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To determine whether serum sex steroid hormone levels, or the subsequent change in those levels over time, represent a risk factor for the development of nephrolithiasis in men.We retrospectively identified patients participating in a long-term cohort study (Rochester Epidemiology Project) in Olmsted County, Minnesota. Patients had previously undergone baseline detailed clinical examination and sex steroid hormone studies, including estradiol, testosterone, and bioavailable testosterone. Patients were followed on a biennial basis. Records were then reviewed to assess for formation of nephrolithiasis.We identified 684 patients, with a median follow-up for stone formation of 12.8 years. All 684 patients had measurement of testosterone, of which 78.9% were in normal range. Five hundred eighteen men had baseline-free testosterone, of whom 88.6% were normal. Three hundred seventy-one patients had baseline estradiol, of whom 88.7% were normal. One hundred two men (14.9%) were found to have stones, with 61 of those (59.8%) occurring before first hormone measurement and 41 (40.2%) occurring after. On multivariate analysis, there was no significant association of serum hormones with nephrolithiasis, although a trend toward higher baseline testosterone and stones was seen (odds ratio [OR] 1.29; 95% confidence intervals [CI] 0.71, 2.33). Using a time-to-event for incident stone formation, we found no significant association of baseline hormones or percentage change in hormone levels over time with risk of stones.We found no significant association of sex steroid hormone levels with the risk of nephrolithiasis formation in men, although a weak trend toward an increased risk with elevated testosterone was seen.

BACKGROUND Data regarding the prognostic significance of tumor volume (TV) in prostate cancer are conflicting. Herein, we evaluated the association of TV with prostate cancer mortality following radical prostatectomy (RP), and assessed the additive prognostic value of TV to an established predictive model. METHODS We identified 13,687 patients who underwent RP without preoperative therapy between 1987 and 2009. TV was estimated using the prolate ellipsoid formula. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of TV with mortality. The ability of TV to enhance the performance of an established prognostic model (Mayo Clinic GPSM (Gleason, PSA, seminal vesicle and margin status) score) was assessed using the c-index. RESULTS Median TV was 1.57 cm(3) (interquartile range (IQR) 0.48-4.19). Increasing TV was associated with significantly higher risks of seminal vesicle invasion (hazard ratio (HR) 1.58; P

BACKGROUND: It remains unclear whether the hemodilution effect of body mass index (BMI) on PSA levels translates to inappropriate prostate cancer (PCa) screening in obese men. To address this, we conducted two nested case–control studies within prospective cohorts of men undergoing radical prostatectomy for newly diagnosed PCa. METHODS: We identified 1817 men with BMI ⩾30 kg m−2 (cases) and 1244 men with BMI

BACKGROUND: Although a positive surgical margin (PSM) at radical prostatectomy (RRP) has been consistently linked to an increased risk of biochemical recurrence, the impact of margin status on patient survival continues to be debated. We evaluated long-term outcomes of patients with a PSM at RRP and determined predictors of systemic progression (SP) and mortality in these men. METHODS: We reviewed our institutional registry of 16749 patients who underwent RRP between 1990 and 2008 to identify 2895 patients with a PSM. Median follow-up was 10.6 years. Postoperative survival was estimated using the Kaplan–Meier method. Cox proportional hazard regression models were used to analyze clinicopathological variables associated with SP and death from prostate cancer. RESULTS: A 15-year SP-free and cancer-specific survival was 90 and 93%, respectively. On multivariate analysis, higher tumor volume, increased pathological Gleason score and advanced pathological tumor stage were associated with significantly increased risks of SP and death from prostate cancer, whereas number and location of PSM did not predict mortality. CONCLUSIONS: The risks of SP and prostate cancer death in patients with a PSM remain low on long-term follow-up. Tumor variables are the primary determinants of cancer death. These results should be considered when evaluating patients with a PSM for adjuvant therapy.

BACKGROUND Nomograms for biochemical recurrence (BCR) of prostate cancer (PC) after radical prostatectomy can yield very different prognoses for individual patients. Since the nomograms are optimized on different cohorts, the variations may be due to differences in patient risk-factor distributions. In addition, the nomograms assign different relative scores to the same PC risk factors and rarely stratify for tumor growth rate. METHODS We compared BCR-free probabilities from the GPSM model with a cell kinetics (CK) model that uses the individual's tumor state and growth rate. We first created a cohort of 143 patients that reproduced the GPSM patient distribution in Gleason score, Prostate specific antigen (PSA), Seminal vesicle involvement and Margin status since they form the GPSM score. We then performed 143 CK calculations to determine BCR-free probabilities for comparison with the GPSM results for all scores and with four other prominent nomograms for a high-risk patient. RESULTS The BCR-free probabilities from the CK model agree within 10% with those from the GPSM study for all scores once the CK model parameters are stratified in terms of the GPSM risk factors and the PSA doubling time (PSADT). However, the probabilities from widely used nomograms vary significantly. CONCLUSIONS The CK model reproduces the observed GPSM BCR-free probabilities with a broad stratification of model parameters for PC risk factors and can thus be used to describe PC progression for individual patients. The analysis suggests that nomograms should stratify for PSADT to be predictive. Prostate 72:280–290, 2012. © 2011 Wiley Periodicals, Inc.

Study Type – Prognosis (individual cohort series) Level of Evidence 2b OBJECTIVE To evaluate the influence of the pathological Gleason score on the predictive value of the prostate-specific antigen (PSA) doubling time (DT), as this variable predicts a patient’s risk of disease progression both before and after definitive therapy for prostate cancer, and there is an inverse correlation between the Gleason score and PSA production. PATIENTS AND METHODS We evaluated all men treated with radical prostatectomy (RP) between 1990 and 1999 who did not receive neoadjuvant or adjuvant therapy. We identified 2296 patients who had multiple PSA values available before RP, and 1323 who had biochemical recurrence after RP and had at least two PSA values available before starting secondary therapy. Systemic progression and cancer-specific survival (CSS) rates were estimated using the Kaplan-Meier method and Cox proportional hazard regression models. RESULTS A PSA DT of 18 months predicted a lower 10-year systemic progression-free survival for patients with tumours having a pathological Gleason score of

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

Increased rates of secondary bladder malignancies have been reported after external beam radiation therapy (EBRT) for gynecological malignancies with relative risks of 2 to 4. This study was designed to determine if there was an increase in bladder cancer after EBRT for prostate cancer.We retrospectively reviewed the Mayo Clinic Cancer Registry for patients who received EBRT for prostate cancer (1980 to 1998). Patients diagnosed with bladder cancer were identified. Comparative incidence rates were obtained from the national Surveillance, Epidemiology and End Results database. Subset analysis included patients treated with adjuvant radiation and those residing locally. Medical histories of patients with bladder cancer were reviewed.A total of 1,743 patients received EBRT for prostate cancer at our institution. In more than 12,353 man-years of followup no increase in bladder cancer risk was encountered. Subset analysis of men who received adjuvant radiation demonstrated that the relative risk of bladder cancer was increased but was not statistically significant. When the analysis was restricted to patients residing in the local area, the number of patients in whom subsequent bladder cancer developed was similar to Surveillance, Epidemiology and End Results rates. However, in the adjuvant radiation subset there was a statistically significant increase in subsequent bladder cancer. Patients in whom bladder cancer develops after EBRT often present with low grade disease but many have recurrence and progression.This retrospective review suggests there is not evidence of increased risk of bladder cancer after radiation therapy, assuming unbiased followup and complete ascertainment of cases. The natural history of bladder cancer in this population does not seem to be altered by a history of radiation.

In the first paper in this section, authors from the Mayo Clinic describe their experience and 15-year outcomes in the controversial subject of radical prostatectomy in patients with clinical T3 prostate cancer. The findings were interesting in many respects, but the authors concluded that radical prostatectomy as part of multimodal treatment for patients with clinical T3 disease offers cancer control and good survival rates. There follows a series of papers on both prostate cancer and bladder cancer, but the final paper in this section from the UK attempts to define the accuracy of urologists and oncologists in assessing patient life-expectancy. Using various methods they found that, rather disappointingly, doctors were poor at predicting 10-year survival, leading to the possible outcome that some patients may be denied treatment after a pessimistic assessment of life-expectancy. OBJECTIVE To report a long-term experience with extirpative surgery in patients presenting with locally advanced (cT3) prostate cancer, as the best management of such patients remains a problem. PATIENTS AND METHODS In a single-institution retrospective study identifying 5652 men who had radical prostatectomy (RP) for histologically confirmed prostate cancer since the advent of prostate-specific antigen (PSA) testing (1987–97), 15% (842) had RP for cT3 disease. The median follow-up of these men was 10.3 years. Cancer-specific, overall and disease-free survival was plotted and compared with those of patients having RP for cT2 disease during the same period. Perioperative morbidity, continence and erectile function rates were examined, with a multivariate analysis for risk factors of disease recurrence. RESULTS Freedom from local or systemic disease at 5, 10, and 15 years after RP for cT3 disease was 85%, 73% and 67%; the respective cancer-specific survival rates were 95%, 90% and 79%. Significantly many men who did not receive neoadjuvant therapy (27%) were clinically over-staged (pT2) and most men with pT3 disease (78%) received adjuvant therapy. The mean time to adjuvant therapy after RP was not significantly different between men with cT3 and cT2 disease (4.0 and 4.3 years). Pathological grade (≥7), positive surgical margins, and nondiploid chromatin were all independently associated with a significant risk for clinical disease recurrence, while preoperative PSA level had little effect on outcome. Complications and continence rates after RP in patients with cT3 mirrored those in patients with cT2 disease. CONCLUSIONS Significantly many patients with cT3 prostate cancer are overstaged (pT2) in the PSA era. RP as part of a multimodal treatment strategy for patients with cT3 disease offers cancer control and survival rates approaching those achieved for cT2 disease. Pathological grade, ploidy and margin status are all significant predictors of outcome after RP. Complications and incontinence rates in patients with cT3 disease mirror those after RP for cT2 disease.

Recent data suggest that extended lymph node dissection in prostate cancer may be necessary for accurate staging. With limited lymph node dissection apparently node negative cases might be under staged. We determined the impact that the number of lymph nodes removed at radical retropubic prostatectomy (RRP) has on cancer progression and cause specific survival in pTXNO cases.We reviewed the RRP prostate cancer database on 7,036 patients with clinical T1 to T3 disease, no adjuvant therapy and node negative disease in the prostate specific antigen (PSA) era from 1987 to 2000. Factors evaluated were the number of lymph nodes obtained at RRP, preoperative PSA, clinical and pathological stage and grade, margin status, year of surgery and specific surgeon for 5 surgeons who operated throughout the period and performed more than 500 RRPs. Cox analysis was done to determine the RR of progression (PSA or systemic) and prostate cancer death for the number of lymph nodes excised.Median patient age was 65 years and median preoperative PSA was 6.6 ng/ml. At pathological evaluation 5,379 tumors (77%) were organ confined, 4,491 (65%) were Gleason score 5 to 6 and 2,027 (29%) were Gleason score 7 to 10. The median number of nodes obtained significantly decreased from 14 in 1987 to 1989 to 5 in 1999 to 2000 (p0.001). Ten years after RRP Kaplan-Meier estimates were 63% of cases free of PSA progression, 95% free of systemic progression and 98% free of prostate cancer related death. Median followup was 5.9 years. After adjusting for pathological factors (PSA, grade, stage, margin status and surgical date) the number of lymph nodes obtained at lymphadenectomy was not significantly associated with PSA progression (for each additional node (RR 0.99, 95% CI 0.98 to 1.02, p = 0.90), systemic progression (RR 0.99, 95% CI 0.96 to 1.03, p = 0.68) or cause specific survival (RR 1.01, 95% CI 0.96 to 1.06, p = 0.75).The extent of lymphadenectomy does not appear to affect prostate cancer outcome in lymph node negative cases. This includes patients with high preoperative PSA, high pathological grade and extracapsular disease. These results suggest that under staging is not present in apparently node negative cases with limited lymphadenectomy and, even if present, its impact on outcome is likely to be negligible.

Therapy for men with detectable prostate specific antigen (PSA) following radical prostatectomy (RP) for prostate cancer remains controversial. Salvage radiotherapy (SRT) is commonly used because of its relatively low morbidity. We present a single institution retrospective review of patients treated with SRT.A longitudinal cohort study (between April 1987 and April 2000) using the referral based Mayo Clinic Prostate Cancer Registry was conducted. A total of 211 patients were included in this study if detectable serum PSA was the sole indication for SRT and no hormonal therapy was administered.Median followup from surgery to death or last followup was 7.2 years, from RP to SRT was 1.7 years and from SRT to last contact was 4.2 years. Median PSA and prostate specific antigen doubling time (PSADT) at SRT initiation was 0.60 ng/ml and 7.32 months; respectively. Of the patients 90% had nadir PSA less than 0.4 ng/ml within 3 years of SRT. Biochemical disease-free rates at 5 years for PSADT less than 12 or 12 months or greater was 48% and 66%; respectively (p = 0.080). By 10 years there was no significant difference in biochemical disease-free rate (34% vs 35%). Clinical metastasis (10% and 29%) developed in patients with a PSADT less than 12 months at a significantly higher rate than in patients with a PSADT of 12 months or more (0% and 17%, p = 0.045) at 5 and 10 years, respectively. Multivariate analysis revealed pre-SRT PSADT (less than 12 months, H.R. 3.88, p = 0.032), seminal vesicle invasion (H.R. 3.22, p = 0.008), pathological grade (H.R. 1.58, p = 0.023) and PSA at SRT (H.R. 1.29 for a 2-fold increase, p = 0.044) to be significant independent predictors of clinical recurrence. The interval from RP to SRT did not add to the model (p = 0.22).A biochemical response can be expected in the majority of patients within 3 years of receiving SRT. Patients with a pre-SRT PSADT of 1 year or less have a less sustained biochemical response to SRT than patients with a PSADT greater than 1, yet the majority of patients appear to receive long-term benefit from this adjunctive therapy. PSADT is an independent predictor of biochemical and clinical disease recurrence following SRT.

The association between androgen receptor gene polymorphisms and benign prostatic hyperplasia was investigated among 510 men randomly selected from Olmsted County, Minnesota. From 1990 through 2000, lower urinary tract symptom severity was assessed by the American Urological Association Symptom Index (AUASI), and peak urinary flow rate, prostate volume, and serum prostate-specific antigen level were measured. Androgen receptor CAG and GGN genotyping was performed. A CAG repeat length of21 was associated with an enlarged prostate (hazard ratio (HR) = 1.4, 95% confidence interval (CI): 1.0, 1.9) and a serum prostate-specific antigen level1.4 ng/ml (HR = 1.5, 95% CI: 1.1, 2.0). A GGN repeat length of16 was associated with an AUASI7 (HR = 1.6, 95% CI: 1.1, 2.3) and a serum prostate-specific antigen level1.4 ng/ml (HR = 1.5, 95% CI: 1.0, 2.3). Having21 CAG repeats and16 GGN repeats compared with having neither was associated with an enlarged prostate (HR = 2.5, 95% CI: 1.5, 4.2), a serum prostate-specific antigen level1.4 ng/ml (HR = 2.8, 95% CI: 1.6, 4.7), a peak flow rate12 ml/second (HR = 1.9, 95% CI: 1.1, 3.4), and an AUASI7 (HR = 1.6, 95% CI: 1.0, 2.7). Androgen receptor gene polymorphisms may have a potential role in the pathogenesis of benign prostatic hyperplasia.

The association of infection or inflammation of the prostate with prostate cancer has been suggested but not established. This study was undertaken to investigate this association.Cases were Olmsted County, Minnesota, residents with histologically proven prostate cancer diagnosed between January 1980 and December 1996. Cases (n = 409) were each matched to 2 control subjects (n = 803) on age at diagnosis of prostate cancer, residency in Olmsted County, and duration of the community medical record. The medical record of each subject was reviewed for a history of acute or chronic bacterial prostatitis or chronic pelvic pain syndrome (inflammatory type).The relative odds of prostate cancer were elevated in men with history of any type of prostatitis (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1-2.6) or acute prostatitis (2.5; 1.3-4.7). The mean time from most recent episode of acute prostatitis to the diagnosis of prostate cancer was 12.2 years. After exclusion of men with acute prostatitis 2 years before the index date, the relationship was somewhat reduced (1.9; 0.9-3.8). Chronic bacterial prostatitis was more weakly associated with prostate cancer (1.6; 0.8-3.1), whereas chronic pelvic pain syndrome was not associated at all (0.9; 0.4-1.8).Infection in the form of acute or chronic bacterial prostatitis may be associated with prostate cancer. However, our data do not provide compelling evidence to support this. As a result of the limitations of current methods of assessing chronic prostatitis, biochemical or tissue markers of infection or inflammation of the prostate may help clarify their role in the pathogenesis of prostate cancer.

Objective: Glucose intolerance has been shown to be a better predictor of morbidity and mortality than impaired fasting glucose. However, glucose tolerance tests are inconvenient and expensive. This study evaluated the relative frequencies of glucose intolerance and impaired fasting glucose and sought to determine if 2-hour glucose could be predicted from simple demographic and laboratory data in an obese population. Research Methods and Procedures: Eighty-nine obese subjects (median BMI 35 kg/m2, range 30 to 40 kg/m2) underwent glucose tolerance testing. Using step-wise linear and logistic regression analysis, fasting glucose, high-sensitivity C-reactive protein (hsCRP), fasting insulin, high-density lipoprotein cholesterol, triglycerides, weight, height, BMI, waist circumference, hip circumference, waist-to-hip ratio, sex, and age were assessed as predictors of glucose intolerance. Results: Impaired glucose tolerance was more prevalent (27%) than impaired fasting glucose (5.6%). Only fasting glucose and hsCRP were significant (p 140 mg/dL). A fasting glucose ≥ 100 mg/dL or an hsCRP > 0.32 mg/dL (upper quartile of the normal range) detected 81% (sensitivity) of obese subjects with impaired glucose tolerance; however, specificity was poor (46%). Fasting insulin ≥ 6 μU/mL had better sensitivity (92%) but poorer specificity (30%). Discussion: Impaired glucose tolerance is more common than impaired fasting glucose in an obese population. Possible strategies to avoid doing glucose tolerance tests in all obese patients would be to do glucose tolerance testing only in those whose fasting glucose is ≥ 100 mg/dL or whose hsCRP exceeds 0.32 mg/dL or those whose fasting insulin is ≥ 6 μU/mL.

OBJECTIVE To obtain community-based information about the incidence of interstitial cystitis, a chronic disabling condition of the bladder where knowledge is limited because there are no definitive diagnostic criteria. PATIENTS AND METHODS All residents of Olmsted County, MN, USA who had received a physician-assigned diagnosis of interstitial cystitis between 1976 and 1996 were identified through the resources of the Rochester Epidemiology Project. The clinical findings at diagnosis and during the follow-up were ascertained from the community medical records for each study subject. RESULTS In all, 16 women and four men received a diagnosis of interstitial cystitis during the study period. The overall age- and sex-adjusted (95% confidence interval) incidence rate was 1.1 (0.6–1.5) per 100 000 population. The age-adjusted incidence rates were 1.6 per 100 000 in women and 0.6 per 100 000 in men (P = 0.04). The median (range) age at initial diagnosis was 44.5 (27–76) years in women and 71.5 (23–79) years in men (P = 0.26). The median number of episodes of care-seeking for symptoms before the diagnosis was one for women and 4.5 for men (P = 0.03). The median duration from the onset of symptoms until the first diagnosis was 0.06 and 2.2 years in women and men, respectively (P = 0.2). CONCLUSIONS These findings suggest that the incidence of interstitial cystitis in the community is extremely low. Although the gender difference may be real, the trend toward a later diagnosis in men than in women suggests a potential for missed diagnosis in men. This might explain some of the gender difference in the incidence of interstitial cystitis in men and women.

BACKGROUND In the Mayo Lung Project Screening Trial, there were more carcinomas identified in the screened group compared with the control group. The screened group had better survival, but there was no difference in lung carcinoma mortality between the screened group and the control group. The purpose of this study was to review all available original pathology from the trial to determine whether overdiagnosis (carcinomas that do not result in the death of the patient) or misdiagnosis of lung carcinoma may explain this discrepancy. METHODS All available lung pathology slides from patients who underwent surgery at the Mayo Clinic were reviewed independently by three blinded lung pathologists. Tumors were classified according to the 1999 World Health Organization criteria. In addition, agreement among the pathologists was assessed. RESULTS Among 106 patients who underwent surgery at the Mayo Clinic, slides were available for review from 105 patients, including 77 slides from the screened group and 28 slides from the control group. The original diagnosis of carcinoma was confirmed in all patients. In 7 patients (6.7%), there was unanimous agreement that the lesion was preinvasive (carcinoma in situ), and these lesions all were from the screened group. In 90 patients (85.5%), there was unanimous agreement that the tumors were invasive. In 8 patients (7.8%), there was some disagreement between the observers about whether lesions were invasive or preinvasive; 7 of these 8 lesions were from the screened group. The level of agreement among pathologists for invasive carcinomas was > 94% for all comparisons, and the κ statistic ranged from 0.67 (substantial agreement) to 0.84 (almost perfect agreement). There was good agreement among the pathologists about tumor cell type with the κ statistic ≥ 0.65. CONCLUSIONS The histologic diagnosis of carcinoma was confirmed for all 105 slides that were reviewed. The results of this study indicate that misdiagnosis does not explain the increased numbers of carcinomas identified in the screened group. The increased numbers of in situ carcinomas in the screened group resulted in increased numbers of squamous carcinomas in the screened group compared with the control group and may have contributed to the better survival. It is possible that carcinoma in situ accounted for some instances of overdiagnosis. Cancer 2002;95:2361–5. © 2002 American Cancer Society. DOI 10.1002/cncr.10930

Objective To determine whether long-term improvement could be observed after orbital radiotherapy for Graves' disease; in addition, to evaluate ancillary treatments needed for those who have received radiotherapy, to search for late-emerging adverse consequences of radiotherapy, and to relate orbital changes to serum levels of thyroid-stimulating immunoglobulin (TSI). Design Three-year follow-up of noncomparative interventional case series. Participants Forty-two patients. Intervention All patients had received orbital radiotherapy within 6 months of study entry. Twelve months after study entry, patients were free to select any additional treatment for their ophthalmopathy. Main outcome measures Need for surgery, steroid therapy, volume of extraocular muscles and fat, proptosis, area of diplopia fields and range of extraocular muscle motion, volume changes after decompression and correlations of eye findings with serum TSI levels, retinal status. Results Half of the patients elected to have a surgical procedure on their eyes or orbits. Among patients who were not decompressed, we found only slight improvement in some of the main outcome measures. TSI did not positively correlate with baseline status or with any observed change in major outcome measures. After orbital decompression, the volumes of both muscle and fat increase, but bony orbital volume increases more and proptosis diminishes. Retinal microvascular abnormalities consistent with radiation retinopathy developed de novo in five eyes of three patients within 3 years of radiation therapy. Conclusions In this 3-year uncontrolled follow-up phase, limited evidence for a clinically significant improvement was observed, which may be the result of treatment or of natural remission. In either case, the changes are of little clinical significance. Because it is neither effective nor innocuous, radiotherapy does not seem to be indicated for treatment of mild to moderate ophthalmopathy.

Neuroendocrine cells are ubiquitous but uncommon in benign and neoplastic prostate epithelium, and they are considered important for regulating cell growth and differentiation. The predictive value of neuroendocrine immunoreactivity for patient outcome after radical prostatectomy is uncertain. In this study we determined the expression of 2 important neuroendocrine markers, chromogranin and serotonin, in benign epithelium, primary prostate cancer and lymph node metastases, and correlated cellular expression with patient outcome.We studied 196 patients with node positive prostate adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical prostatectomy at Mayo Clinic between 1987 and 1992. Mean followup was 6.8 years (range 0.3 to 11). The cellular expression of chromogranin and serotonin in matched samples of benign tissue, primary prostate cancer and lymph node metastases from the same patients was evaluated by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, pathological findings (Gleason score, DNA ploidy and cancer volume) and patient outcome, including clinical progression, cancer specific and all cause survival.Chromogranin immunoreactivity was greater in benign prostatic epithelium and primary cancer cases (99% each) than in those of lymph node metastases (37.5%) (pairwise comparisons with metastases p0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 6% (median 5%), 6% (median 3%) and 2.2% (median 0%), respectively. Serotonin immunoreactivity was greatest in benign prostate epithelium cases (98.5%) with less in primary cancer (95%) and lymph node metastases (21.5%) (pairwise comparisons p0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 2.2% (median 3%), 2.4% (median 2%) and 0.4% (median 0%), respectively. Chromogranin expression was invariably greater than that of serotonin for all 3 diagnostic categories (p0.0001). There was a marginally significant positive trend in the level of chromogranin expression in benign prostatic epithelium and systemic progression (p = 0.05) but no significant association with cancer specific or all cause survival (p0.1). No significant association was observed of chromogranin expression in primary cancer or lymph node metastases with any patient outcomes (p0.1). There was a significant association of the level of serotonin expression in benign prostatic epithelium with cancer specific survival (p = 0.03) but no significant association with systemic progression or all cause survival (p0.1). There were positive trends in the association of serotonin immunoreactivity in primary cancer with systemic progression (p = 0.09) and cancer specific survival (p = 0.05) but not with all cause survival (p0.1). No significant association was observed of serotonin expression in lymph node metastases with any patient outcomes (p0.1).Benign prostatic epithelium and primary prostate cancer express a significantly greater number of chromogranin and serotonin immunoreactive cells than lymph node metastases, suggesting that decreased expression of neuroendocrine markers is involved in cancer progression. However, neuroendocrine expression was marginally useful for predicting the outcome in patients with node positive prostate cancer treated with radical prostatectomy.

Purpose: Factors important for determining appropriate therapy for localized prostate cancer are biopsy tumor grade, patient age and co-morbidity. We estimated the probability of dying from prostate cancer or other competing causes stratified by age at diagnosis and clinical histological grade in men diagnosed with clinically nonmetastatic prostate cancer who were treated with radical prostatectomy.Materials and Methods: A total of 751 men comprised a retrospective cohort with clinically nonmetastatic prostate cancer diagnosed and treated with bilateral pelvic lymphadenectomy and radical prostatectomy at our institution between 1971 and 1984. All patients were between 55 and 74 years old (median age 65) at diagnosis and they were followed a median of 14.7 years. The cumulative incidence of prostate cancer death or death from any cause was estimated using methods of competing risk survival analysis.Results: Overall 435 men died with 32% of the deaths attributable to prostate cancer. In 62%, 27% and 11% of ...

PURPOSE: To compare measurements of proptosis obtained by clinicians and computed tomography. DESIGN: Cohort study. METHODS: In a prospective randomized study of orbital radiotherapy for Graves’ ophthalmopathy, measurements of proptosis were made on the same visit by an endocrinologist and an ophthalmologist using the Krahn exophthalmometer and by a technician using orbital computed tomography (CT) scans taken with head fixation to minimize position artifact. RESULTS: Both clinical observers recorded proptosis measurements that were greater by 0.6 to 1.6 mm than those observed on the CT scan. This discrepancy resulted in part from the clinical measurements being made to the anterior corneal surface, whereas the CT measurements were made to the posterior corneal surface (a difference of approximately 0.5 mm). The aggregated observations of the clinicians did not vary significantly from each other but wide discrepancies (as much as 5 mm) were noted between single measurements made on the same patient and on the same day by different clinicians. CONCLUSIONS: The degree of variance observed in clinical measurements emphasizes the importance of defining reproducibility of the measurement techniques in prospective studies of therapeutic efficacy in patients with Graves’ ophthalmopathy. The systematic difference between CT and clinical measurements of proptosis should be noted when results of clinical trials are compared.

Loss of 8p22 and gain of 8q24 are known to be common chromosomal alterations in prostate cancer. We have previously demonstrated that concurrent 8q24 overrepresentation and 8p22 loss were associated with a poor prognosis in patients with high-grade, locally advanced prostate cancer. We evaluated the alteration of 8p22 and 8q24 in a large cohort of pathologic organ-confined prostate cancer using fluorescence in situ hybridization (FISH) analysis. All 195 patients with Gleason scores > 5, pathologic stage T(2)N(0)M(0) (pT(2)N(0)M(0)) prostate cancer, who underwent a radical prostatectomy at the Mayo Clinic between 1987 and 1991, and for whom blocks were available, were selected for this study. The median follow-up period was 9.5 years, and endpoints of this study were biochemical and clinical disease progression. The latter includes local as well as systemic disease progression. FISH analysis using paraffin-embedded tissues was performed for 8p22 (LPL), centromere 8 (8cen), and 8q24 (MYC) and was successful for 156 tumors (80.0%). Of these tumors, 104 (66.6%) had one or more numeric alterations of the 3 loci evaluated. An increased copy number of 8q24 was observed in 66 (42.3%) tumors, of which 20 (12.8%) had an additional increase (AI) of 8q24, and 46 (29.5%) had a gain of 8q24 with an equivalent gain of 8cen. Losses and gains of 8p22 were detected in 81 (51.9%) and 20 (12.8%) tumors, respectively. An AI of 8q24 was significantly associated with the tumor Gleason score (P = 0.042). Univariate analysis indicated that loss of 8p22 was a significant predictor of biochemical and clinical disease progression (P = 0.025 and P = 0.011, respectively). Furthermore, the group with loss of 8p22 concurrent with an AI of 8q24 (Loss 8p22-any 8cen-AI 8q24) had an increased rate of biochemical disease progression (P = 0.052). Multivariate analysis demonstrated that neither individual nor the Loss-any-AI combination of alterations was a significant independent predictor of disease progression when adjusting for Gleason score, preoperative PSA levels, and DNA ploidy. These data suggest that loss of 8p22 is associated with a poor prognosis, specifically when it is accompanied by AI of 8q24 in pT(2)N(0)M(0) prostate cancer.

Early renal functional adaptation was examined in 81 haploidentical donor and recipient pairs, as well as long-term stability of glomerular filtration rate (GFR) in 78 recipients. GFR was determined pre- and 1 month postnephrectomy in donors and 1 month post-transplant and yearly thereafter in recipients. Compensatory increase in filtration (CIF) of transplanted and native kidneys was calculated using donor pretransplant GFR: [CIF= (GFR at 1 month/donor prenephrectomy GFR) x 100]. Annual rates of change in GFR were estimated using within-patient linear regression analysis (slopes). Recipients without rejection (n = 62) and their donors had similar early GFR and CIF. Those with acute rejection (n = 19) had significantly lower GFR and CIF than their donors (61 +/- 16 mL/min/1.73 m2 and 57 +/- 14% vs. 75 +/- 11 and 69 +/- 9; p = 0.01 and p0.001). Recipients without cyclosporine (n = 52) had 1 month GFR and CIF of 70 +/- 14 and 67 +/- 14 vs. 72 +/- 11 and 69 +/- 11 for their donors. Those with cyclosporine (n = 29) had 1 month GFR and CIF of 64 +/- 14 and 62 +/- 16 vs. 69 +/- 12 and 67 +/- 11 for their donors (p = 0.15 and 0.16). Comparison of median (25th, 75th) rates of change of GFR with and without acute rejection or cyclosporine did not demonstrate significant effects of either on stability of allograft function, although there was a trend towards greater loss of GFR in cyclosporine-treated patients [-1.1 (-2.5, 0.8) vs. 0.0 (-1.8, 1.2) mL/min/1.73 m2/year, p = 0.47]. We conclude that, in the absence of rejection, the transplanted kidney maintains the same capacity for functional adaptation as its native partner. Therapy with cyclosporine does not significantly inhibit early physiological adaptation of renal transplants.

Purpose: We evaluated the long-term outcome of radical prostatectomy for pathological Gleason score 8 or greater prostate cancer and characterized the prognostic significance of other pathological variables.Materials and Methods: A total of 6,419 patients underwent radical prostatectomy between 1987 and 1996. There were 407 patients classified as having pathological Gleason 8 or greater, including 8 in 48%, 9 in 49% and 10 in 3%. Adjuvant treatment was used in 45% of patients and adjuvant hormonal therapy was administered to 155 (38%). Progression-free, including local or systemic, and/or prostate specific antigen (PSA) 0.4 ng./ml. or greater, and cancer specific survival were determined by the Kaplan-Meier method. The effect of pathological grade and stage, preoperative PSA, DNA ploidy, margin status, tumor dimension, seminal vesicle invasion, and adjuvant treatment was assessed with the univariate and multivariate analyses.Results: Pathological stage distribution was pT2 in 26% of patients, pT3 48% and ...

The Gleason grading system in prostatectomy specimens following receipt of neoadjuvant therapy has been considered inaccurate. However, with continuing expansion of novel therapeutics, it is important to understand whether the Gleason system can be effectively utilized in this setting. The aim of this study was to assess the ability of the Gleason grading system to predict systemic progression among prostatectomy specimens treated with neoadjuvant hormone therapy (NHT).This was a single-institution retrospective analysis from 1987 to 2009 of 13,427 patients who underwent radical prostatectomy (RP) without NHT and 1148 patients with NHT. NHT consisted of leuprolide alone (n = 415), antiandrogen therapy alone (n = 400) and combined treatment (n = 333). Kaplan-Meier analysis estimated 15-year systemic progression-free survival among NHT and non-NHT patients. Cox proportional hazard regression models estimated risk of systemic progression following RP according to NHT use and nonuse.Median duration of NHT was 3 months (interquartile range (IQR) 2-4) whereas median follow-up after RP was 8.3 years (IQR 5-10.8). NHT patients were more likely to be D'Amico high risk, have locally advanced pathologic T stage (≥ pT3), pathologic Gleason scores (GS) of 8-10 and lymph node involvement (P0.0001 for all). NHT use was associated with lower rates of positive surgical margins, more downgrading to pT0 and less GS upgrading from biopsy (P ≤ 0.001 for all). GS could not be assigned to only 3% of NHT patients. On multivariate analysis, pathologic GS remained a predictor of systemic progression (SP) following NHT (hazard ratio (HR) 1.6, P = 0.005), but the association was less strong compared with non-NHT patients (HR 2.9, P0.0001).Utilization of the Gleason system appears feasible among hormonally pretreated prostatectomy specimens and shows continued prognostication for systemic progression. Confirmatory investigations are needed before the Gleason system can be reliably applied in the setting of neoadjuvant therapy.

Purpose: Recent prospective randomized studies have shown that adjuvant hormonal therapy combined with local treatment can significantly improve overall survival in patients with locally advanced disease. This finding challenges the previous belief that adjuvant hormonal therapy may not be beneficial for minimal stages TxN + M0 or less prostate cancer, particularly when combined with local treatment. We reviewed the benefits of adjuvant hormonal therapy in patients at risk for disease progression, especially when administered after radical prostatectomy.Materials and Methods: We retrospectively reviewed the current literature and evaluated clinical information on stage pT3b cancer from a large single institution prostate cancer database to determine the current role of adjuvant hormonal therapy after radical prostatectomy for prostate cancer.Results: Retrospective experimental and clinical studies have proved the impact of adjuvant hormonal therapy for decreasing prostate specific antigen (PSA) and clinic...

Context Although widely used for more than 85 years, the efficacy of radiotherapy for Graves’ ophthalmopathy (GO) has not been established convincingly. Objective To evaluate the efficacy of radiotherapy for GO. Design Prospective, randomized, internally controlled, double-blind clinical trial in a tertiary care academic medical center. Participants The patients were ethnically diverse males and females over age 30 seen in a referral practice. The patients had moderate, symptomatic Graves’ ophthalmopathy (mean clinical activity score, 6.2) but no optic neuropathy, diabetes, recent steroid treatment, previous decompression, or muscle surgery. Forty-two of 53 consecutive patients were enrolled after giving informed consent and fulfilling study entry criteria. Eleven eligible patients declined to participate because of inconvenience, desire for alternative therapy, or concern about radiation. Intervention One randomly selected orbit was treated with 20 Gy of external beam therapy; sham therapy was given to the other side. Six months later, the therapies were reversed. Main outcome measures Every 3 months for 1 year, we measured the volume of extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width. Effective treatment for GO will modify one or more of these parameters. Results No clinically or statistically significant difference between the treated and untreated orbit was observed in any of the main outcome measures at 6 months. At 12 months, muscle volume and proptosis improved slightly more in the orbit that was treated first. Conclusions In this group of patients, representative of those for whom radiotherapy is frequently recommended, we were unable to demonstrate any beneficial therapeutic effect. The slight improvement noted in both orbits at 12 months may be the result of natural remission or of radiotherapy, but the changes are of marginal clinical significance.

BACKGROUND With a lack of data from randomized trials, the optimal management of men with nonmetastatic prostate carcinoma is controversial. The authors sought to define the outcomes of three common strategies for managing patients with nonmetastatic prostate carcinoma: expectant management, radiotherapy, and radical prostatectomy. METHODS The authors conducted a retrospective cohort study with standardized collection of key prognostic data, including centralized assignment of Gleason grades from original biopsy specimens. Participants included all Connecticut hospitals (the expectant management cohort) and three academic medical centers in other states (the radiotherapy and surgery cohorts). Two thousand three hundred eleven consecutive men ages 55–74 years who were diagnosed during 1971–1984 with nonmetastatic prostate carcinoma and were treated at the participating sites were included. RESULTS Kaplan–Meier estimates with 95% confidence intervals (95% CI) of overall survival at 10 years for each cohort were as follows: expectant management cohort, 42% of patients (95% CI, 38–46%); radiotherapy cohort, 52% of patients (95% CI, 46–58%); and radical prostatectomy cohort, 69% of patients (95% CI, 67–71%); for disease specific mortality, the estimates were as follows: expectant management cohort, 75% of patients (95% CI, 71–79%); radiotherapy cohort, 67% of patients (95% CI, 61–73%); and radical prostatectomy cohort, 86% of patients (95% CI, 84–88%). There were large differences in distributions of important prognostic factors among men in the different treatment groups. CONCLUSIONS These data provide precise estimates of the outcomes of patients who have been treated with different modalities for nonmetastatic prostate carcinoma in the recent past. Direct comparisons of outcomes between treatment groups are inadvisable because of the different characteristics of patients who select these alternative management strategies. Cancer 2001;91:2302–14. © 2001 American Cancer Society.

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).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 levelor =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.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).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.

Tested was the hypothesis that high-dose omega (omega)-3 fatty acids will be more effective than low-dose omega-3 fatty acids in preserving renal function in patients with severe IgA nephropathy in a randomized, open-label, parallel-group clinical trial. Patients were assigned to receive either high-dose fatty acids (EPA 3.76 g and DHA 2.94 g) or low-dose fatty acids (EPA 1.88 g and DHA 1.47 g), both given daily in a highly purified ethyl ester concentrate (Omacor). Patients were treated for a minimum of 2 yr in the absence of a treatment failure or until study closure (January 2000). Seventy-three patients were enrolled in the trial with two ranges of elevated serum creatinine (SC): 63 patients (86%) with a range of 1.5 to 2.9 mg/dl and 10 patients (14%) with a range of 3.0 to 4.9 mg/dl. The primary end point, within-patient rates of change in SC (2-yr minimum), showed an annualized median increase in SC of 0.08 mg/dl per yr in the low-dose group and 0.10 mg/dl per yr in the high-dose group (P: = 0.51). Patients in the lower entry SC range had lower SC slopes (P: = 0.02) and less end-stage renal disease (ESRD) (P: < 0.001) compared with those in the higher entry SC range. No patient died, and 18 patients developed ESRD: 10 in the low-dose group and 8 in the high-dose group (P: = 0.56). SC slopes were significantly lower, and survival free of ESRD was significantly higher (both, P: = 0.04) in the 63 Omacor-treated patients compared with the 22 placebo-treated patients from our previously reported clinical trial in which both groups had a similar level of renal impairment. Patient compliance was excellent, and no serious adverse events were noted. Low-dose and high-dose omega-3 fatty acids were similar in slowing the rate of renal function loss in high-risk patients with IgA nephropathy, particularly those with moderately advanced disease.

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 hadregular 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 seve...

BACKGROUND The presence of lymph node metastasis is a poor prognostic sign for patients with prostate carcinoma. Results of published reports on survival among patients with lymph node metastasis are difficult to assess because of treatment selections. The extent to which lymph node status will have an impact on a patient's survival is uncertain. METHODS The authors analyzed 3463 consecutive Mayo Clinic patients who underwent radical prostatectomy and bilateral pelvic lymphadenectomy for prostate carcinoma between 1987 and 1993. Of these patients, 322 had lymph node metastasis at the time of surgery, and 297 lymph node positive patients also received adjuvant hormonal therapy within 90 days of surgery. The progression free rate and the cancer specific survival rate were used as outcome endpoints in univariate and multivariate Cox proportional hazards models. The median follow-up was 6.3 years. Progression was defined by elevation of serum prostate specific antigen (PSA) ≥ 0.4 ng/mL after surgery, development of local recurrence, or distant metastasis documented by biopsy or radiographic examination. RESULTS The 5-year and 10-year progression free survival rates (± standard error [SE]) for patients with lymph node metastasis were 74% ± 2% and 64% ± 3%, respectively, compared with 77% ± 1% and 59% ± 2%, respectively, for patients without lymph node metastasis. The 5-year and 10-year cancer specific survival rates were 94% ± 1% and 83% ± 4%, respectively, compared with 99% ± 0.1% and 97% ± 0.5%, respectively, for patients without lymph node metastasis. Among patients with a single lymph node metastasis, the 5-year and 10-year cancer specific survival rates were 99% ± 1% and 94% ± 3%, respectively. After adjustment for extraprostatic extension, seminal vesicle invasion, Gleason grade, surgical margins, DNA ploidy, preoperative serum PSA concentration, and adjuvant therapy, the hazard ratio for death from prostate carcinoma among patients with a single lymph node metastasis compared with patients who were without lymph node metastasis was 1.5 (95% confidence interval, 0.5–5.0; P = 0.478), whereas the hazard ratio for death from prostate carcinoma was 6.1 (95% confidence interval, 1.9–19.6; P = 0.002) for those with two positive lymph nodes and 4.3 (95% confidence interval, 1.4–13.0; P = 0.009) for those with three or more positive lymph nodes. There was no significant difference in the progression free survival rate among patients with or without lymph node metastasis in multivariate analysis after controlling for all relevant variables, including treatments (hazard ratio,1.0; 95% CI, 0.7–1.3; P = 0.90). CONCLUSIONS Patients with prostate carcinoma who have multiple regional lymph node metastases had increased risk of death from disease, whereas patients with single lymph node involvement appeared to have a more favorable prognosis after radical prostatectomy and immediate adjuvant hormonal therapy. Excellent local disease control was achieved by using combined surgery and adjuvant hormonal therapy in patients with positive lymph nodes. Cancer 2001;91:66–73. © 2001 American Cancer Society.

We determine the importance of clinical and pathological variables for predicting biochemical progression in patients after surgery for specimen confined prostate cancer. We developed a simple scoring algorithm for biochemical progression in node negative cases and tested the algorithm performance on an independent group.Our study included 2,518 patients with pT2N0 or pT3N0 disease treated between 1990 and 1993. Gleason score, preoperative prostate specific antigen (PSA), margin status, extraprostatic extension, seminal vesicle involvement, DNA ploidy and adjuvant treatment were primary variables analyzed univariately. The Cox proportional hazards model was used on 2,000 randomly selected patients to develop a multivariate scoring algorithm for the aforementioned factors to predict biochemical progression-free survival. The final model included Gleason score, preoperative PSA, margin status, seminal vesicle involvement and adjuvant treatment. The prognostic score derived from this model was validated by applying it to the remaining 518 patients. Harrell's measure of concordance (C) was used to compare competing models.For patients who did not receive adjuvant therapy the derived score based on the Cox model coefficient was Gleason +1 (PSA 4 to 10), +2 (PSA 10.1 to 20), +3 (PSA greater than 20), +2 (positive seminal vesicle) and +2 (positive margin). The score was reduced by 4 if adjuvant hormonal therapy was given and by 2 for only adjuvant radiotherapy. The 5-year progression-free survival was 94% for scores less than 5, 60% for 10 and 32% for greater than 12 (C = 0. 718). Applying the score to the independent validation data set (518) resulted in 5-year progression-free survival of 96% for scores less than 5, 53% for 10 and 30% for greater than 12 (C = 0.759).Progression-free survival determined by the model score group identified a wide range of risk levels for patients with specimen confined prostate cancer. This simple predictive model allows identification of patients at high risk for cancer progression with specimen confined disease who may be targeted for closer surveillance and adjuvant therapy, while those at lower risk may be simply observed.

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 compar...

OBJECTIVE To investigate survival and renal recovery after dialysis in patients with acute renal failure with use of synthetic membranes compared with substituted cellulose membranes. PATIENTS AND METHODS We prospectively studied survival and recovery of renal function of 66 patients with acute renal failure who required intermittent heinodialysis. Patients were randomized to exclusive treatment with either cellulose acetate (CA) or polysulfone (PS) hemodialysis membranes. Additionally, markers of bio compatibility (complement, leukocyte counts, cytokine concentration) were measured at initiation and 1 hour after initiation of dialysis among 10 patients equally distributed between the CA and PS groups . RESULTS The cohorts were indistinguishable with respect to age, sex, presence of diabetes mellitus, Acute Physiology and Chronic Health Evaluation II scores, per centage in the intensive care unit (ICU), and adequacy of dialysis. Survival (76% CA, 73% PS; P=.78) and recovery of renal function at 30 days (58% CA, 39% PS; P=.14) were not statistically different in the 2 groups. Among 26 CA patients and 27 PS patients treated in the ICU, survival was not statistically different (73% CA, 67% PS; P=.61); however, the proportion of patients recovering renal function suggested a benefit favoring CA membranes (65% CA, 37% PS; P=.04). Additionally, markers of biocompatibility were not significantly different between groups among the 10 patients equally distributed between the CA and PS groups. CONCLUSIONS Overall clinical outcomes among patients with acute renal failure treated with CA hemodialysis membranes and those treated with PS membranes were not significantly different. The observed advantage favoring renal recovery among this ICU population treated with CA hemodialysis membranes warrants further investigation.

Background The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996. Methods A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test. Results The median follow-up time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P: for difference =.09). For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P: =.0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm. Conclusions Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm.

Purpose: Cure from malignancy is commonly defined as a disease-free state lasting 5 years after treatment. We analyzed clinical and biochemical progression rates after radical prostatectomy for men with clinically localized prostate cancer with particular attention to recurrence beyond 5 years. Annual hazard rates of progression were calculated to determine the probability of recurrence at specific intervals following surgery.Materials and Methods: The records of 2,782 men with clinically localized prostate cancer (cT1–T2) undergoing radical prostatectomy between 1987 and 1993 were reviewed. All patients were treated in the prostate specific antigen (PSA) era so that serial followup PSA values were available from the time of surgery. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Disease progression was defined as documented local recurrence, systemic progression and/or PSA 0.4 ng./ml. or greater. Lymph node positive cases were eliminated f...

Purpose:: We assess temporal trends in prostate biopsy incidence, utilization and cancer yield in the community before and after the introduction of serum prostate specific antigen (PSA) to the community medical practiceMaterials and Methods:: Study subjects comprised all Olmsted County men with a first prostate biopsy performed between January 1, 1980 and December 31, 1997. Medical records of all study subjects (1,729) were reviewed for clinical information from the first and all subsequent biopsies.Results:: Annual age adjusted prostate biopsy incidence increased from 113/100,000 (95% confidence interval 76, 150) in 1980 to 487/100,000 (421, 554) in 1992 and decreased to 264/100,000 (219, 309) in 1997. For men 50 to 59 years old biopsy incidence increased 400% from 137/100,000 in 1980 to 1986 to 686/100,000 in 1993 to 1997. Overall, there were 93/100,000 more negative biopsies and 49/100,000 more positive biopsies in 1993 to 1997 than in 1980 to 1986. The overall cancer yield of 36% was essentially unch...

Purpose: Positive surgical margins are common after radical prostatectomy, and the role of adjuvant therapy in such cases is controversial. We determined the benefit of postoperative external beam radiation therapy in patients with margin positive prostate cancer with respect to biochemical progression or cancer recurrence. To decrease confounding factors that may affect the likelihood of biochemical progression our study was limited to men with organ confined cancer and a single positive margin. Materials and Methods: We retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml. Results: Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88% ± 5% versus 59% ± 11% of patients treated with adjuvant radiation therapy versus no radiation therapy (p = 0.005). No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (p = 0.015). When stratified by site of margin positivity, the 5-year estimated clinical and biochemical progression-free rate in 18 cases and controls with a positive base margin was 95% ± 15% and 65% ± 13%, respectively (p = 0.02). The rate in 35 cases and cases with a positive apex margin was 95% ± 5% and 64% ± 15%, respectively (p = 0.07). Limited sample size precluded analysis of the other sites. Conclusions: Patients with localized prostate cancer and a singe positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.

Evaluation of extranodal tumor extension may provide prognostic information for patients with epithelial malignancies. However, its importance for the patient who has prostate cancer with regional lymph node metastasis requires further investigation and clarification. This study was performed to evaluate the prognostic significance of extranodal extension (ENE) in a large series of node-positive patients. The study group included 212 node-positive patients who were treated by bilateral pelvic lymphadenectomy, radical retropubic prostatectomy, and androgen deprivation between 1987 and 1992 at the Mayo Clinic. ENE was defined as cancer perforating through the lymph node capsule into perinodal tissue. Nodal cancer volume was measured by the grid method. Univariate and multivariate risk ratios (RR) for distant metastasis-free and cancer-specific survival were estimated using the Cox proportional model. The mean follow-up was 6.3 years (median, 6.1 years). Distant metastasis-free and cancer-specific survival at 5 years for all patients was 91% and 95%, respectively. ENE was found in 126 of 212 patients (59%). The presence of ENE was not significantly associated with distant metastasis-free (RR = 1.6; 95% confidence interval [CI], 0.7 to 3.9) or cancer-specific survival (RR = 2.2; 95% CI, 0.7 to 6.8). Among 98 patients with a single positive node, there was no significant difference in distant metastasis or cancer-specific survival according to the presence of ENE (P = .88 and P = .36, respectively). After adjusting for Gleason score, DNA ploidy, and ENE, only nodal cancer volume was significantly associated with adverse distant metastasis-free (RR = 1.9; 95% CI, 1.5 to 2.8) and cancer-specific survival (RR = 1.4; 95% CI, 1.1 to 1.9). Our data indicate that the presence of ENE is not associated with unfavorable survival in patients with node-positive prostate cancer treated by radical retropubic prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy. In contrast, nodal cancer volume was predictive of distant metastasis-free survival and cancer-specific survival.

Background: Parenteral iron therapy is required in a majority of chronic dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran. Methods: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30–60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000). Results: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 µg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 µg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations. Conclusions: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.

The pathologic tumor-node-metastasis (pTNM) system is universally used to define the extent of disease in human malignancies. This study evaluated the impact of initial therapy on cause-specific mortality (CSM) rates and recurrence rates in pTNM stage III papillary thyroid carcinoma.Three hundred patients (median age, 58 years) were followed on average for 14 postoperative years. Of these, 246 patients (82%) had complete primary tumor resection; 208 patients (69%) had nodal metastases; 161 (54%) had locally invasive primary tumors; 45 patients (15%) underwent initial unilateral lobectomy (UL). Bilateral lobar resection (BLR) accounted for 242 patients (near-total, 54%; total thyroidectomy, 23%).The 30-year rates for CSM, distant metastases, nodal metastases, and local recurrence (LR) were 29%, 22%, 19%, and 16%, respectively. The 20-year rates for CSM were significantly higher (50% vs 14%) when primary tumor was incompletely resected (P = .0001). After complete resection, 20-year rates for CSM and LR after BLR were 12% and 10%, respectively, which were significantly lower (P.05) than the 23% and 26% rates seen after UL. There were no significant differences in nodal metastases or distant metastases rates between UL and BLR (P.4). The 20-year LR rate after total thyroidectomy (13%) was not different (P = .5) from the 11% seen after near-total thyroidectomy.In this nonrandomized evaluation of patients with pTNM stage III papillary thyroid carcinoma, the extent of primary thyroid resection appeared to significantly impact CSM and LR but did not apparently influence regional or distant metastasis.

RESULTS. The overall margin positivity rate was 29%. Seventy-two patients (19%) had only positive surgical margins without evidence of EPE (“surgical incision”), 53 (14%) had only EPE, 37 (10%) had both, and 215 (57%) had neither. Positive margins were correlated with the finding of EPE (P 5 0.003). Progression free survival rates at 5 and 10 years were 88% and 67%, respectively. In univariate analysis, preoperative PSA concentration, positive surgical margins, Gleason grade, cancer volume, and DNA ploidy were significant in predicting progression (P values, ,0.001, ,0.001, 0.01, 0.007, and ,0.001, respectively). In multivariate analysis, margin status and DNA ploidy were independent predictors of progression (relative risk for margin status, 1.9; 95% confidence interval [CI], 1.1‐3.4; P 5 0.03; relative risk for DNA ploidy, 5.1; 95% CI, 2.4 ‐10.9; P , 0.001). Among patients with positive margins, 5-year progression free survival was 78% for those with negative EPE and 55% for those with positive EPE. CONCLUSIONS. Surgical margin status and DNA ploidy were independent predictors of progression after radical prostatectomy. To improve cancer control, adjuvant therapy may be considered for patients with positive surgical margins or nondiploid cancer. Cancer 1999;86:1775‐ 82. © 1999 American Cancer Society.

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

BACKGROUND Dedifferentiation is a distinctive feature of cancer progression. Detailed histologic analysis of primary prostate carcinoma and synchronous lymph node metastases may improve our understanding of the complex process of cancer progression and metastasis. METHODS The authors studied 242 regional lymph node positive prostate carcinoma patients who underwent radical prostatectomy and bilateral lymphadenectomy between 1987 and 1992 at the Mayo Clinic. Patients ranged in age from 47–79 years (median, 66 years). The median follow-up was 6.1 years. Gleason scores of lymph node metastases and primary tumors were compared and correlated with systemic disease progression. Histologic dedifferentiation was defined as a higher Gleason grade in the lymph node metastases than in the primary tumor. Systemic disease progression was defined as the presence of distant metastases documented by biopsies, abdominal computed tomography, plain radiograph, or bone scan. RESULTS The 5-year systemic progression free survival (PFS) rate was 90%. The Gleason score in the lymph node metastases was higher than in the primary tumor in 45% of patients, lower in 12% of patients, and matched exactly in 43% of patients. The 5-year PFS was significantly different between patients with histologic dedifferentiation (88% ± 3) and those without dedifferentiation (94% ± 2) (P = 0.04). Adjusting for the Gleason grade of the primary tumor and total lymph node tumor volume, the relative risk for disease progression associated with dedifferentiation was 1.8 (95% confidence interval, 0.7–4.7; P = 0.25). CONCLUSIONS The findings of the current study demonstrate the morphologic heterogeneity of metastases from prostate carcinoma. There is a trend toward histologic dedifferentiation when prostate carcinoma metastasizes to regional lymph nodes. This dedifferentiation, although univariately significant, was not associated with disease progression when adjusted for lymph node tumor volume. Cancer 1999;86:657–63. © 1999 American Cancer Society.

It was reported previously that dietary fish oil supplementation retarded the progression of renal disease in patients with IgA nephropathy in a multicenter, placebo-controlled, randomized, 2-yr clinical trial. The aim of this study was to determine the long-term influence of fish oil treatment on renal progression in observations on the study cohort of 106 patients extending beyond the 2-yr trial. Renal function was assessed by serial serum creatinine and 24-h urine protein measurements. Vital, end-stage renal disease (ESRD), and BP status and treatment beyond completion of the 2-yr trial were determined. As in the trial, the primary end point was an increase of 50% or more in the serum creatinine, and the secondary end point was ESRD. After a mean follow-up of 6.4 yr, 46 patients-17 in the fish oil group versus 29 in the placebo group-reached the primary end point (P = 0.002), and 27 patients-eight in the fish oil group versus 19 in the placebo group-developed ESRD (P = 0.009). At the end of the 2-yr trial, 75 patients (45 fish oil, 30 placebo) remained at risk for the primary end point. This is also when the double-blind part of the trial ended, allowing physicians to stop supplements, switch original placebo-assigned patients to fish oil, and continue fish oil in original fish oil-assigned patients. A significantly greater number of nonsupplemented placebo patients developed the primary end point (P = 0.02) and ESRD (P = 0.003) compared with long-term supplemented fish oil patients. Conversely, more fish oil-supplemented patients had stable renal function than nonsupplemented patients (P = 0.02). By intention, BP control, primarily treated with angiotensin-converting enzyme inhibition, was equal in the fish oil and placebo groups. Proteinuria was modestly reduced in both groups. It is concluded that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgA nephropathy.

BACKGROUND Alterations of the p53 tumor suppressor gene are associated with advanced stage prostate carcinoma. The biologic significance of p53 nuclear accumulation in prostate cancer patients with regional lymph node metastases is uncertain. METHODS The authors investigated p53 alterations by immunohistochemistry in 220 lymph node positive patients who were treated with radical prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy between 1987–1992 at the Mayo Clinic. The mean follow-up was 6.3 years. Tumor volume of lymph node metastases was measured using the grid method. RESULTS p53 immunoreactivity was detected in 109 of 211 primary tumors (52%) and 83 of 144 matched regional lymph node metastases (58%); this expression was strongly concordant (correlation coefficient = 0.53; P = 0.0001). Overexpression of p53 protein in lymph node metastases was associated with distant metastasis free survival by univariate analysis (P = 0.03), but did not reach statistical significance by multivariate analysis (P = 0.07). Regional lymph node cancer volume was the single most important predictor of distant metastases after adjusting for Gleason score, DNA ploidy, and p53 expression. CONCLUSIONS The findings of the current study suggest that assessment of biologic changes (including p53 alterations in regional lymph node metastases) could be of value in the assessment of the biologic aggressiveness of prostate carcinoma, whereas p53 expression in the primary tumor does not appear to influence patient outcome. Cancer 1999;85:2455–9. © 1999 American Cancer Society.

Untreated stage pTxN+ prostate cancer is associated with a poor outcome. Monotherapy (surgery, radiation, hormonal therapy) alone is associated with a high progression rate. We evaluate whether radical prostatectomy and pelvic lymphadenectomy plus early adjuvant orchiectomy impart a survival advantage compared to pelvic lymphadenectomy and orchiectomy alone in a matched cohort of patients.Between 1966 and 1995, 382 and 79 patients with stage pTxN+ prostate cancer underwent pelvic lymphadenectomy and radical prostatectomy plus early adjuvant orchiectomy (within 3 months of prostatectomy), and pelvic lymphadenectomy and orchiectomy only, respectively. We selected 79 matched controls from the prostatectomy plus orchiectomy group for the orchiectomy group. Patients were matched according to the number of positive nodes, clinical grade, clinical stage, age, year of surgery and preoperative prostate specific antigen (after 1987). The Kaplan-Meier method and stratified Cox proportional hazards model were used to estimate overall and cause specific survival for the 2 groups.There was an overall survival advantage at 10 years for the prostatectomy plus orchiectomy (66+/-6%) compared to the orchiectomy (28+/-6%) group (p0.001, risk ratio 0.36, 95% confidence interval 0.20 to 0.66). There was also an advantage in cause specific survival at 10 years in the prostatectomy plus orchiectomy (79+/-5%) versus the orchiectomy (39+/-7%) group (p0.001, relative risk 0.28, 95% confidence interval 0.13 to 0.59). After 1987, when matched on preoperative prostate specific antigen, the apparent survival advantage at 5 years with radical prostatectomy was smaller (79+/-8 versus 63+/-9% orchiectomy) and not significant (p = 0.19).This retrospective study of patients with stage pTxN+ PC suggests that radical prostatectomy with early adjuvant orchiectomy may provide a significant advantage in overall and cause specific survival compared to orchiectomy alone.