Jay D. Pearson

The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer.

Clinical stage, Gleason score and serum prostate specific antigen (PSA) levels are used separately to predict pathological stage in patients with localized prostate cancer. Because the degree of tumor differentiation has a profound influence on the expression of serum PSA, serum PSA levels alone do not reflect tumor burden accurately. To overcome this obstacle we tested these 3 variables alone and in combinations as predictors of final pathological stage in 703 men with clinically localized prostate cancer at our institution. All patients were assigned a clinical stage by 1 urologist. The Gleason score was determined from preoperative needle biopsy and serum PSA levels were measured on an ambulatory basis. Final pathological stage was determined to be either organ confined, established capsular penetration, seminal vesicle involvement or lymph node involvement. Logistic regression analysis with the likelihood ratio chi-square test determined that serum PSA, Gleason score and clinical stage all predicted final pathological stage well. The results were improved with combinations of the 3 variables (serum PSA, Gleason score and clinical stage) and the combination provided the best separation. From these analyses probability plots and nomograms have been constructed to assist urologists in the preoperative prediction of final pathological stage for patients with clinically localized prostate cancer.

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.

Gender differences in a longitudinal study of age‐associated hearing loss

Current studies are inconclusive regarding specific patterns of gender differences in age-associated hearing loss. This paper presents results from the largest and longest longitudinal study reported to date of changes in pure-tone hearing thresholds in men and women screened for otological disorders and noise-induced hearing loss. Since 1965, the Baltimore Longitudinal Study of Aging has collected hearing thresholds from 500 to 8000 Hz using a pulsed-tone tracking procedure. Mixed-effects regression models were used to estimate longitudinal patterns of change in hearing thresholds in 681 men and 416 women with no evidence of otological disease, unilateral hearing loss, or noise-induced hearing loss. The results show (1) hearing sensitivity declines more than twice as fast in men as in women at most ages and frequencies, (2) longitudinal declines in hearing sensitivity are detectable at all frequencies among men by age 30, but the age of onset of decline is later in women at most frequencies and varies by frequency in women, (3) women have more sensitive hearing than men at frequencies above 1000 Hz but men have more sensitive hearing than women at lower frequencies, (4) learning effects bias cross-sectional and short-term longitudinal studies, and (5) hearing levels and longitudinal patterns of change are highly variable, even in this highly selected group. These longitudinal findings document gender differences in hearing levels and show that age-associated hearing loss occurs even in a group with relatively low-noise occupations and with no evidence of noise-induced hearing loss.

VALIDATION OF PARTIN TABLES FOR PREDICTING PATHOLOGICAL STAGE OF CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE The accurate prediction of pathological stage of prostate cancer using preoperative factors is a critical aspect of treatment. In 1997 Partin et al published tables predicting pathological stage using clinical stage, Gleason score and prostate specific antigen (PSA). We tested the validity of the Partin tables. MATERIALS AND METHODS From 1990 to 1996 inclusively 5,780 patients underwent bilateral pelvic lymphadenectomy and radical prostatectomy for prostate cancer at the Mayo Clinic. However, only 2,475 of these patients met all inclusion criteria of no preoperative treatment, known biopsy Gleason score, available preoperative PSA done either before biopsy or more than 28 days after biopsy and clinical stage T1, T2 or T3a. Among the 2,475 patients 15 had positive lymph nodes and planned prostatectomy was abandoned. The receiver operating characteristics (ROC) curve area, observed and predicted Partin rates of each pathological stage, and positive and negative predictive values were used to compare the Mayo study to the Partin tables. RESULTS The distribution of pathological stage was organ confined in 67% of Mayo cases versus 48% in the Partin study, extracapsular without seminal vesicle or node involvement in 18% versus 40%, seminal vesicle involvement without nodes in 9% versus 7% and were positive nodes in 6% versus 5%. Using the predicted probabilities of Partin et al the ROC curve area for predicted node positive disease was 0.84 for Mayo cases compared to an estimated 0. 82 in the Partin series. The ROC curve area for predicting organ confined cancer was 0.76 for the Mayo Clinic compared to an estimated 0.73 for the Partin series. The observed rates of node positive disease were similar to those predicted (Partin) based on clinical stage, PSA and Gleason score. For organ confined disease Mayo rates were consistently higher than those predicted from the Partin series using a cut point of 0.50 or greater. Positive and negative predictive values were 0.83 and 0.49 versus 0.63 and 0.70 for the Mayo Clinic and Partin series. CONCLUSIONS Our study provides strong evidence that sensitivity and specificity of the Partin tables for external clinical sites are similar to what was reported.

Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity

OBJECTIVES To evaluate short-term and long-term variability between prostate-specific antigen (PSA) measurements to determine the most appropriate PSA sampling interval and rate of PSA change (PSA velocity) to distinguish between men with and without prostate cancer. METHODS Retrospective study of PSA variability and PSA velocity in three groups of men without a diagnosis of prostate cancer and PSA levels less than 10 ng/mL: 56 men with a histologic diagnosis of benign prostatic hyperplasia (BPH; histologic BPH group) and 527 men with no history of cancer (noncancer group) who were part of the Baltimore Longitudinal Study of Aging and had PSA sampled at 2-year intervals (long-term), and 223 men with a clinical diagnosis of BPH (clinical BPH group) who had PSA sampled at 3-month intervals (short-term). PSA variability (deviation between consecutive measurements) and PSA velocity based on both two consecutive measurements and three consecutive measurements (average velocity) were calculated for each study group. RESULTS PSA velocity is the deviation in PSA measurements relative to the elapsed time between the measurements. Because the variability in PSA between measurements was similar for the groups, the major factors that influenced PSA velocity were the sampling interval between PSA measurements, and to a lesser extent, the number of repeat PSA measurements. The 99th percentile for PSA velocity was 0.7 (histologic BPH group) and 0.75 ng/mL per year for the noncancer group when three measurements with a 24-month PSA sampling interval were used. However, the 99th percentile for PSA velocity was 5.8 and 2.4 ng/mL per year when three measurements with 3-month and 6-month PSA sampling intervals were used. Using three measurements, the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was 1% for the groups with a 24-month PSA sampling interval and 28% and 17% for 3-month and 6-month PSA sampling intervals, respectively. The 99th percentile for PSA velocity and the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was higher using two measurements compared to three measurements regardless of PSA sampling interval. CONCLUSIONS PSA velocity is inversely related to the interval between PSA measurements. A PSA velocity more than 0.75 ng/mL per year is useful in distinguishing between men with and without prostate cancer when: (1) velocity is based on three consecutive measurements; and (2) PSA is sampled long-term (2 years) but not short-term (3 to 6 months).

Age‐ and gender‐specific reference ranges for hearing level and longitudinal changes in hearing level

This paper presents age-specific reference ranges for hearing level and change in hearing level for men and women at 500, 1000, 2000, and 4000 Hz. The percentiles are constructed from data obtained from persons in the Baltimore Longitudinal Study of Aging who were rigorously screened for otological disorders and evidence of noise-induced hearing loss. The resulting percentile curves represent norms for changes in hearing level in the absence of any known otologic disease. These percentile curves provide a reference for detecting when a person deviates from a normal pattern of change, thus helping in diagnosing problems with hearing or in monitoring hearing in occupational settings. The smoothed means and standard deviations of the hearing levels were used to construct the longitudinal percentiles. The percentiles for cross-sectional change were constructed using the skew normal distribution to allow for the percentiles to be asymmetric on either side of the median level. These percentiles are the first reference curves that (1) provide standards for hearing level changes over periods of up to 15 years, (2) account for age differences in the distribution of hearing levels, and (3) are based on data from persons who have been systematically screened for otological disorders and evidence of noise-induced hearing loss.

Basal DNA damage in individual human lymphocytes with age

A role for DNA damage is central to many theories of aging, but attempts to show an increase in DNA damage with age have yielded contradictory results. However, previous experiments have been of limited sensitivity, only able to examine induced (not basal) damage or pooled (not individual) cells. In this report, we apply a novel technique (Singh et al., 1988) to directly measure basal levels of DNA single-strand breaks and alkali-labile sites in individual human peripheral blood lymphocytes (PBL) obtained from young (less than 60 years) and old (more than 60 years) male donors. This approach shows that while average changes with age are small, changes in certain individuals and in certain cells may be large: the mean increase in damage was only 12%, but the increase in a subpopulation of highly damaged lymphocytes was 5-fold. However, most of this increase was contributed by just 3 of 17 older subjects. Further characterization of these individuals may shed light on the relationship between DNA damage and aging.

Linear Transformations of Linear Mixed-Effects Models

Abstract A number of articles have discussed the way lower order polynomial and interaction terms should be handled in linear regression models. Only if all lower order terms are included in the model will the regression model be invariant with respect to coding transformations of the variables. If lower order terms are omitted, the regression model will not be well formulated. In this paper, we extend this work to examine the implications of the ordering of variables in the linear mixed-effects model. We demonstrate how linear transformations of the variables affect the model and tests of significance of fixed effects in the model. We show how the transformations modify the random effects in the model, as well as their covariance matrix and the value of the restricted log-likelihood. We suggest a variable selection strategy for the linear mixed-effects model.

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.

Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-alpha in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.