Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine.

OBJECTIVE: An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design. Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions. SETTING: Two managed care organizations in California. Subjects. Number of 189,629 women who received ≥1 dose of HPV4 between 08/2006 and 03/2008. OUTCOME: Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with ≥12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC). RESULTS: Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto's disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study. CONCLUSIONS: No autoimmune safety signal was found in women vaccinated with HPV4.

Assessment of changes in kidney allograft function using creatinine-based estimates of glomerular filtration rate.

These analyses assessed whether creatinine based estimates of glomerular filtration rate (eGFR) accurately represent (1) graft function at different times post-transplant and (2) changes in function over time. These analyses compared iothalamate GFR to eGFR in 684 kidney allograft recipients. Changes in graft function over time (GFR slope) were measured in 360 of 459 recipients (78%) who were followed for at least 3 years. Ninety-five percent of the patients were Caucasians and 72% received kidneys from living donors. All eGFR calculations correlated significantly with GFR at all time points. However, eGFR were less precise and less accurate during the first-year post-transplant than thereafter. The average rate of GFR change (slope) was -2.93 +/- 11.3%/year (-1.06 +/- 5.3 mL/min/1.73 m(2)/year). Fifty-four percent of patients had stable or positive GFR slopes. The GFR and eGFR slopes were highly correlated. However, eGFR slope, particularly when calculated by MDRD, significantly underestimated the number of patients with declining graft function. For example, 165 out of 360 patients (46%) lost GFR faster than -1 mL/min/1.73 m(2)/year. eMDRD identified only 83 of these patients (50%) while the eMayo formula identified 134 (81%). In conclusion, eGFR correlate with GFR but they have relatively low precision and accuracy particularly early post-transplant. eGFR slopes underestimate graft functional loss although some formulas are significantly better than others for this calculation.

Renal stone epidemiology in Rochester, Minnesota: an update.

Studies in Western countries have suggested an increasing incidence of nephrolithiasis (NL) in the latter part of the 20th century. Therefore, we updated NL epidemiology data for the Rochester population over the years 1970-2000. All Rochester residents with any diagnostic code that could be linked to NL in the years of 1970, 1980, 1990, and 2000 were identified, and the records reviewed to determine if they met the criteria for a symptomatic kidney stone as defined in a previous Rochester, MN study. Age-adjusted incidence (+/-s.e.) of new onset symptomatic stone disease for men was 155.1 (+/-28.5) and 105.0 (+/-16.8) per 100,000 per year in 1970 and 2000, respectively. For women, the corresponding rates were 43.2 (+/-14.0) and 68.4 (+/-12.3) per 100,000 per year, respectively. On average, rates for women increased by about 1.9% per year (P=0.064), whereas rates for men declined by 1.7% per year (P=0.019). The overall man to woman ratio decreased from 3.1 to 1.3 during the 30 years (P=0.006). Incident stone rates were highest for men aged 60-69 years, whereas for women, they plateaued after age 30. Therefore, since 1970 overall NL incidence rates in Rochester have remained relatively flat. However, NL rates for men have declined, whereas rates for women appear to be increasing. The reasons remain to be determined.

Glomerular filtration rate estimated by cystatin C among different clinical presentations.

Glomerular filtration rate (GFR) estimates from serum creatinine has not been generalizable across all populations. Cystatin C has been proposed as an alternative marker for estimating GFR. The objective of this study was to compare cystatin C with serum creatinine for estimating GFR among different clinical presentations. Cystatin C and serum creatinine levels were obtained from adult patients (n=460) during an evaluation that included a GFR measurement by iothalamate clearance. Medical records were abstracted for clinical presentation (healthy, native chronic kidney disease or transplant recipient) at the time of GFR measurement. GFR was modeled using the following variables: cystatin C (or serum creatinine), age, gender and clinical presentation. The relationship between cystatin C and GFR differed across clinical presentations. At the same cystatin C level, GFR was 19% higher in transplant recipients than in patients with native kidney disease (P<0.001). The association between cystatin C and GFR was stronger among native kidney disease patients than in healthy persons (P<0.001 for statistical interaction). Thus, a cystatin C equation was derived using only patients with native kidney disease (n=204). The correlation with GFR (r(2)=0.853) was slightly higher than a serum creatinine equation using the same sample (r(2)=0.827), the Modification of Diet in Renal Disease equation (r(2)=0.825) or the Cockcroft-Gault equation (r(2)=0.796). Averaged estimates between cystatin C and serum creatinine equations further improved correlation (r(2)=0.891). Cystatin C should not be interpreted as purely a marker of GFR. Other factors, possibly inflammation or immunosuppression therapy, affect cystatin C levels. While recognizing this limitation, cystatin C may improve GFR estimates in chronic kidney disease patients.

Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer.

OBJECTIVES: To characterize the clinical progression of disease in men who have undergone prostatectomy for clinically localized prostate cancer and have postoperative biochemical failure (elevated prostate-specific antigen [PSA] level) and to identify predictors of clinical disease progression, including the possible effect of PSA doubling time (PSADT). PATIENTS AND METHODS: Between 1987 and 1993, 2809 patients underwent radical retropubic prostatectomy for clinically localized (< or =T2) disease. In our database, all patients with postoperative biochemical failure (PSA level > or =0.4 ng/mL) were identified. The PSADT was estimated using log linear regression on all PSA values (excluding those values determined after administration of hormonal therapy) within 15 months after biochemical failure. All patients had regular PSA measurements from the time of surgery through the follow-up period. Systemic progression (SP) was defined as evidence of metastatic disease on a bone scan. Local recurrence (LR) was defined on the basis of digital rectal examination, transrectal ultrasonography, and biopsy. The SP-free survival and LR/SP-free survival (survival free of both LR and SP) after biochemical failure was estimated with use of the Kaplan-Meier method. Patients with prostate cancer treatment after biochemical failure had their follow-up censored from this study at the time of treatment. RESULTS: Postoperative biochemical failure occurred in 879 men (31%). The mean follow-up from time of biochemical failure was 4.7 years (range, 0.5-11 years). The mean time to biochemical failure was 2.9 years (median, 2.4 years). The overall mean SP-free survival from time of biochemical failure was 94% and 91% at 5 and 10 years, respectively. The mean LR/SP-free survival was 64% and 53% at 5 and 10 years, respectively. By using univariate analysis on the 587 patients with PSADT data, significant risk factors for SP were PSADT (P<.001) and pathologic Gleason score (P=.005); for LR/SP, significant risk factors included PSADT (P<.001) and pathologic Gleason score (P<.001). In multivariate Cox models analysis, only PSADT remained a significant risk factor for both SP and LR/SP (P<.001). Mean 5-year SP-free survival was 99%, 95%, 93%, and 64% for patients with PSADT of 10 years or longer, 1.0 to 9.9 years, 0.5 to 0.9 year, and less than 0.5 year, respectively; the respective mean LR/SP-free survivals were 87%, 62%, 46%, and 38%. The percentage of patients with PSADT of less than 0.5 year was considerably higher if the type of first clinical event was SP (48%) compared with LR (18%) (P<.001). CONCLUSIONS: For patients who have undergone radical prostatectomy, a rising PSA level suggests evidence of residual or recurrent prostate cancer. Many men remain free of clinical disease for an extended time after biochemical failure following radical prostatectomy for clinically localized prostate cancer. The PSADT appears to be an important predictor of SP and also of any clinical progression (local or systemic). These data may be useful when counseling men regarding the timing of adjuvant therapies.

Contemporary identification of patients at high risk of early prostate cancer recurrence after radical retropubic prostatectomy.

OBJECTIVES: To develop a model that will identify a contemporary cohort of patients at high risk of early prostate cancer recurrence (greater than 50% at 36 months) after radical retropubic prostatectomy for clinically localized disease. Data from this model will provide important information for patient selection and the design of prospective randomized trials of adjuvant therapies. METHODS: Proportional hazards regression analysis was applied to two patient cohorts to develop and cross-validate a multifactorial predictive model to identify men with the highest risk of early prostate cancer recurrence. The model and validation cohorts contained 904 and 901 men, respectively, who underwent radical retropubic prostatectomy at Johns Hopkins Hospital. This model was then externally validated using a cohort of patients from the Mayo Clinic. RESULTS: A model for weighted risk of recurrence was developed: R(W)'=lymph node involvement (0/1)x1.43+surgical margin status (0/1)x1.15+modified Gleason score (0 to 4)x0.71+seminal vesicle involvement (0/1)x0.51. Men with an R(W)' greater than 2.84 (9%) demonstrated a 50% biochemical recurrence rate (prostrate-specific antigen level greater than 0.2 ng/mL) at 3 years and thus were placed in the high-risk group. Kaplan-Meier analyses of biochemical recurrence-free survival demonstrated rapid deviation of the curves based on the R(W)'. This model was cross-validated in the second group of patients and performed with similar results. Furthermore, similar trends were apparent when the model was externally validated on patients treated at the Mayo Clinic. CONCLUSIONS: We have developed a multivariate Cox proportional hazards model that successfully stratifies patients on the basis of their risk of early prostate cancer recurrence.

Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point?

PURPOSE: The most appropriate definition of biochemical progression after radical prostatectomy and radiation therapy is uncertain. We analyzed the effect of using various prostate specific antigen (PSA) end point definitions for defining biochemical progression after radical prostatectomy and attempted to determine the best PSA cut point to use. Aspects of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after radiation therapy are also analyzed in our radical prostatectomy cases. MATERIALS AND METHODS: A total of 2,782 men with clinically localized prostate cancer (cT1-T2) who had undergone radical prostatectomy between 1987 and 1993 were reviewed. All patients had regular PSA determinations from surgery through followup. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Biochemical, PSA progression-free percent after radical prostatectomy was determined by the Kaplan-Meier method using several PSA cut points, including 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater, as well as 0.4 ng./ml. or greater and increasing. Progression-free percent was also assessed using the ASTRO definition, which is 3 increases in PSA. To determine which PSA level was most appropriate to define progression after radical prostatectomy, the percentage of patients with a continued PSA increase after reaching each cut point was determined. The relationship between the maximum PSA within 3 years of surgery and subsequent development of clinical disease was also assessed. RESULTS: Progression-free percent was dependent on the PSA cut point used. Biochemical progression-free percentages for cut points 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater were 62%, 72%, 76% and 78% at 5 years, and 43%, 54%, 59% and 61% at 10 years, respectively. A subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA 0.2, 0.3 and 0.4 ng./ml., respectively. Subsequent clinical progression (local or systemic) was directly related to the maximum PSA attained within 3 years of radical prostatectomy (p=0.0001). Progression-free percent for definitions requiring multiple increases in PSA were dependent on when the event was said to occur. Backdating of events at or before the first PSA (ASTRO definition) resulted in poorer, short-term progression-free percent (78% at 5 years), with little apparent likelihood of long-term failure (78% at 10 years). Coding the event at the last PSA increase when all event criteria had been met resulted in more realistic progression-free percent estimates (85% at 5 and 59% at 10 years). CONCLUSIONS: Biochemical, PSA progression rates vary markedly depending on the method used to define PSA failure. Methods that require multiple increasing PSA values, for example the ASTRO definition, give misleading results, especially if the event time is backdated. Standards for defining PSA progression would allow more consistent and comparable progression estimates after radical prostatectomy. PSA 0.4 ng./ml. or greater may be the most appropriate cut point to use since a significant number of patients with lower PSA do not have a continued increase in it.

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.

Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy.

CONTEXT: Prophylactic mastectomy is a preventive option for women who wish to reduce their risk of breast cancer. There has been concern about possible negative psychological sequelae following this procedure. However, few data are available regarding long-term satisfaction and psychological and social function following this procedure. OBJECTIVE: To evaluate patients' long-term satisfaction and psychological and social function following prophylactic mastectomy. DESIGN, SETTING, AND PARTICIPANTS: Descriptive study of all women known to be alive (n = 609) who had a family history of breast cancer and elected to undergo bilateral prophylactic mastectomy at a large, tertiary US health care clinic between 1960 and 1993, 94% (n = 572) of whom completed a study questionnaire. MAIN OUTCOME MEASURES: Satisfaction with procedure and effects on psychological and social function, based on responses to the study-specific questionnaire. RESULTS: Mean time from prophylactic mastectomy to last follow-up was 14.5 years. Most women (70%) were satisfied with the procedure; 11% were neutral; and 19% were dissatisfied. Among the psychological and social variables, the most striking finding was that 74% reported a diminished level of emotional concern about developing breast cancer. The majority of women reported no change/favorable effects in levels of emotional stability (68%/23%), level of stress (58%/28%), self-esteem (69%/13%), sexual relationships (73%/4%), and feelings of femininity (67%/8%). Forty-eight percent reported no change in their level of satisfaction with body appearance; 16% reported favorable effects. However, 9%, 14%, 18%, 23%, 25%, and 36% reported negative effects in these 6 variables, respectively. CONCLUSIONS: This study suggests that positive outcomes following prophylactic mastectomy include decreased emotional concern about developing breast cancer and generally favorable psychological and social outcomes. These must be weighed against the irreversibility of the decision, potential problems with implants and reconstructive surgery, and occurrence of adverse psychological and social outcomes in some women. JAMA. 2000;284:319-324

Fluorescence in situ hybridization aneuploidy as a predictor of clinical disease recurrence and prostate-specific antigen level 3 years after radical prostatectomy.

OBJECTIVE: To determine if fluorescence in situ hybridization (FISH) analysis of fresh-tissue biopsy specimens obtained at the time of radical prostatectomy is able to predict prospectively clinical disease progression or prostate-specific antigen (PSA) level in patients 3 to 4 years after surgery. MATERIALS AND METHODS: FISH analysis was performed on fresh-tissue touch preparations obtained from 90 randomly selected radical prostatectomy specimens. Cut surface touch preparations from 40 specimens resected in 1992 were analyzed with DNA probes for chromosomes 4, 6-12, 17, 18, X, and Y. Needle-biopsy specimens were obtained from 50 tumors resected in 1993, and touch preparations from these specimens were studied with DNA probes for chromosomes 7, 8, 11, and 12. Serum PSA levels and clinicopathologic data were recorded, and each patient was followed up from the time of surgery to determine cancer progression. RESULTS: Of 90 patients undergoing radical prostatectomy in 1992 and 1993, 89 returned for follow-up. Three patients received preoperative hormonal therapy, and in 2 patients, antiandrogen therapy was continued postoperatively. Fifteen patients underwent intraoperative orchiectomy immediately after radical prostatectomy, while 9 patients had postoperative adjuvant hormonal therapy. Six patients underwent postoperative radiation therapy. Fourteen patients (15.7%) demonstrated systemic, local, or PSA progression. Only 2 (4.7%) of 43 patients with FISH diploid tumors demonstrated cancer progression. Conversely, 10 (30.3%) of 33 FISH aneuploid and 12 (26.1%) of 46 FISH nondiploid tumors demonstrated cancer progression (P=.004 and P=.006, respectively). Unlike FISH, flow cytometric aneuploidy was not associated with early cancer progression. Elevated preoperative PSA concentration, increased preoperative and postoperative Gleason score, and increased preoperative and postoperative T or N stage were not statistically significantly associated with cancer progression. While chromosome 7 and 8 aneusomies were not statistically associated with cancer progression, 2 of 5 (P=.04) chromosome 12 aneusomic tumors demonstrated cancer progression. CONCLUSION: Early (within 4 years) local, systemic, or PSA progression occurred more frequently (P<.05) in radical prostatectomy patients with FISH aneuploid, nondiploid, and chromosome 12 aneusomic tumors. Flow cytometric ploidy status, preoperative serum PSA concentration, and clinical or pathologic grade or stage, including seminal vesicle involvement, margin status, and capsular perforation status, were not associated with early prostate cancer progression in this group of 89 patients. FISH analysis appears to be a useful preoperative tool for predicting aggressive vs indolent prostate cancer.

Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma.

BACKGROUND: Chromosome 8 alterations, including loss of 8p21-22 and gain of 8q24, are commonly observed in prostate carcinoma. We examined whether these alterations are associated with poor prognosis in prostate cancer. METHODS: We used dual-probe fluorescence in situ hybridization and DNA probes for 8p22 (lipoprotein lipase gene), centromere 8 (8cen), and 8q24 (c-myc gene) to determine the corresponding copy numbers in tumor samples from 144 patients with high-grade, advanced (stage III) prostate carcinoma. Cox models were used for multivariate analysis of systemic progression or patient death from prostate cancer. All statistical tests are two-sided. RESULTS: We classified the 8p22, 8cen, and c-myc copy number as normal, loss, and gain. An additional increase (AI) category of c-myc relative to the centromere copy number (i.e., overrepresentation and amplification of c-myc) was also used. Alterations of 8p22 were not statistically significantly associated with either systemic progression or patient death. Alterations of c-myc were associated with both systemic progression (P =.024) and patient death (P =.039); AI of c-myc showed the poorest outcome. We also evaluated the prognostic relevance of the combined 8p22-8cen-c-myc loci anomaly pattern for the following six patterns: normal-normal-normal, loss-any 8cen-normal, loss-gain-gain, gain-gain-gain, non-loss-any 8cen-AI, and loss-any 8cen-AI, where any 8cen is normal, loss, or gain of the chromosome 8 centromere. Patients with the loss-any 8cen-AI pattern had earlier systemic progression (P =.009) and earlier cause-specific death (P =.013) than did patients with other patterns. Multivariate analyses demonstrated that the loss-any 8cen-AI pattern was an independent risk factor for systemic progression (P<.001) and cause-specific death (P =.002). CONCLUSIONS: Genetic alterations of chromosome 8 appear to accumulate in parallel with the progression of prostate carcinomas. AI of the c-myc gene, especially with loss of 8p22, appears to be associated with poor patient prognosis.

Androgen receptor expression in prostatic intraepithelial neoplasia and cancer.

PURPOSE: Androgen receptors are present in virtually all epithelial cells of the prostate, including benign epithelium, high grade prostatic intraepithelial neoplasia and cancer. However, there have been variable results regarding the clinical significance of cells expressing androgen receptors in prostate cancer. We evaluated the predictive accuracy of androgen receptor expression in prostatic intraepithelial neoplasia and cancer for clinical progression and survival in patients with organ confined prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: The study consisted of 172 previously untreated patients who underwent radical prostatectomy at our clinic between 1987 and 1991 with intermediate to high grade (Gleason score 6 to 9), pathological stage T2 cancer and negative surgical margins. Mean followup was 7.4 years (range 1.2 to 10.1). Mouse monoclonal anti-human androgen receptor antibody was used for immunohistochemical studies on select tissue sections from each case. We counted 100 nuclei from 3 separate areas of benign epithelium, prostatic intraepithelial neoplasia and cancer (total 300 nuclei for each diagnostic category) for each case. Mean nuclear androgen receptor expression was determined from the mean of the individual cases for each diagnostic category. Intensity was also evaluated using a subjective scale from 0 (no staining) to 3 (strong staining). We determined the correlation of clinical progression and the number of androgen receptor immunoreactive prostatic intraepithelial neoplasia or cancer nuclei, and then performed multivariate analysis which included deoxyribonucleic acid ploidy, radical prostatectomy Gleason score and preoperative serum prostate specific antigen using the Cox proportional hazards model. Progression was defined as a positive biopsy, positive bone scan or biochemical progression (postoperative serum prostate specific antigen greater than 0.2 ng./ml.). RESULTS: Nuclear immunoreactivity for androgen receptors was observed in all cases. Mean percent of immunoreactive nuclei was higher in benign epithelium than in prostatic intraepithelial neoplasia and cancer (56.3, 46.1 and 53.6%, respectively, pairwise comparisons p <0.05 for each pair). With rare exceptions, basal cells in benign epithelium and prostatic intraepithelial neoplasia were negative. The most intense nuclear staining was observed in benign epithelium. Immunoreactivity was also faint but detectable in the cytoplasm in prostatic intraepithelial neoplasia but not in benign epithelium or cancer. Mean number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer was not a significant univariate or multivariate predictor of clinical and/or biochemical progression, or all cause survival (all p >0.05). CONCLUSIONS: Androgen receptor expression was present in all cases of benign epithelium, prostatic intraepithelial neoplasia and cancer. The greatest extent and intensity of expression were observed in benign epithelium, with about half of the nuclei showing intense immunoreactivity. The number of androgen receptor immunoreactive nuclei in prostatic intraepithelial neoplasia and cancer in patients with organ confined prostate cancer treated with radical prostatectomy was not predictive of progression or survival.

Androgen receptor expression in prostate cancer lymph node metastases is predictive of outcome after surgery.

PURPOSE: Androgens mediate the growth of prostate cancer cells. The predictive value of androgen receptor immunostaining in patient outcome is controversial. We studied the expression of androgen receptors in a large series of patients with node positive cancer, and correlated the results with clinical progression and survival. MATERIALS AND METHODS: We evaluated 197 patients with a mean age of 65.5 years who had node positive adenocarcinoma, and who underwent bilateral pelvic lymphadenectomy and/or radical prostatectomy at our clinic between 1987 and 1992. Mean followup was 6.3 years. Immunohistochemical studies were performed using an antihuman androgen receptor monoclonal antibody. In each case 100 nuclei were counted from 3 separate areas (total 300 nuclei per diagnostic category) of benign epithelium, cancer and lymph node metastases. Mean androgen receptor expression was determined from the mean of the individual cases. The intensity of immunoreactivity was evaluated on a scale of 0-no staining to 3-strong staining. We assessed the correlation of androgen receptor immunoreactivity, deoxyribonucleic acid ploidy, Gleason score and preoperative serum prostate specific antigen (PSA) with clinical progression, all cause survival and cancer specific survival using the Cox proportional hazards model. Clinical progression was defined as a positive bone scan. RESULTS: There was heterogeneous staining in the majority of cells in benign and malignant prostatic epithelium. The mean number of immunoreactive nuclei was similar in all groups (56, 53 and 56% of benign epithelium, cancer and lymph node metastases, respectively). Pairwise comparisons revealed that the only significant difference was between benign epithelium and cancer (p = 0.001) with greater immunoreactivity in benign epithelium. Intensity was lower in benign epithelium than in cancer and lymph nodes (p <0.05). Androgen receptor expression in lymph node metastases was associated with all cause and cancer specific survival on univariate analysis (p = 0.03 and 0.04, respectively). The 7-year cause specific survival was 98, 94 and 86% in patients with 51 to 69, less than 50 and greater than 70% androgen receptor expression in lymph node metastases, respectively (p <0.05). The association of androgen receptor expression in lymph node metastases was significant on multivariate analysis for cancer specific survival (p = 0.021) but not all cause survival (p = 0.16) after controlling for Gleason score, deoxyribonucleic acid ploidy and preoperative PSA. Androgen receptor immunoreactivity in lymph nodes was not a significant univariate or multivariate predictor of clinical progression, while androgen receptor expression in the primary cancer was not predictive of clinical progression or survival (p >0.05). CONCLUSIONS: Androgen receptor expression was similar in benign epithelium, primary cancer and lymph node metastases with approximately half of the epithelial cell nuclei staining. Androgen receptor immunoreactivity in lymph node metastases was predictive of cancer specific but not all cause survival in univariate and multivariate models. Gleason score was the strongest predictor of all cause survival in this cohort of patients. Our results indicate that it may be clinically useful to determine lymph node androgen receptor expression in men with advanced prostate cancer when combined with Gleason score and PSA.

Deoxyribonucleic acid ploidy and serum prostate specific antigen predict outcome following salvage prostatectomy for radiation refractory prostate cancer.

PURPOSE: We assessed clinical and pathological variables for the ability to predict improved outcome following salvage prostatectomy for radiation refractory prostate cancer. We identify factors that might assist in selection of candidates for this procedure. MATERIALS AND METHODS: Between 1966 and 1996, 108 patients (mean age 64.7 years) underwent salvage radical retropubic prostatectomy for radiation refractory prostate cancer. Preoperative serum prostate specific antigen (PSA), available in 70 patients treated since 1987, was less than 4 in 19, 4 to 10 in 31 and greater than 10 ng./ml. in 20. Serum PSA before radiotherapy was available in 37 patients. Serum PSA before radiotherapy and salvage surgery, tumor grade, deoxyribonucleic acid (DNA) ploidy and margin status were analyzed for the ability to predict cancer specific and progression-free survival (local, systemic and PSA 0.2 ng./ml. or greater). Complication rates were compared between early (before 1990) and late (1990 to 1996) salvage prostatectomy groups. RESULTS: Overall cancer specific and progression-free survival at 10 years was 70 and 44%, respectively. The pathological stage was pT2N0 in 39%, pT3-4N0 in 42% and pTxN+ in 19% of cases. DNA ploidy was predominately nondiploid, that is diploid in 25%, tetraploid in 64% and aneuploid in 11% of tumors. Although preoperative serum PSA was not predictive of pathological stage, patients with preoperative PSA less than 10 ng./ml. had better progression-free survival than those with higher levels (p = 0.05). DNA ploidy was the strongest predictor of cancer specific (p = 0.002) and progression-free (p = 0.002) survival. Controlling for grade and PSA using the Cox proportional hazards model, DNA ploidy remained a significant predictor of prostate cancer death (p <0.001) and disease progression (p <0.001). Complication rates improved somewhat in more recently treated patients but incontinence and bladder neck contracture rates remained significant. CONCLUSIONS: DNA ploidy and preoperative serum PSA appear to be the most important predictors of outcome following salvage prostatectomy for radiation refractory prostate cancer. Preoperative consideration of these factors may be helpful in selecting candidates for this procedure.

Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation.

BACKGROUND: The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. METHODS AND RESULTS: The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (>/=30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or >/=10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. CONCLUSIONS: Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

Pathologic classification of prostate carcinoma: the impact of margin status.

BACKGROUND: A proposed pathologic (pTNM) classification system for prostate carcinoma was analyzed for its impact on survival outcome in the prostate specific antigen (PSA) era. The impact of margin status on the survival outcome of patients with otherwise organ-confined disease (i.e., without extraprostatic extension or seminal vesicle involvement) was assessed. METHODS: Among 5467 patients, the original pathologic classification was T2 in 2094 patients; those with evidence of positive margins, extraprostatic extension, or seminal vesicle involvement were initially classified as having pT3 disease (2920 patients) or pT4 residual disease (211 patients). According to the proposed pTNM system, 1512 patients for whom margin status was considered independent of T classification were reclassified. RESULTS: After reclassification, 803 specimens had been down-classified to pT2, resulting in 2932 (54%) with pT2N0 organ-confined disease and a margin positivity rate of 27%; originally, only 38% of patients had been classified as pT2N0. When the old and new classifications were compared, 5-year progression free survival to the combined endpoint of clinical and/or PSA progression (< or = 0.2 ng/mL) was 86% versus 84% and 70% versus 67% for disease classified as pT2N0 and pT3N0, respectively. Multivariate analysis assessed the effect of margin status on 2334 pT2N0 patients (classified according to the proposed pTNM system) who did not receive adjuvant therapy; adjustments were made for Gleason grade, preoperative PSA, and DNA ploidy. In this analysis, the relative risk (with 95% confidence interval) associated with positive margins was 1.65 (1.24-2.18); this was significant for the combined endpoint of clinical/PSA progression. The 5-year survival, free of clinical/PSA progression, was 86% for those without versus 75% for those with positive margins. CONCLUSIONS: This analysis supports the adoption of the proposed pTNM system, which will allow for uniform reporting of pathologic data on prostate carcinoma. For patients with organ-confined disease, positive margins are associated with higher rates of PSA progression. Accordingly, patients should be stratified based on margin positivity in addition to pT classification.

Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects.

Normative data are limited on autonomic function tests, especially beyond age 60 years. We therefore evaluated these tests in a total of 557 normal subjects evenly distributed by age and gender from 10 to 83 years. Heart rate (HR) response to deep breathing fell with increasing age. Valsalva ratio varied with both age and gender. QSART (quantitative sudomotor axon-reflex test) volume was consistently greater in men (approximately double) and progressively declined with age for all three lower extremity sites but not the forearm site. Orthostatic blood pressure reduction was greater with increasing age. HR at rest was significantly higher in women, and the increment with head-up tilt fell with increasing age. For no tests did we find a regression to zero, and some tests seem to level off with increasing age, indicating that diagnosis of autonomic failure was possible to over 80 years of age.

Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy.

OBJECTIVES: The impact of a positive surgical margin in otherwise confined prostate cancer after radical prostatectomy remains unclear. We analyzed the outcome of a large number of patients with organ-confined prostate cancer according to the presence and anatomic site of margin positivity. METHODS: We evaluated 2712 prostatectomy patients with Stage pT2N0 cancer (ie, no evidence of extra-prostatic disease, seminal vesicle or regional node involvement) and no prior therapy who were treated by radical prostatectomy between 1987 and 1995 at Mayo Clinic. A total of 697 patients (26%) had positive margins. To assess the effect of margin status in the absence of treatment, 378 patients with postoperative adjuvant therapy were not considered for the study group: the final group consisted of 2334 patients. RESULTS: Overall, 253 (58%) tumors were positive at the apex and/or urethra, 85 (19%) at the prostate base, 11 (2.5%) at the anterior prostate, and 174 (40%) at the posterior prostate; 89 (20%) had at least two margins involved and 21 (8.3%) had more than two involved. The apex/urethra was the only positive anatomic site in 183 (42%). Five-year survival free of clinical recurrence or prostate-specific antigen (PSA) biochemical failure (postoperative serum PSA of 0.2 ng/mL or more) for patients with a single positive margin was 79% for apex or urethra, 78% for anterior/posterior, and 56% for prostate base. Five-year survival free of clinical recurrence or PSA (biochemical) failure was slightly higher for those with one versus two margin-positive regions (77% versus 68%, respectively). Multivariate analysis revealed that positive surgical margins were a significant predictor of clinical recurrence and PSA (biochemical) failure (relative risk [95% confidence interval]: 1.65 [1.24, 2.18]) after controlling for Gleason grade, preoperative PSA, and deoxyribonucleic acid (DNA) ploidy. The effect of margin positivity on recurrence at a specific anatomic site (versus negative margins or positive at a different anatomic site) revealed the prostate base to be the only significant anatomic site when adjusted for grade, PSA, and ploidy. Five-year survival free of the combined clinical or PSA failure end point for those with versus those without positive margins at the prostate base was 56% versus 85%, respectively (P < 0.0001). CONCLUSIONS: Positive surgical margins are a significant predictor of recurrence in Stage pT2N0 cancer, which is independent of grade, PSA, and DNA ploidy. The impact of positive margin status on recurrence-free survival appears to be anatomic and site-specific, with prostate base positivity significantly associated with poor outcome. The benefit of adjuvant therapy based on anatomic site-specific margin positivity remains to be tested in order to optimize recurrence-free survival.

Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma.

BACKGROUND & AIMS: Barrett's esophagus and adenocarcinoma are complications of gastroesophageal reflux disease. The aim of this study was to look for evidence of a familial predisposition to reflux. METHODS: Index patients with adenocarcinoma (n = 27), Barrett's esophagus (n = 40), and reflux esophagitis (n = 55) were recruited from tertiary care and community populations. Parents and siblings of patients (n = 243) and their spouses' relatives (n = 230) completed reflux symptom questionnaires (response rate, 86%). RESULTS: Reflux symptoms were significantly more prevalent among parents and siblings of patients with adenocarcinoma (43% vs. 23%) and Barrett's esophagus (46% vs. 27%) than spouse control relatives. No significant difference was found for the reflux esophagitis group (33% vs. 29%). Reflux was more prevalent in siblings than spouses of patients with Barrett's esophagus (41% vs. 12%) and adenocarcinoma (40% vs. 6%), a difference that was not found with reflux esophagitis (24% vs. 32%). Reflux was associated with obesity, 41% vs. 28% in the nonobese; smoking, 45% vs. 31% in nonsmokers; and men, 39% vs. 27% in women. CONCLUSIONS: There may be a genetic predisposition to the development of reflux in families of patients with Barrett's esophagus and esophageal adenocarcinoma. For uncomplicated reflux esophagitis, environmental factors appear more important.