically Significant Prostate Cancer among Men on Active Surveillance.

PURPOSE: Transperineal prostate biopsy offers improved sampling of the anterior prostate compared to the transrectal approach. The objective of this study was to determine if transperineal prostate biopsy is associated with an increased incidence of cancer upgrading among men on active surveillance for very low or low risk prostate cancer. MATERIALS AND METHODS: Our active surveillance registry was queried to identify patients who underwent a surveillance biopsy following the introduction of transperineal prostate biopsy at our institution. Patients were dichotomized by the type of biopsy performed. The baseline characteristics and rates of cancer upgrading were compared between groups. RESULTS: Between November 2017 and June 2020, 790 men with very low or low risk prostate cancer underwent a surveillance biopsy. In total, 59 of 279 men (21.2%) in the transperineal prostate biopsy group were upgraded to grade group ≥2 as compared to 75 of 511 (14.7%) in the transrectal biopsy group (p=0.01). Among patients who were upgraded to grade group ≥2, 26 of 59 (44%) had grade group ≥2 detected in the anterior/transition zone with transperineal prostate biopsy compared to 14 of 75 (18.7%) with transrectal biopsy (p=0.01). Additionally, 17 of 279 men (6.1%) who underwent transperineal prostate biopsy were upgraded to grade group ≥3 vs 17 of 511 (3.3%) who underwent transrectal biopsy (p=0.05). After adjusting for age, prostate specific antigen density, use of magnetic resonance imaging, and number of prior transrectal biopsies, transperineal prostate biopsy was significantly associated with upgrading to grade group ≥2 (OR 1.49, 95% CI 1.11-2.19, p=0.01). CONCLUSIONS: Among men on active surveillance for very low or low risk prostate cancer, transperineal prostate biopsy was associated with an increased likelihood of upgrading to clinically significant prostate cancer. This is likely due to improved sampling of the anterior prostate with the transperineal approach.

Prostate Health Index and multiparametric magnetic resonance imaging to predict prostate cancer grade reclassification in active surveillance.

OBJECTIVE: To identify the value of combining the Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI), tools which have previously been shown to be independently predictive of prostate cancer (PCa) grade reclassification (GR; Gleason score >6), for the purpose of predicting GR at the next surveillance biopsy to reduce unnecessary prostate biopsies for men in PCa active surveillance (AS). PATIENTS AND METHODS: Between 2014 and 2019, we retrospectively identified 253 consecutive men in the Johns Hopkins AS programme who had mpMRI and PHI followed by a systematic ± targeted biopsy. PHI and PHI density (PHID) were evaluated across Prostate Imaging-Reporting and Data System version 2.0 (PI-RADSv2) scores and compared to those with and without GR. Next, the negative predictive value (NPV) and area under the receiver operating curve (AUC) were calculated to compare the diagnostic value of PI-RADSv2 score combined with PHI, PHID, or prostate-specific antigen density (PSAD) for GR using their respective first quartile as a cut-off. RESULTS: Of the 253 men, 38 men (15%) had GR. Men with GR had higher PHI values (40.7 vs 32.0, P = 0.001), PHID (0.83 vs 0.57, P = 0.007), and PSAD (0.12 vs 0.10, P = 0.037). A PI-RADSv2 ≤3 alone had a NPV of 91.6% for GR (AUC 0.67). Using a PHI cut-off of 25.6 in addition to PI-RADSv2 ≤3, the NPV and AUC were both increased to 98% and 0.70, respectively. Using a PSAD cut-off of 0.07 ng/mL/mL with PI-RADSv2 had an AUC of 0.69 and NPV of 95.4%. PHI and PI-RADSv2 together could have avoided 20% of biopsies at the cost of missing 2.6% of GRs. CONCLUSIONS: The combination of PHI and mpMRI can aid in the prediction of GR in men on AS and may be useful for decreasing the burden of surveillance prostate biopsies.

Utility of multiparametric magnetic resonance imaging in the risk stratification of men with Grade Group 1 prostate cancer on active surveillance.

OBJECTIVE: To assess if the adoption of multiparametric magnetic resonance imaging (mpMRI) in active surveillance (AS) has improved the identification of occult higher-grade prostate cancer (PCa). PATIENTS AND METHODS: We retrospectively identified men from the Johns Hopkins AS registry enrolled since 2013 (year of mpMRI adoption) with Grade Group (GG) 1 PCa and who underwent a single mpMRI. Men in this group were dichotomised by the presence (n = 207) or absence (negative mpMRI, n = 225) of one or more lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of ≥ 3. Both groups were compared to a third cohort of men with GG1 PCa enrolled in AS prior to 2013 (pre-mpMRI era, n = 669). The risk of upgrading to GG ≥ 2 PCa on follow-up biopsies (performed with or without MRI targeting) was evaluated among the groups using survival analysis. RESULTS: Men in both mpMRI groups underwent a median (interquartile range [IQR]) of 2 (2-3) biopsies separated by a median (IQR) interval of 13 (12-16) months, whereas men in the pre-MRI era underwent a median (IQR) of 3 (2-5) biopsies, separated by a median (IQR) interval of 12 (12-14) months. The 2- and 4-year upgrade-free survival rates were 93% and 83%, 74% and 59%; and, 87% and 76% for the negative mpMRI, PI-RADS ≥ 3, and pre-mpMRI-era groups, respectively (P < 0.001). On multivariable analysis, both mpMRI groups had significantly different risk of upgrading compared to pre-mpMRI-era group (negative mpMRI group: hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, P = 0.03; PI-RADS ≥ 3 group: HR 1.96, 95% CI 1.36-2.82, P < 0.001). CONCLUSIONS: mpMRI improves the risk stratification of men on AS and should be used to aid enrolment and monitoring decisions.

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance.

PURPOSE: Age at prostate cancer diagnosis has been positively associated with prostate cancer specific mortality and in men on active surveillance with a higher risk of biopsy grade reclassification to Gleason score 3 + 4 or greater (Grade Group 2 or greater). However, to our knowledge the association between age and biopsy grade reclassification to an aggressive phenotype (Gleason score 4 + 3 or greater [Grade Group 3 or greater]) has not been explored. MATERIALS AND METHODS: From 1995 to 2016 we followed 1,625 men 41 to 81 years old with NCCN® (National Comprehensive Cancer Network®) very low (68%) or low (32%) risk prostate cancer on active surveillance. We determined the rate of biopsy grade reclassification to Grade Group 3 or greater. Competing risk analysis was applied to evaluate the association between age at enrollment and the risk of biopsy grade reclassification. Additionally, in men who underwent radical prostatectomy after biopsy grade reclassification we assessed the rate of radical prostatectomy grade reclassification (ie radical prostatectomy Grade Group greater than biopsy Grade Group). RESULTS: The 5-year incidence of biopsy grade reclassification to Grade Group 3 or greater was 4%, 7% and 14% in men younger than 60, 60 to 69 and 70 years old or older, respectively (p <0.001). On univariate analysis older age was associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.43, p <0.001). On multivariable analysis adjusting for year of diagnosis, race, prostate specific antigen density and cancer volume at diagnosis older age remained associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.19, p <0.001). In men who underwent radical prostatectomy after biopsy grade reclassification those who were older had a higher rate of radical prostatectomy grade reclassification (p <0.05). CONCLUSIONS: In men on active surveillance older age at diagnosis was positively associated with biopsy grade reclassification to Grade Group 3 or greater and radical prostatectomy grade reclassification. These observations imply that for many older men, active surveillance as opposed to watchful waiting remains a more appropriate management strategy.

Evaluating the impact of length of time from diagnosis to surgery in patients with unfavourable intermediate-risk to very-high-risk clinically localised prostate cancer.

OBJECTIVE: To evaluate the impact of length of time from diagnostic biopsy to radical prostatectomy (RP) on oncological outcomes amongst men diagnosed with unfavourable intermediate- to very-high-risk clinically localised prostate cancer. PATIENTS AND METHODS: We performed a retrospective review of men with a diagnosis of grade group (GG) ≥3 prostate cancer on biopsy, who underwent RP within 6 months of diagnosis, at our institution between 2005 and 2018. We assessed patient demographics, pre-biopsy disease characteristics, and receipt of neoadjuvant therapy. We categorised time between biopsy and RP into two intervals: <3 and 3-6 months. For each GG, we compared receipt of adjuvant therapy, pathological outcomes at RP (positive surgical margin [PSM], extraprostatic extension [EPE], seminal vesicle invasion [SVI], and lymph node involvement [LNI]), risk of 2- and 5-year biochemical recurrence-free survival (BCRFS), and 2-, 5-, and 10-year metastasis-free survival (MFS) between patients who underwent RP at <3 vs 3-6 months after diagnosis. RESULTS: Amongst 2303 men who met the study inclusion criteria, 1244 (54%) had GG 3, 608 (26%) had GG 4, and 451 (20%) had GG 5 disease. In all, 72% underwent RP at <3 months after diagnosis. For each diagnostic GG, there was no significant difference in rates of adjuvant therapy, PSM, EPE, SVI, or LNI in men who had RP at <3 vs 3-6 months after diagnosis. In all, 1568 men had follow-up after RP of >1 year. For each diagnostic GG, there was no significant difference in 2- and 5-year BCRFS between patients who had RP at <3 vs 3-6 months after diagnosis (GG 3: 78% vs 83% and 69% vs 66%, respectively, P = 0.6; GG 4: 68% vs 74% and 51% vs 57%, respectively, P = 0.4; GG 5: 58% vs 74% and 48% vs 54%, respectively, P = 0.2). Similarly, for each diagnostic GG, there was no significant difference in 2-, 5-, and 10-year MFS between patients who had RP at <3 vs 3-6 months after diagnosis, although we were not able to calculate 10-year MFS for patients with GG 5 disease due to limited follow-up in that group (GG 3: 98%, 92%, and 84% vs 97%, 95%, and 91%, respectively, P = 0.4; GG 4: 97%, 90%, and 72% vs 94%, 91%, and 81%, respectively, P = 0.8; GG 5: 89% and 81% vs 91% and 71%, respectively, P = 0.9). CONCLUSIONS: Waiting for RP up to 6 months after diagnosis is not associated with adverse outcomes amongst patients with unfavourable intermediate- to very-high-risk prostate cancer.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Optimizing active surveillance strategies to balance the competing goals of early detection of grade progression and minimizing harm from biopsies.

BACKGROUND: Active surveillance (AS) for prostate cancer includes follow-up with serial prostate biopsies. The optimal biopsy frequency during follow-up has not been determined. The goal of this investigation was to use longitudinal AS biopsy data to assess whether the frequency of biopsy could be reduced without substantially prolonging the time to the detection of disease with a Gleason score ≥ 7. METHODS: With data from 1375 men with low-risk prostate cancer enrolled in AS at Johns Hopkins, a hidden Markov model was developed to estimate the probability of undersampling at diagnosis, the annual probability of grade progression, and the 10-year cumulative probability of reclassification or progression to Gleason score ≥ 7. It simulated 1024 potential AS biopsy strategies for the 10 years after diagnosis. For each of these strategies, the model predicted the mean delay in the detection of disease with a Gleason score ≥ 7. RESULTS: The model estimated the 10-year cumulative probability of reclassification from a Gleason score of 6 to a Gleason score ≥ 7 to be 40.0%. The probability of undersampling at diagnosis was 9.8%, and the annual progression probability for men with a Gleason score of 6 was 4.0%. On the basis of these estimates, a simulation of an annual biopsy strategy estimated the mean time to the detection of disease with a Gleason score ≥ 7 to be 14.1 months; however, several strategies eliminated biopsies with only small delays (<12 months) in detecting grade progression. CONCLUSIONS: Although annual biopsy for low-risk men on AS is associated with the shortest time to the detection of disease with a Gleason score ≥ 7, several alternative strategies may allow less frequent biopsying without sizable delays in detecting grade progression. Cancer 2018;124:698-705. © 2017 American Cancer Society.

Tumor Volume on Biopsy of Low Risk Prostate Cancer Managed with Active Surveillance.

PURPOSE: Contemporary clinical guidelines recommend active surveillance of men with low risk prostate cancer. Low risk disease spans any potential volume of Gleason score 6 cancer without sufficient attention to tumor volume in the past. Therefore, we compared tumor characteristics in men at low risk on active surveillance to men treated with radical prostatectomy. MATERIALS AND METHODS: We evaluated an institutional cohort of 1,633 men with very low risk disease (clinical stage T1c, prostate specific antigen density less than 0.15 ng/ml/cm3, 2 or more positive cores and 50% or greater core involvement) and low risk disease (clinical stage T2a or less, prostate specific antigen less than 10 ng/ml and Gleason score 6 or less). Among patients at low risk we calculated the proportion who failed to meet very low risk volume criteria (greater than 2 positive cores or greater than 50% core involvement). Clinical and pathological metrics in the active surveillance cohort were compared to those in a cohort of men at low risk who underwent radical prostatectomy in the current era of 2011 to 2016. RESULTS: In the active surveillance cohort 1,119 men (69%) met very low risk criteria and 514 (31%) had low risk disease. In the low risk population only 138 men (27%) harbored higher volume cancer exceeding very low risk criteria compared to 815 (82%) at low risk who underwent radical prostatectomy (p <0.001). Overall the low risk active surveillance population had fewer positive biopsy cores (median 1 vs 3, p <0.001) and a lower maximum percent of core involvement (median 10% vs 40%, p <0.001) compared to patients at low risk who underwent radical prostatectomy. CONCLUSIONS: Data supporting the safety of active surveillance in men at low risk at our institution were derived from a distinct subgroup harboring a limited cancer volume. Until acceptable outcomes are confirmed for higher volume tumors it is important to remain mindful of these limitations before broadly recommending active surveillance to all low risk men.

Comparison of Biochemical Recurrence-Free Survival after Radical Prostatectomy Triggered by Grade Reclassification during Active Surveillance and in Men Newly Diagnosed with Similar Grade Disease.

PURPOSE: We compared biochemical recurrence between men on active surveillance who underwent radical prostatectomy triggered by grade reclassification and men diagnosed with similar grade disease treated with immediate radical prostatectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of men who underwent surgery from 1995 to 2015 at our institution. We identified 4 groups, including 94 and 56 men on active surveillance who underwent radical prostatectomy following reclassification to Gleason 7 (3 + 4) or greater (grade groups 2 or greater) and Gleason 7 (3 + 4) (grade group 2), and 3,504 and 1,979 in the immediate prostatectomy group diagnosed with grade group 2 or greater and 2, respectively. Biochemical recurrence was assessed by Kaplan-Meir analysis and a multivariable Cox model. RESULTS: Men on active surveillance had a lower incidence of biochemical recurrence than men in the immediate radical prostatectomy groups for biopsy grade groups 2 or greater and 2 (each p <0.05). One, 5 and 10-year biochemical recurrence-free survival for men in the active surveillance group vs the immediate radical prostatectomy group was 97.9% vs 85.5%, 76.6% vs 65.1% and 69.0% vs 54.2% in biopsy grade groups 2 or greater (p = 0.009) and 96.4% vs 91.2%, 89.6% vs 74.0% and 89.6% vs 63.9%, respectively, in biopsy grade group 2 (p = 0.071). For biopsy grade groups 2 or greater there was no significant difference in the risk of biochemical recurrence between the groups after adjusting for age, biopsy extent of cancer and prostate specific antigen density. CONCLUSIONS: Patients on active surveillance reclassified to grade groups 2 or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades.

Risk prediction tool for grade re-classification in men with favourable-risk prostate cancer on active surveillance.

OBJECTIVE: To create a nomogram for men on active surveillance (AS) for prediction of grade re-classification (GR) above Gleason score 6 (Grade group >2) at surveillance biopsy. PATIENTS AND METHODS: From a cohort of men enrolled in an AS programme, a multivariable model was used to identify clinical and pathological parameters predictive of GR. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision curve analysis. RESULTS: Of 1 374 men, 254 (18.50%) were re-classified to Gleason ≥7 on surveillance prostate biopsy. Variables predictive of GR were earlier year of diagnosis [≤2004 vs ≥2005; odds ratio (OR) 2.16, P < 0.001], older age (OR 1.05, P < 0.001), higher prostate-specific antigen density [OR 1.19 (per 0.1 unit increase), P = 0.04], bilateral disease (OR 2.86, P < 0.001), risk strata (low-risk vs very-low-risk, OR 1.79, P < 0.001), and total number of biopsies without GR (OR 0.68, P < 0.001). On internal validation, a nomogram created using the multivariable model had an area under the curve of 0.757 (95% confidence interval 0.730-0.797) for predicting GR at the time of next surveillance biopsy. CONCLUSION: The nomogram described is currently being used at each return visit to assess the need for a surveillance biopsy, and could increase retention in AS.