Conditional progression-free survival in men on active surveillance for prostate cancer stratified by NCCN risk.

222 Background: Active surveillance (AS) is an accepted management strategy for men with very low, low, and select cases of favorable intermediate National Comprehensive Cancer Network (NCCN) risk prostate cancer (PCa). However, how patients’ risk of disease progression evolves over time during AS has not been well defined. Conditional survival measures the probability a patient will continue to survive some number of years, given that they have already survived a certain number without progression. We evaluated our AS cohort to investigate overall and conditional progression free survival on AS, stratified by the NCCN risk groups. Methods: We reviewed our institutional database of 1254 men enrolled in AS for localized PCa from 1996-2016. Our AS protocol includes prostate specific antigen (PSA) and digital rectal exam (DRE) every 4-6 months for 3 years, then annually. Mandatory confirmatory 12 core biopsy is done at 12-18 months. Multiparametric magnetic resonance imagining (mpMRI) or additional systematic or MRI-fusion biopsies are done at the discretion of physician and patient. Overall freedom from pathologic grade progression on follow-up biopsy and treatment free survival were estimated using the Kaplan-Meier method. Survival curves were compared pairwise using the Log-rank test and adjusted for false discovery rates with the Benjamini-Hochberg procedure. Three-year conditional survival estimates were derived for both outcomes from the Kaplan-Meier estimator. Results: Of 1254 men, 521 (41.6%) met criteria for very low, 606 (48.4%) for low, and 125 (10.0%) for favorable intermediate NCCN risk at diagnosis. Median follow-up time was 6.5 years (IQR 4.1-9.4). Median pathologic grade progression free survival in years was significantly longer for very low risk (7.8, 95% CI 6.8-11.2) compared to low risk men (5.6, 95% CI 4.7-6.9), however neither was significantly different from favorable intermediate risk men (5.9). There was no significant difference in treatment free survival between the three risk groups. At diagnosis, the three-year risk for pathologic grade progression (24%, 95% CI 21-27%) and progression to treatment (22%, 95% CI 20-25%) were similar. However, with increasing time of event-free AS, the conditional probability of pathologic grade progression increased, while that of progression to treatment decreased. Conclusions: Our results demonstrate that despite a mild increase in pathologic progression free survival in very low risk men, there was no clear difference in overall treatment free survival between very low, low, and select favorable intermediate NCCN risk men. Further, with increased time spent on AS, despite elevated rates of pathologic progression, patient progression to treatment decreased. This trend may be indicative of changes in goals of care as men with PCa age and should be closely monitored during AS.

Active surveillance before radiotherapy — outcome and predictive factors for multiple biopsies before treatment

Introduction: We aimed to investigate whether patients on active surveillance (AS) had worse outcomes than patients who received immediate treatment with radiotherapy and whether a Gleason grade progression on repeat biopsy influenced outcome. Methods: From our institutional database, we identified 2001 patients treated between 2005 and 2019 with primary external beam radiation therapy or brachytherapy. Biochemical recurrence (BCR) was analyzed in relation to clinical factors such as a Gleason grade progression or having multiple biopsies vs. only one biopsy. Patients on AS were identified as those who had undergone ≥2 biopsies. We used log-rank tests for univariate analysis (UVA) and Cox regression analysis for multivariable analysis (MVA). Results: Of 2001 patients, 374 (19%) patients had ≥2 biopsies before treatment, of which 48% presented with a Gleason grade progression of mostly to Gleason 3+4 (36%); 32% had a cancer volume increase on biopsy and 16% had no significant change on biopsy. For patients with ≥2 biopsies, median time from first biopsy to treatment was 22.0 months (interquartile range [IQR] 14.7–36.1). By UVA, patients with Gleason grade progression (n=105) had a worse BCR-free rate (p=0.02) than patients who had no grade progression on repeat biopsy or only one biopsy. On MVA, this effect was lost. Having ≥2 biopsies was not a significant negative prognostic factor on UVA (p=0.2) or MVA. Conclusions: In our experience, radiotherapy after a period of AS, even with Gleason grade progression, did not lead to worse outcomes compared to patients who had radiotherapy after only one biopsy.

High-Grade Progression Confers Poor Survival in Pancreatic Neuroendocrine Tumors

Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, p < 0.001). Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

Social Promotion in Primary School: Effects on Grade Progression

<p>This paper evaluates the effect of relaxing promotion criteria in early primary school on grade delay in later years. Exploiting variation in primary school repetition policies across Brazilian municipalities, we find that social promotion in junior primary years reduces grade delay, and that some of this reduction persists through the transition to senior primary school. Cohorts of twelve-year-old students who have been exposed to the social promotion policy since they were seven have almost 5 percentage points fewer members who are delayed a year or more in their studies than do similar cohorts who faced the threat of retention every year. We also find that, when the option is available, students sort across schools in response to the policy in a way consistent with negative selection into social promotion.</p>

Molecular characterization of longitudinally tracked prostate cancer foci in men on active surveillance for low-risk disease.

56 Background: The biological trajectory of Gleason score 6 (GS6) prostate cancer (PCa) in men on active surveillance (AS) is unknown. We herein evaluate the potential for high grade PCa to arise clonally from GS 6 disease and determine the capacity of tissue-based biomarkers to predict grade progression. Methods: Men on AS with GS6 PCa who underwent magnetic resonance imaging/ultrasound (MRI/US) fusion biopsy on two occasions from 2012 through 2017 were enrolled. Tumor foci were tracked and re-sampled using the MRI/US fusion biopsy platform. ERG immunohistochemistry (IHC) and DNA/RNA next generation sequencing (NGS) were performed on formalin-fixed paraffin-embedded (FFPE) initial and repeat biopsy specimens to assess tumor clonality and evaluate candidate molecular markers of PCa grade progression. Results: Sixty-seven men of median age 64 years (IQR 59-69) and PSA 4.9 ng/ml (IQR 3.3-6.4) underwent repeat sampling of a single tracked tumor focus using MRI/US fusion biopsy. The median interval to repeat biopsy was 11 months (IQR 6-13). On repeat biopsy, 31 (46%) men progressed to high-grade (GS≥7) disease (n = 24, GS 3+4 = 7; n = 7, GS ≥4+3 = 7). Among the 67 subjects, ERG IHC status was concordant between initial and repeat biopsy in 64 (96%). Of 134 total specimens obtained (67 initial + 67 repeat biopsies), ERG status determined by NGS was concordant with ERG status by IHC in 132 (99%). Comparing the initial biopsy specimens in men who did versus did not undergo grade progression on follow up biopsy, derived cell cycle progression (CCP) scores (median 57.3 vs. 44.0, p = 0.11) and genomic prostate scores (GPS; median 73.8 vs. 64.4, p = 0.15) were not significantly different. Similarly, expression of FOLH1, PCAT4, SCHLAP1, and SPINK1 on initial biopsy did not significantly differ among men who did and did not undergo grade progression. Conclusions: Use of MRI/US fusion biopsy facilitated resampling of the same clonal focus of cancer over time, with high concordance of ERG status determined by both IHC and NGS. Derived genomic classifiers and candidate individual gene expression markers measured on initial biopsy tissue were not significantly different between patients who progressed and those who did not.

The Effects of Electrification on School Enrollment in Bangladesh: Short- and Long-Run Perspectives

This paper aims to show the impact of access to electricity on school enrollment in Bangladesh. It offers an empirical investigation of the relationship between access to electricity and school enrollment statuses, such as grade progression, repetition, and non-attendance. The data were taken from Bangladesh’s Multiple Indicator Cluster Survey (MICS) database 2012–2013 provided by the Bangladesh Bureau of Statistics (BBS) and UNICEF; the data include two years of grading information for children of ages ranging from 5–15. We applied the propensity score matching (PSM) and the Markov schooling transition model using matched sample data. The results show that access to electricity has a significant positive effect on grade progression and a significant negative effect on non-attendance in the short run as well as in the long run. The simulation result shows that the non-attendance rate is lower and the school enrollment rate for children grades 9-11 is higher in the electrified areas compared to unelectrified areas. This result suggests that access to electricity is an important strategic indicator for increasing school enrollment in both primary and secondary schools.