A Prospective, Randomized, Double-blind, Placebo-controlled Study of Orbital Radiotherapy for Graves' Ophthalmopathy.

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.

The effect of Gleason score on the predictive value of prostate-specific antigen doubling time.

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 vs >18 months predicted a lower 10-year systemic progression-free survival for patients with tumours having a pathological Gleason score of <7 (98% vs 99%, P = 0.005), 7 (82% vs 91%, P = 0.003) and 8-10 (57% vs 73%, P = 0.042). A PSA DT after RP of <12 months was significantly associated with a lower 10-year systemic progression-free survival for patients with tumours having a Gleason score of <7 (77% vs 94%, P < 0.001) and 7 (61% vs 86%, P < 0.001), but not 8-10 (61% vs 75%, P = 0.11). The ability of PSA DT before and after RP to predict systemic progression and CSS decreased with increasing Gleason score. CONCLUSIONS: The PSA DT remains associated with outcome both before and after RP across increasing pathological Gleason scores, although the predictive ability of PSA DT is diminished in Gleason 8-10 cancers.

Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era.

PURPOSE: While the incidence of lymph node positive prostate cancer has decreased during the prostate specific antigen era, the optimal treatment of these patients remains in question. We examined the impact of lymph node metastases on the outcome of patients following radical prostatectomy and investigated prognostic factors that affect survival. MATERIALS AND METHODS: We identified 507 men treated with radical prostatectomy between 1988 and 2001 who had lymph node positive disease. Of the 507 patients 455 (89.7%) were treated with adjuvant hormonal therapy. Median followup was 10.3 years (IQR 6.1-13.5). Postoperative survival rates were estimated using the Kaplan-Meier method and the impact of various clinicopathological factors on outcome was analyzed using Cox proportional hazard regression models. RESULTS: Ten-year cancer specific survival for patients with positive lymph nodes was 85.8% with 56% of the men free from biochemical recurrence at last followup. On multivariate analysis pathological Gleason score 8-10 (p = 0.004), positive surgical margins (p = 0.016), nondiploid tumor ploidy (p = 0.023) and 2 or greater positive nodes (p = 0.001) were adverse predictors of cancer specific survival. Tumor stage, year of surgery and total number of nodes removed did not significantly affect outcome. Adjuvant hormonal therapy decreased the risk of biochemical recurrence (p <0.001) and local recurrence (p = 0.004) but it was not associated with systemic progression (p = 0.4) or cancer specific survival (p = 0.4). CONCLUSIONS: Radical prostatectomy may offer long-term survival to patients with lymph node positive prostate cancer. Gleason score, margin status, tumor ploidy and the number of involved nodes predict survival, while the role of adjuvant hormonal therapy continues to be defined.

Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis.

BACKGROUND: A troubling aspect of cancer screening is the potential for overdiagnosis, i.e., detection of disease that, in the absence of screening, would never have been diagnosed. Overdiagnosis is of particular concern in lung cancer screening because newer screening modalities can identify small nodules of unknown clinical significance. Previously published analyses of data from the Mayo Lung Project, a large randomized controlled trial conducted among 9211 male cigarette smokers in the 1970s and early 1980s indicated that overdiagnosis might exist in lung cancer screening. At the end of follow-up (July 1, 1983), no difference in lung cancer mortality was observed, but an excess of 46 cases in the intervention arm suggested overdiagnosis. Because that excess could instead have resulted from short follow-up time, we investigated this possibility by conducting long-term lung cancer incidence follow-up. METHODS: We investigated the lung cancer status through 1999 of the 7118 participants in the Mayo Lung Project who were alive and without diagnosed lung cancer in 1983 by use of medical records, surveys mailed to participants or next-of-kin, and state death certificates. RESULTS: Information was available for 6101 participants, including 811 with inconclusive lung cancer status. From November 1971 through December 31, 1999, 585 participants in the intervention arm and 500 in the usual-care arm were diagnosed with lung cancer. CONCLUSIONS: The persistence of excess cases in the intervention arm after 16 additional years of follow-up provides continued support for overdiagnosis in lung cancer screening.

Polymorphisms in genes involved in sex hormone metabolism may increase risk of benign prostatic hyperplasia.

BACKGROUND: This study investigates associations between polymorphisms in genes involved in sex hormone metabolism and measures of benign prostatic hyperplasia (BPH). METHODS: Community-dwelling Caucasian men (n=510, median age 60 years in 2000) from the Olmsted County, MN, participated in a longitudinal study of BPH. From 1990 through 2000, urologic measures of BPH were assessed biennially from lower urinary tract symptom severity, peak flow rates, prostate volume, serum prostate specific antigen (PSA) level, acute urinary retention, and treatment for BPH. Men were genotyped for polymorphisms in genes involved in sex hormone metabolism. RESULTS: With the wildtype genotype as reference, men with HSD3B1 (c.1100 A/C) heterozygous genotype (hazard ratio (HR)=0.7, 95% confidence intervals (CI)=0.6, 0.9) were at decreased risk of an enlarged prostate and men with CYP19 (TTTA)(n) genotype homozygous for >or=175 TTTA repeats (HR=1.5, 95% CI=1.1, 2.1), and CYP19 (c.1531 C/T) homozygous T variant (HR=1.6, 95% CI=1.1, 2.2) were at increased risk of an enlarged prostate. The homozygous A variant of the PSA gene (g.-252 G/A), was associated with treatment for BPH (HR=2.3, 95% CI=1.2, 4.4). In multivariate analyses, the homozygous variant genotypes of AKR1C3 (c.15 G/A and c.90 G/A) were associated with a decreased risk of an enlarged prostate (HR=0.56, 95% CI=0.35, 0.90 and HR=0.57, 95% CI=0.33, 0.98). CONCLUSIONS: Polymorphisms in HSD3B1, CYP19, AKR1C3 genes may be associated with an enlarged prostate in older men. These data provide insights into genes that should be examined further for their potential role in the pathogenesis of BPH.

International registry for primary hyperoxaluria.

BACKGROUND/AIMS: Primary hyperoxaluria (PH) is an inherited disorder that causes calcium urolithiasis and renal failure. Due to its rarity, experience at most centers with this disease is limited. METHODS: A secure, web-based, institutional review board/ethics committee and American Health Insurance Portability and Accountability Act (HIPAA)-compliant registry was developed to facilitate international contributions to a data base. To date 95 PH patients have been entered. RESULTS: PH type was confirmed in 84/95 (PH1 79%, PH2 9%). Mean age +/- SD at symptom onset was 9.5 +/- 10.2 (median 5.5) years whereas age at diagnosis was 15.0 +/- 15.2 (median 10.0) years. Urolithiasis was present at diagnosis in 90% (mean 7, median 1, stones prior to diagnosis) and nephrocalcinosis in 48%. Surprisingly 15% of the patients were asymptomatic at the time of diagnosis. Nineteen of the 95 patients were first recognized to have PH after they had reached end-stage renal disease, with the diagnosis made only after kidney transplantation in 7 patients. Patients were followed for 12.1 +/- 10.6 (median 9.4) years. Thirty-four of 95 progressed to end-stage renal failure, before (19 patients) or after (15 patients) diagnosis. In the PH1 cohort actuarial renal survival was 64% at 30 years of age, 47% at 40 years, and 29% at 50 years. CONCLUSION: We have developed a PH registry, and demonstrated the feasibility of this secure, web-based approach for data entry. By facilitating accumulation of an increasing cohort of patients, this registry should allow more complete characterization of clinical expression of PH, an appreciation of geographic variability, and identification of treatment outcomes.

Decline in the overall incidence of regional-distant prostate cancer in Olmsted County, MN, 1980-2000.

OBJECTIVE: To describe trends in the incidence of regional-distant prostate cancer over the entire course of the disease, before and after the introduction of prostate-specific antigen screening in 1987. PATIENTS AND METHODS: All residents of Olmsted County, MN, USA, with a diagnosis of prostate cancer from 1964 to 2000 were identified using the resources of the Rochester Epidemiology Project. Their community medical records were examined to identify men with documented evidence of locally advanced (T3/4 or N+ disease) or metastatic prostate cancer between 1980 and 2000. RESULTS: In all, 407 men had regional-distant prostate cancer, based on clinical or pathological staging at the time of initial diagnosis of prostate cancer and/or on radiological information over the entire course of their illness. The age-adjusted incidence per 100,000 men increased from 47.4 in 1980-86 to 65.8 in 1987-93, and declined to 33.3 in 1994-2000 (P < 0.001). Based on clinical and radiological information over the entire course of illness (268 men) the age-adjusted incidence of regional-distant disease was 42.3 in 1980-86, 41.2 in 1987-93, and declined to 18.1 in 1994-2000 (P < 0.001). These latter rates were 27%, 32% and 47% higher for the three periods, respectively, than rates based on clinical staging at initial diagnosis of prostate cancer. CONCLUSIONS: The overall incidence of regional-distant stages of prostate cancer has declined in recent years, regardless of the stage at initial diagnosis. This may be a result in part of early detection and curative treatments. These findings also indicate that assessing the incidence of regional-distant prostate cancer only at the initial diagnosis underestimates the full impact of the benefits of early detection and treatment.

Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome.

UNLABELLED: 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 (> or =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.

The extent of lymphadenectomy for pTXNO prostate cancer does not affect prostate cancer outcome in the prostate specific antigen era.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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 (p <0.001). 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). CONCLUSIONS: 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.

Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation.

BACKGROUND: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum creatinine level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients.

Polymorphisms in the 5alpha reductase type 2 gene and urologic measures of BPH.

BACKGROUND: The objective of the study was to examine associations between SRD5A2 polymorphisms and measures of benign prostatic hyperplasia (BPH). METHODS: Participants were 510 Caucasian men (median age 60 years), randomly selected from the Olmsted County, MN community to participate in a longitudinal study of BPH. From 1990 through 2000, biennial measurements of lower urinary tract symptom severity (assessed from the American Urological Association Symptom Index, AUASI), peak urinary flow rates (Qmax), and prostate volume were made. Genotyping of SRD5A2 V89L, A49T, and TA repeat polymorphisms were performed. RESULTS: Compared with the VV genotype, the LL genotype was associated with an enlarged prostate (Hazard ratio (HR)=1.62, 95% confidence interval (CI)=1.06, 2.43) but not with AUASI, Qmax, or PSA. The A49T and TA repeat polymorphisms were not associated with BPH. When the LL/VL, AT/TT, and TA0/TA0 genotypes were considered high risk, the number of high risk genotypes increased with increasing prostate volume (32.3, 30.7, 34.1, and 38.7, respectively, P for trend=0.04). CONCLUSIONS: These findings do not demonstrate consistent associations between SRD5A2 genotypes and BPH. However, they suggest that the associations of V89L polymorphisms and prostate volume should be investigated further.

Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.

BACKGROUND: The National Kidney Foundation has advocated the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate (GFR) from serum creatinine measurements in clinical laboratories. However, healthy persons were not included in the development of the MDRD equation. OBJECTIVES: To assess the accuracy of the MDRD equation in patients with chronic kidney disease compared with healthy persons and to develop a new equation that uses both patients with chronic kidney disease and healthy persons. DESIGN: Cross-sectional study. SETTING: The Mayo Clinic, a tertiary-care medical center. PARTICIPANTS: Consecutive patients (n = 320) who had an iothalamate clearance test specifically for chronic kidney disease evaluation and consecutive healthy persons (n = 580) who had an iothalamate clearance test specifically for kidney donor evaluation. MEASUREMENTS: Serum creatinine levels, GFR, demographic characteristics, and clinical characteristics were abstracted from the medical record. RESULTS: The MDRD equation underestimated GFR by 6.2% in patients with chronic kidney disease and by 29% in healthy persons. Re-estimated coefficients for serum creatinine and sex were similar to the original MDRD equation in the chronic kidney disease series but not in the healthy series. At the same serum creatinine level, age, and sex, GFR was on average 26% higher in healthy persons than in patients with chronic kidney disease (P < 0.001). A quadratic GFR equation was developed to estimate logarithmic GFR from the following covariates: 1/SCr, 1/SCr2, age, and sex (where SCr = serum creatinine). LIMITATIONS: The new equation was not developed in a general population sample. Elderly and African-American persons were underrepresented. CONCLUSION: The MDRD equation systematically underestimates GFR in healthy persons. A new equation developed with patients who have chronic kidney disease and healthy persons may be a step toward accurately estimating GFR when the diagnosis of chronic kidney disease is unknown.

Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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 impact of surgical approach (nerve bundle preservation versus wide local excision) on surgical margins and biochemical recurrence following radical prostatectomy.

PURPOSE: Surgical margin (SM) status is widely reported as a significant risk factor for prostate cancer recurrence following radical prostatectomy (RP). It has been presupposed that preserving the neurovascular bundle may compromise cancer control due to the limited surgical margin obtained with a resultant increase in treatment failure. We examined whether neurovascular bundle preservation during RP is a risk factor for positive SMs and progression-free survival after adjusting for disease severity. MATERIALS AND METHODS: Outcomes following RP in 7,268 men between 1990 and 2000 were examined retrospectively. Median followup in those last known to be alive is 6.4 years. RP was performed by a total of 21 surgeons in the same basic fashion with strict attention to anatomical detail. RESULTS: Overall a positive SM was identified in 38% of patients. The positive SM rate was higher for wide excision than for nerve sparing (NS) (42% vs 34%) (p

Correlation of quantitative digital image analysis with the glomerular filtration rate in chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is characterized by progressive renal functional loss and histologic abnormalities of one or more tissue compartments. In this study, correlations between histologic abnormalities and graft function [glomerular filtration rate (GFR, measured by iothalamate clearance), serum creatinine (SCr) and urinary protein (UPr)] were investigated using biopsies from 49 patients with newly diagnosed CAN. Extent of tubulointerstitial fibrosis (%TIF), as assessed by a semi-quantitative score, correlated significantly with GFR, SCr and UPr. The close correlation between %TIF and GFR suggested that quantitative measurement of %TIF may predict functional consequences of CAN. Calculation of %TIF by computerized digital analysis was performed using four strategies: (a) quantitation of blue material in Masson's trichrome (MT)-stained sections, (b) quantitation of red material in Sirius Red-stained sections (SR-nonpolarized), (c) quantitation of birefringent material in Sirius Red stained-sections examined under polarized light (SR-polarized) and (d) quantification of brown material in sections stained by immunoperoxidase for alpha-smooth muscle actin. Only the SR-nonpolarized score correlated significantly with GFR at the time of biopsy-diagnosis of CAN. We conclude that digital analysis strategies demonstrate variable accuracy in quantifying %TIF. Validation of the SR-nonpolarized strategy against histologic scoring and GFR supports the application of this technique to longitudinal studies of CAN.

Prostatitis as a risk factor for prostate cancer.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Measured and estimated GFR in healthy potential kidney donors.

BACKGROUND: Nonradiolabeled iothalamate clearance is an accurate way to determine glomerular filtration rate (GFR). Objectives of this study are to define the normal range of nonradiolabeled iothalamate clearance in potential kidney donors and assess whether creatinine-based GFR estimates are accurate in this population. METHODS: Medical records of 365 potential kidney donors were reviewed. GFR was measured using clearance of nonradiolabeled iothalamate. Linear regression analysis was used to determine age- and sex-specific normal range values for GFR and serum creatinine. The abbreviated Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault prediction equations were used to estimate GFR from serum creatinine levels. RESULTS: GFR declined significantly with increasing age (P < 0.001) and was lower in women than men (P < 0.001). Men at the age of 20 years had an estimated mean GFR of 129 mL/min that declined by 4.6 mL/min/decade. Women at the age of 20 years had a mean GFR of 123 mL/min that declined by 7.1 mL/min/decade. Regression analysis of GFR normalized to body surface area (nGFR) was significant for age (P < 0.001), but not sex (P = 0.826). A 20-year-old had a mean nGFR of 111 mL/min/1.73 m2 that declined by 4.9 mL/min/1.73 m2/decade. Correlation between measured nGFR and estimated GFR was weak (r = 0.26 for abbreviated MDRD equation; r = 0.35 for Cockcroft-Gault equation). CONCLUSION: This study of nonradiolabeled iothalamate clearance for the measurement of GFR in potential kidney donors established age-adjusted normal values. In healthy individuals, GFR cannot be estimated accurately using the abbreviated MDRD or Cockcroft-Gault prediction equations.

Androgen receptor gene polymorphisms and increased risk of urologic measures of benign prostatic hyperplasia.

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 of <21 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 level >1.4 ng/ml (HR = 1.5, 95% CI: 1.1, 2.0). A GGN repeat length of <16 was associated with an AUASI >7 (HR = 1.6, 95% CI: 1.1, 2.3) and a serum prostate-specific antigen level >1.4 ng/ml (HR = 1.5, 95% CI: 1.0, 2.3). Having <21 CAG repeats and <16 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 level >1.4 ng/ml (HR = 2.8, 95% CI: 1.6, 4.7), a peak flow rate <12 ml/second (HR = 1.9, 95% CI: 1.1, 3.4), and an AUASI >7 (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 long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy.

PURPOSE: Information regarding the clinical impact of delayed (5 years or greater) biochemical failure (BF) after radical prostatectomy (RP) is lacking. We undertook an investigation to differentiate the innocuous recurrence of serum prostate specific antigen (PSA) from that which heralds an eventual clinical failure (CF), and to determine if there is a period following RP when a patient is cured of clinical disease. MATERIALS AND METHODS: Men with clinically localized prostate cancer (PCA) undergoing RP (1987 to 1995) were identified from our longitudinal PCA registry. Outcome measurements were based on the detection of post-RP serum PSA 0.4 ng/ml or greater, clinical identification of cancer recurrence and disease related death. RESULTS: Following RP in 3,903 eligible men, 33% had a detectable PSA (median followup 8.8 years). Of these BFs 27% occurred after 5 or more disease-free years. Currently, 29% of all men with BF have clinical evidence of PCA, with 8% dying of PCA (median actuarial survival time from CF to death 9.8 years). Progression from BF to CF was not significantly altered by the disease-free interval (p = 0.544). A PSA doubling time less than 12 months significantly increased the risk of CF regardless of the interval from surgery. Risk factors for BF were significant throughout the duration of followup. CONCLUSIONS: Patients are at prolonged risk for BF and CF following RP. Regardless of the timing of the initial PSA recurrence the PSA doubling time is the most powerful predictor of progression, stratifying patients with BF into high and low risk groups for CF.

Urinary albumin to osmolality ratio predicts 24-hour urine albumin excretion in diabetes mellitus.

BACKGROUND: Urinary albumin to creatinine ratio (ACR) in a single urine sample has been proposed to provide an estimate of microalbuminuria by adjusting for variability in urine concentrations. We hypothesized that adjusting the urine albumin concentration of single-void specimens for actual urine osmolality (urinary albumin to osmolality ratio [AOR]) may provide a more accurate estimate of 24-hour urine albumin excretion rates (AERs). METHODS: Patients with diabetes mellitus (DM; n = 136) had urinary concentrations of albumin, glucose, and creatinine and osmolality measured on single-void samples, and albumin levels, on 24-hour samples. Microalbuminuria is defined as an AER between 30 and 300 mg/d. RESULTS: Correlation between AOR on single-void samples and AER on 24-hour samples (r = 0.87; P < 0.001) was similar to that between ACR and AER (r = 0.88; P < 0.001). Using a cutoff value of 18.4 mg/kg/mOsm x 10(2) (18.4 mg/mmol x 10(2)) for AOR resulted in a sensitivity and specificity of 82% and 86% in detecting microalbuminuria, respectively. The area under the curve (AUC) for AOR was 0.89. Using a cutoff value of 15.0 mg/g (1.7 mg/mmol) for ACR resulted in a sensitivity and specificity of 85% and 85% in detecting microalbuminuria, respectively. The AUC for ACR was 0.90. The ability of AOR to predict AER was maintained at varying degrees of glycosuria (glucose < 100 mg/dL [<5.5 mmol/L]; r = 0.77; 100 to 750 mg/dL [5.5 to 42 mmol/L]; r = 0.85; and >750 mg/dL [>42 mmol/L]; r = 0.92). CONCLUSION: Urinary AOR correlates closely with 24-hour microalbuminuria determination, and the correlation is not appreciably affected by glycosuria. Thus, AOR can be used as an alternative test to ACR in the assessment of microalbuminuria in the population with DM.