Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance.

BACKGROUND: To assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS). METHODS: The Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate magnetic resonance imaging and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ⩾3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3) and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score >6) during follow-up. RESULTS: In total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (interquartile range (IQR) 1-3) and from fPCA3 to sPCA3 was 5 years (IQR 4-6). During median follow-up of 6 years (IQR 5-8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0 vs 24.5, P=0.007) and sPCA3 (63.5 vs 36.0, P=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07 vs 0.06, P=0.53). In a multivariable model including age, risk classification and PSA density, fPCA3 remained significantly associated with GR (log(fPCA3) odds ratio=1.77, P=0.04). CONCLUSIONS: PCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.

Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. Tosoian JJ, Mamawala M, Epstein JI, Landis P, Wolf S, Trock BJ, Carter HB.J Clin Oncol. 2015 Oct 20;33(30):3379-85. [Epub 2015 Aug 31]. doi: 10.1200/JCO.2015.62.5764.

PURPOSE: To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active surveillance program. METHODS: Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model. RESULTS: A total of 1,298 men (median age = 66y) with a median follow-up of 5 years (range: 0.01-18.00y) contributed 6,766 person-years of follow-up since 1995. Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years. The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years. The median treatment-free survival was 8.5 years (range: 0.01-18y). Factors associated with grade reclassification were older age (hazard ratio [HR] = 1.03 for each additional year; 95% CI: 1.01-1.06), prostate-specific antigen density (HR = 1.21 per 0.1 unit increase; 95% CI: 1.12-1.46), and greater number of positive biopsy cores (HR = 1.47 for each additional positive core; 95% CI: 1.26-1.69). Factors associated with intervention were prostate-specific antigen density (HR = 1.38 per 0.1 unit increase; 95% CI: 1.22-1.56) and a greater number of positive biopsy cores (HR = 1.35 for one additional positive core; 95% CI: 1.19-1.53). CONCLUSION: Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.

Plasma selenium level before diagnosis and the risk of prostate cancer development.

PURPOSE: Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS: A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS: After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001). CONCLUSIONS: Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men.

Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging.

OBJECTIVES: To evaluate the relationship between low prostate-specific antigen (PSA) levels that are considered normal and the long-term risk of prostate cancer. METHODS: The relative risk of, and cumulative probability of freedom from, prostate cancer by PSA level and age decade was evaluated in male participants of a longitudinal aging study, the Baltimore Longitudinal Study of Aging (National Institute on Aging). The relative risk was estimated from a Cox proportional hazards regression model for men aged 40 to 49.9 (n = 351) and 50 to 59.9 (n = 445). The disease-free probability was determined by Kaplan-Meier survival analysis. RESULTS: The relative risk of prostate cancer for men aged 40 to 49.9 was 3.75 (range 1.6 to 8.6) when the PSA level was at or greater than the median (0.60 ng/mL) compared with men with PSA levels less than the median. This risk was similar for men aged 50 to 59.9 when comparing those with PSA levels greater than and less than the median (0.71 ng/mL). At 25 years, the cumulative probability of freedom from prostate cancer for men aged 40 to 49.9 was 89.6% (range 81% to 97%) and 71.6% (range 60% to 83%) when the PSA level was less than and greater than the median, respectively. The 25-year disease-free probability for men aged 50 to 59.9 was 83.6% (range 76% to 91%) and 58.9% (range 48% to 70%) when the PSA level was less than and greater than the median, respectively. CONCLUSIONS: The association between the baseline serum PSA level and the subsequent risk of prostate cancer suggests that the biologic events that predispose to prostate cancer begin early in middle age. Men who have baseline PSA levels that are "normal" but reflect a higher risk of prostate cancer may be the most appropriate candidates for future prevention trials. Those men with the lowest risk of prostate cancer on the basis of the baseline PSA measurements are unlikely to benefit from frequent PSA surveillance in an effort to detect prostate cancer early.

Today men with prostate cancer have larger prostates.

OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy.

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer.

Insulin-like growth factors (IGFs) may play a role in prostate growth, hyperplasia, and malignancy. High plasma IGF-I has been associated with increased prostate cancer risk. In a prospective, cohort, case-control study in the Baltimore Longitudinal Study on Aging population, we examined prostate volume by magnetic resonance imaging, and prostate-specific antigen (PSA), IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in sera obtained approximately 9 yr before diagnosis of prostate cancer in cases (n = 72) or age-matched controls (n = 127) and in 76 additional Baltimore Longitudinal Study on Aging men (normal subjects) with measured prostate volumes and no prostate cancer. We calculated adjusted odds ratios (OR) by logistic regression, relative risks for significant ORs, and receiver operator curves for prostate cancer, using serum measures alone and in combination. Adjusted ORs for the high vs. low tertile were: for IGF-I, 3.1 [confidence interval (CI), 1.1-8.7]; for IGF-II, 0.2 (CI, 0.07-0.6); for IGFBP-3, 0.71 (CI, 0.3-1.7); and for PSA, 12.5 (CI, 3.8-40.9). For significant ORs, relative risk estimates remained significant at 2.0 for IGF-I, 0.3 for IGF-II, and 5.5 for PSA. Receiver operator curves showed PSA to be the most powerful predictor of prostate cancer. Adding IGF-II to PSA improved prediction. IGF-II was significantly and inversely related (r = -0.219; P < 0.01) and PSA was directly and significantly related (r = 0.461; P < 0.0001) to prostate volume, whereas IGF-I and IBFBP-3 were not. High IGF-I and low IGF-II are independently associated with increased risk of prostate cancer, but PSA level is a much stronger predictor of prostate cancer in the ensuing 10 yr than either IGF-I or IGF-II. The absence of a relationship of IGF-I to prostate size is inconsistent with increased ascertainment in men with large prostates as the source of greater prostate cancer risk associated with IGF-I. Our data suggest that IGF-II may inhibit both prostate growth and development of prostate cancer.

Prostate-specific antigen testing of older men.

BACKGROUND: Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection. METHODS: We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age. RESULTS: All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%-100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%-100%) of the cancers would still be detected by age 75 years. CONCLUSIONS: These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.

Prostatic growth rate determined from MRI data: age-related longitudinal changes.

Men with prostatic enlargement are at highest risk of developing symptomatic lower urinary tract symptoms (LUTS) and related outcomes, such as acute urinary retention. The study of prostatic growth rate can identify the age range at which prostate growth peaks. Evaluation of the natural course of prostate growth requires repeated intraindividual volume measurements at time intervals sufficient to document growth. Our objective was to examine age-stratified prostate growth rates from men taking part in a longitudinal study of aging using magnetic resonance imaging (MRI) of the prostate. Sixty-four men (ages 30-71 years) enrolled in the Baltimore Longitudinal Study of Aging (BLSA) who had T2 pelvic MRIs taken approximately every 2 years were studied. Men were age stratified into four groups: <45, 45-55, 56-65, and >65 years old. Whole prostate and central gland (anatomically referred to as the transition zone) volumes were determined from the MRI images by a semi-automated image analysis program. Peripheral gland volumes were calculated as the difference between whole prostate and central gland volumes. Growth rates (cc per year) were calculated as change in volume divided by the time interval. On the basis of measurements from the T2 images (n = 128), we observed a linear trend between prostate volume and age. The overall prostate growth rate was 2.36 +/- 3.52 cc per year. Age-stratified growth rates revealed that prostate growth increased with age, peaked at 4.15 +/- 4.98 cc/year for the 56-65-year-old age group and then declined rapidly for the older-aged men. The central gland growth rates followed a trend similar to total prostate volume. These data suggest that there is an age-related increase in prostate growth rate that peaks in men ages 56-65 and then declines. Identification of this trend in prostate growth may aid physicians in targeting men for early diagnosis of LUTS and for possible early intervention. Future studies with a larger sample size are necessary to substantiate these findings.

Age-associated changes in blood pressure in a longitudinal study of healthy men and women.

BACKGROUND: Current knowledge of age-associated increases in blood pressure is based primarily on unscreened population studies that may not be representative of healthy men and women. We examined longitudinal patterns of change in blood pressure in healthy male and female volunteers from the Baltimore Longitudinal Study of Aging (BLSA). METHODS: Longitudinal mixed-effects regression models are used to estimate the age-associated changes in blood pressure in 1307 men (age 17-97) and 333 women (age 18-93) who have been followed for up to 32 years (mean: 8.4 years for men and 3.4 years for women) and who have been screened for health problems or medications that affect blood pressure. RESULTS: On average, systolic pressure is relatively stable in men and women until approximately age 45, increases at 5-8 mm Hg per decade in middle age, then accelerates in men and stabilizes in women. Diastolic pressure increases at 1 mm Hg per decade at all ages in men, whereas in women the rate of change in diastolic pressure increases in middle age and then plateaus and may decline after age 70. Additional findings include: (a) BLSA cross-sectional and longitudinal findings are more similar than has been observed in studies of unscreened samples; (b) there is no evidence of a gender cross-over in this group of healthy men and women; and (c) compared to previous studies of unscreened samples, healthy BLSA men and women show a weaker association between baseline blood pressure and subsequent rate of blood pressure change. CONCLUSIONS: These findings suggest that several previously described age-associated patterns of blood pressure change partially reflect the effects of hypertension and its treatment, rather than intrinsic age changes in the blood pressure of healthy individuals.

Percentage of free prostate-specific antigen in sera predicts aggressiveness of prostate cancer a decade before diagnosis.

OBJECTIVES: To evaluate serial measurements of free and total prostate-specific antigen (PSA) as a predictor of prostate cancer aggressiveness. METHODS: Twenty men diagnosed with adenocarcinoma of the prostate in the pre-PSA era had serum PSA measurements made on multiple stored frozen sera samples available for up to 18 years prior to diagnosis. Subjects were categorized as having aggressive cancer (n = 12) based on the presence of clinical Stage T3, or nodal or bone metastases (N+, M+), or pathologic positive-margin disease, or a Gleason score of 7 or greater; nonaggressive cancer (n = 8) was identified by the absence of these criteria. RESULTS: There was no statistically significant difference in free PSA levels among men with aggressive and nonaggressive prostate cancers from 0 to 15 years before diagnosis. Total PSA levels were significantly different between the groups by 5 years before diagnosis (P = 0.04). At a time when total PSA levels were not different between groups (10 years before diagnosis), there was a statistically significant difference in the percentage of free PSA between aggressive and nonaggressive cancers (P = 0.008). Among 14 men who had sera available for analysis at 10 years before diagnosis, all 8 men with aggressive cancers had a percent free PSA of 0.14 or less; this compares with only 2 of 6 men (33%) with nonaggressive cancer. CONCLUSIONS: These data suggest that the percentage of free PSA in sera is predictive of tumor behavior at a time when total PSA levels provide no information on tumor aggressiveness. Evaluation of the percentage of free serum PSA may be helpful in making the decision between expectant management and treatment for those men who are diagnosed with early prostate cancers by PSA testing.

Relationship between changes in prostate-specific antigen and the percent of prostatic epithelium in men with benign prostatic hyperplasia.

OBJECTIVES: Pretreatment knowledge of prostate gland histology would allow a more scientifically based selection of medical therapy for men with benign prostatic hyperplasia (BPH) and may increase the effectiveness of the pharmacologic agents available. Changes in prostate-specific antigen (PSA), or PSA velocity, may reflect prostatic epithelial growth in BPH. Our objective was to determine if PSA velocity prior to diagnosis correlated with the relative amount of epithelium in BPH tissue. METHODS: We evaluated 39 men with BPH who had serial PSA determinations (mean, 5.4) on frozen sera from 2.3 to 25.1 years before diagnosis, and archival material from simple prostatectomy available for pathologic evaluation. We used an immunoenzymatic staining technique for PSA to bind prostatic epithelium selectively so that color differences in the stained tissue sections could be used to quantify stroma, epithelium, and glandular lumina. RESULTS: The average percentage of epithelium (%E) was 12.4 and the average stroma-epithelial ratio (SER) was 6.6. The correlation of PSA velocity for the three visits nearest to prostatectomy (n = 32) versus %E and SER was significant (P = 0.003 for both). The PSA value nearest to prostatectomy (n = 39) was directly correlated with %E and SER (P = 0.0001 and P = 0.001, respectively). CONCLUSIONS: These data suggest that PSA and PSA velocity are directly related to the histologic makeup of the prostate in men with BPH. Thus, pretreatment evaluation of PSA could be useful as part of an evaluation to direct BPH therapy.

Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.

OBJECTIVE: Serum prostate-specific antigen (PSA) values are most useful for prediction of disease recurrence after surgery. It is unknown whether a detectable PSA level after surgery indicates a local recurrence potentially benefiting from pelvic irradiation or distant metastases requiring hormonal treatment. METHODS: We analyzed postoperative rate of change of serum PSA levels as a predictor of local versus distant disease recurrence after radical prostatectomy. Between 1982 and 1991, 1,058 men underwent radical prostatectomy for localized prostate cancer and follow-up consisted of determining serum PSA levels and digital rectal examinations. Clinical follow-up of 542 men for four or more years and 78 men for eight or more years yielded ten-year actuarial disease recurrence rates of 4 percent for local recurrence, 8 percent for distant metastases, and 23 percent for an isolated elevation of serum PSA level only. Fifty-one patients with isolated elevations of PSA levels only were followed expectantly until they were diagnosed with either local or distant metastases. RESULTS: A linear mixed effects regression analysis was used to model these data. Using these models, the time to a serum PSA level of 0.5 ng/mL, the PSA level one year following surgery, pathologic stage, Gleason sum, and the rate of change of PSA (PSA velocity [PSAV]) were tested as predictors of local versus distant metastases. A combination of PSAV, pathologic stage, and Gleason grade best distinguished local from distant metastases. CONCLUSIONS: These data suggest that PSAV in men with an isolated elevation of PSA levels following radical prostatectomy might aid in clinical decision making.

Mixed-effects regression models for studying the natural history of prostate disease.

Although prostate cancer and benign prostatic hyperplasia are major health problems in U.S. men, little is known about the early stages of the natural history of prostate disease. A molecular biomarker called prostate specific antigen (PSA), together with a unique longitudinal bank of frozen serum, now allows a historic prospective study of changes in PSA levels for decades prior to the diagnosis of prostate disease. Linear mixed-effects regression models were used to test whether rates of change in PSA were different in men with and without prostate disease. In addition, since the prostate cancer cases developed their tumours at different (and unknown) times during their periods of follow-up, a piece-wise non-linear mixed-effects regression model was used to estimate the time when rapid increases in PSA were first observable beyond the background level of PSA change. These methods have a wide range of applications in biomedical research utilizing repeated measures data such as pharmacokinetic studies, crossover trials, growth and development studies, aging studies, and disease detection.

Articulation patterns and speech intelligibility of 54 Vietnamese children with unoperated oral clefts: clinical observations and impressions.

Evaluations of the articulation patterns and speech intelligibility of 54 Vietnamese children with unrepaired oral clefts indicate a relationship between the type of oral cleft and the proficiency of speech skills attained. The results of the study suggest that consideration of the type of oral cleft and the specific kinds of articulation errors exhibited by the patient may be of value in planning the surgical habilitation of older children and adults with unrepaired clefts of the lip and palate.