Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease.

BACKGROUND: To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. METHODS: Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. RESULTS: At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. CONCLUSIONS: Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. CLINICAL TRIAL REGISTRATION NUMBER: NCT02511418.

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials.

The rate of renal disease progression varies widely among patients with autosomal dominant polycystic kidney disease (ADPKD), necessitating optimal patient selection for enrollment into clinical trials. Patients from the Mayo Clinic Translational PKD Center with ADPKD (n=590) with computed tomography/magnetic resonance images and three or more eGFR measurements over ≥6 months were classified radiologically as typical (n=538) or atypical (n=52). Total kidney volume (TKV) was measured using stereology (TKVs) and ellipsoid equation (TKVe). Typical patients were randomly partitioned into development and internal validation sets and subclassified according to height-adjusted TKV (HtTKV) ranges for age (1A-1E, in increasing order). Consortium for Radiologic Imaging Study of PKD (CRISP) participants (n=173) were used for external validation. TKVe correlated strongly with TKVs, without systematic underestimation or overestimation. A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients. When 1A-1E classifications were used instead of log2HtTKV, eGFR slopes were significantly different among subclasses and, except for 1A, different from those in healthy kidney donors. The equation derived from the development set predicted eGFR in both validation sets. The frequency of ESRD at 10 years increased from subclass 1A (2.4%) to 1E (66.9%) in the Mayo cohort and from 1C (2.2%) to 1E (22.3%) in the younger CRISP cohort. Class and subclass designations were stable. An easily applied classification of ADPKD based on HtTKV and age should optimize patient selection for enrollment into clinical trials and for treatment when one becomes available.

Oncological outcomes following radical prostatectomy for patients with pT4 prostate cancer.

OBJECTIVES: Radical prostatectomy (RP) for locally advanced prostate cancer may reduce the risk of metastasis and cancer-specific death. Herein, we evaluated the outcomes for patients with pT4 disease treated with RP. MATERIALS AND METHODS: Among 19,800 men treated with RP at Mayo Clinic from 1987 to 2010, 87 were found to have pT4 tumors. Biochemical recurrence (BCR)-free survival, systemic progression (SP) free survival and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to assess the association of clinic-pathological features with outcome. RESULTS: Median follow-up was 9.8 years (IQR 3.6, 13.4). Of the 87 patients, 50 (57.5%) were diagnosed with BCR, 30 (34.5%) developed SP, and 38 (43.7%) died, with 11 (12.6%) dying of prostate cancer. Adjuvant androgen deprivation therapy was administered to 77 men, while 32 received adjuvant external beam radiation therapy. Tenyear BCR-free survival, SP-free survival, and OS was 37%, 64%, and 70% respectively. On multivariate analysis, the presence of positive lymph nodes was marginally significantly associated with patients' risk of BCR (HR: 1.94; p=0.05), while both positive lymph nodes (HR 2.96; p=0.02) and high pathologic Gleason score (HR 1.95; p=0.03) were associated with SP. CONCLUSIONS: Patients with pT4 disease may experience long-term survival following RP, and as such, when technically feasible, surgical resection should be considered in the multimodal treatment approach to these men.

Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria.

Stone formation and nephrocalcinosis are both very common features of primary hyperoxaluria, yet the extent of each disease varies markedly between patients. Here we studied whether kidney damage from nephrocalcinosis and/or stone related events contributed to end-stage kidney disease (ESKD). Clinical information was analyzed from 348 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria registry and included demographic, laboratory and imaging features. Among all patients there were 277 with type 1, 37 with type 2, and 34 with type 3 primary hyperoxaluria. Overall, 58% passed a stone (mean 0.3/year) and one or more urologic procedures were required by 70% of patients (mean 0.15/year). Nephrocalcinosis was found in 34% of patients, including 41% with type 1 primary hyperoxaluria. High urine oxalate was associated with increased risk for both nephrocalcinosis and stone number, while low urine citrate was a risk factor for stone events and stone number. After adjustment for the type of primary hyperoxaluria, diagnosis by family screening and age at first image, the overall adjusted hazard ratio for ESKD among those with a history of nephrocalcinosis was 1.7 [95% CI 1.0-3.0], while the risk was 4.0 [1.9-8.5] for new onset nephrocalcinosis during follow-up. In contrast, the number of stones and stone events were not significantly associated with ESKD risk. Thus, nephrolithiasis and nephrocalcinosis appear to be pathophysiologically distinct entities. The presence of nephrocalcinosis implies increased risk for ESKD.

Kidney stones are common after bariatric surgery.

Obesity, a risk factor for kidney stones and chronic kidney disease (CKD), is effectively treated with bariatric surgery. However, it is unclear whether surgery alters stone or CKD risk. To determine this we studied 762 Olmsted County, Minnesota residents who underwent bariatric surgery and matched them with equally obese control individuals who did not undergo surgery. The majority of bariatric patients underwent standard Roux-en-Y gastric bypass (RYGB; 78%), with the remainder having more malabsorptive procedures (very long limb RYGB or biliopancreatic diversion/duodenal switch; 14%) or restrictive procedures (laparoscopic banding or sleeve gastrectomy; 7%). The mean age was 45 years with 80% being female. The mean preoperative body mass index (BMI) was 46.7 kg/m(2) for both cohorts. Rates of kidney stones were similar between surgery patients and controls at baseline, but new stone formation significantly increased in surgery patients (11.0%) compared with controls (4.3%) during 6.0 years of follow-up. After malabsorptive and standard surgery, the comorbidity-adjusted hazard ratio of incident stones was significantly increased to 4.15 and 2.13, respectively, but was not significantly changed for restrictive surgery. The risk of CKD significantly increased after the malabsorptive procedures (adjusted hazard ratio of 1.96). Thus, while RYGB and malabsorptive procedures are more effective for weight loss, both are associated with increased risk of stones, while malabsorptive procedures also increase CKD risk.

Salvage lymph node dissection for prostate cancer nodal recurrence detected by 11C-choline positron emission tomography/computerized tomography.

PURPOSE: We report salvage lymph node dissections for prostate cancer nodal recurrence detected by (11)C-choline positron emission tomography/computerized tomography in the setting of increasing prostate specific antigen after radical prostatectomy. MATERIALS AND METHODS: Retrospective chart review was performed for all patients who underwent salvage lymph node dissection for prostate cancer nodal recurrence. Only patients previously treated with radical prostatectomy were included in the study and those with evidence of local recurrence were excluded from analysis. Primary end points included biochemical recurrence, systemic progression and cancer specific mortality. RESULTS: From 2009 to 2013, 52 men underwent salvage lymph node dissection. Before salvage lymph node dissection 78.8% (41 of 52) had some form of therapy after radical prostatectomy. Median age at salvage lymph node dissection was 60 years and median prostate specific antigen was 2.2 ng/ml (IQR 1.4-3.7). The median number of lymph nodes dissected was 21.5 (IQR 16-30) and the median number of positive nodes was 3.5 (IQR 1.2-6.5). Since salvage lymph node dissection 46.2% of the men (24 of 52) have had no further treatment, 34.6% (18 of 52) are on hormonal therapy and 19.2% (10 of 52) have received multiple different treatments. At the last followup at a median of 20 months (IQR 8-33), 57.7% (30 of 52) had prostate specific antigen remain less than 0.2 ng/ml, 75% (39 of 52) remained free of systemic progression and 96.2% of the men (50 of 52) were alive. Two patients died of prostate cancer. Three-year biochemical recurrence-free, systemic progression-free and cancer specific survival was 45.5%, 46.9% and 92.5%, respectively. CONCLUSIONS: This represents the largest U.S. series of salvage lymph node dissection in the setting of lymph node metastatic prostate cancer after radical prostatectomy. Although followup was short and the study lacked a randomized control group, salvage lymph node dissection may represent a valid treatment option.

The ROKS nomogram for predicting a second symptomatic stone episode.

Most patients with first-time kidney stones undergo limited evaluations, and few receive preventive therapy. A prediction tool for the risk of a second kidney stone episode is needed to optimize treatment strategies. We identified adult first-time symptomatic stone formers residing in Olmsted County, Minnesota, from 1984 to 2003 and manually reviewed their linked comprehensive medical records through the Rochester Epidemiology Project. Clinical characteristics in the medical record before or up to 90 days after the first stone episode were evaluated as predictors for symptomatic recurrence. A nomogram was developed from a multivariable model based on these characteristics. There were 2239 first-time adult kidney stone formers with evidence of a passed, obstructing, or infected stone causing pain or gross hematuria. Symptomatic recurrence occurred in 707 of these stone formers through 2012 (recurrence rates at 2, 5, 10, and 15 years were 11%, 20%, 31%, and 39%, respectively). A parsimonious model had the following risk factors for recurrence: younger age, male sex, white race, family history of stones, prior asymptomatic stone on imaging, prior suspected stone episode, gross hematuria, nonobstructing (asymptomatic) stone on imaging, symptomatic renal pelvic or lower-pole stone on imaging, no ureterovesicular junction stone on imaging, and uric acid stone composition. Ten-year recurrence rates varied from 12% to 56% between the first and fifth quintiles of nomogram score. The Recurrence of Kidney Stone nomogram identifies kidney stone formers at greatest risk for a second symptomatic episode. Such individuals may benefit from medical intervention and be good candidates for prevention trials.

Extended antimicrobial use in patients undergoing percutaneous nephrolithotomy and associated antibiotic related complications.

PURPOSE: Despite global concern about antibiotic related complications the duration of antibiotic therapy at percutaneous nephrolithotomy varies based on individual physician practice. We evaluated perioperative antibiotic related complications in patients who received extended antimicrobial therapy at percutaneous nephrolithotomy. MATERIALS AND METHODS: We reviewed the records of 227 consecutive patients treated with percutaneous nephrolithotomy from 2009 to 2013. Patients with positive urine or stone cultures received extended antimicrobial treatment. All others received 7 days of empirical therapy preoperatively and postoperatively. Adverse antibiotic related events were recorded for up to 3 months. RESULTS: The median duration of antibiotic therapy was 14 days (IQR 14-34). Perioperatively 143 (63%), 67 (30%), 75 (33%) and 41 patients (18%) received nitrofurantoin, trimethoprim/sulfamethoxazole, fluoroquinolones and other antibiotics, respectively. Antibiotic related complications developed in 23 patients (10%) at a median of 12 days (IQR 8-19). Common complications included rash in 7 cases (3%), gastrointestinal upset in 6 (3%) and Clostridium difficile colitis in 1 (0.4%). Trimethoprim/sulfamethoxazole was associated with an increased likelihood of an adverse event (p = 0.04) but patient age, gender, and therapy type (therapeutic vs prophylactic) and duration were not. Finally, antibiotic and multidrug resistance developed in 4 (36%) and 3 patients (27%), respectively, who experienced a urinary tract infection. CONCLUSIONS: We report a low rate of adverse antibiotic related events in patients treated with percutaneous nephrolithotomy who received extended perioperative antibiotic therapy. Exposure to trimethoprim/sulfamethoxazole was the only identifiable risk factor for a complication. These findings should be considered when counseling patients on the risks of perioperative antimicrobial therapy at percutaneous nephrolithotomy.

Thiazide diuretic prophylaxis for kidney stones and the risk of diabetes mellitus.

PURPOSE: Thiazide diuretics used to treat hypertension are associated with a modest risk of diabetes mellitus. It is unknown if there is a similar risk with kidney stone prevention. MATERIALS AND METHODS: We identified and validated incident stone formers in Olmsted County, Minnesota from 1984 to 2011 with manual review of medical records using the Rochester Epidemiology Project. The risk of diabetes mellitus after thiazide therapy was evaluated with and without multivariate adjustment for hypertension, age, gender, race, family history of stones, body mass index and number of stone events. RESULTS: Among 2,350 incident stone formers with a median followup of 10 years, 332 (14%) were treated with thiazide diuretics at some point after the first stone event and 84 (3.6%) received the thiazide diuretic only for kidney stone prevention. Stone formers who received thiazide diuretics were more likely to be older, have hypertension, have higher body mass index and have more stone events. The incidence of diabetes mellitus at 10 years after the first stone event was 9.2% in the group that received thiazide diuretics vs 4.2% in those who did not (HR 2.91; 95% CI 2.02, 4.20). After multivariate adjustment the risk of diabetes mellitus was attenuated (HR 1.20; 95% CI 0.78, 1.83). The risk of diabetes mellitus among those receiving thiazide diuretics solely for kidney stones was further attenuated (multivariate adjusted HR 0.80; 95% CI 0.28, 2.23). CONCLUSIONS: Thiazide diuretic use for kidney stone prophylaxis was not associated with a high risk of diabetes mellitus. Larger studies are needed to determine if there is a modest risk of diabetes mellitus with thiazide diuretics.

Phenotypic characterization of kidney stone formers by endoscopic and histological quantification of intrarenal calcification.

Interstitial Randall's plaques and collecting duct plugs are distinct forms of renal calcification thought to provide sites for stone retention within the kidney. Here we assessed kidney stone precursor lesions in a random cohort of stone formers undergoing percutaneous nephrolithotomy. Each accessible papilla was endoscopically mapped following stone removal. The percent papillary surface area covered by plaque and plug were digitally measured using image analysis software. Stone composition was determined by micro-computed tomography and infrared analysis. A representative papillary tip was biopsied. The 24-h urine collections were used to measure supersaturation and crystal growth inhibition. The vast majority (99%) of stone formers had Randall's plaque on at least 1 papilla, while significant tubular plugging (over 1% of surface area) was present in about one-fifth of patients. Among calcium oxalate stone formers the amount of Randall's plaque correlated with higher urinary citrate levels. Tubular plugging correlated positively with pH and brushite supersaturation but negatively with citrate excretion. Lower urinary crystal growth inhibition predicted the presence of tubular plugging but not plaque. Thus, tubular plugging may be more common than previously recognized among patients with all types of stones, including some with idiopathic calcium oxalate stones.

Effect of age on the clinical presentation of incident symptomatic urolithiasis in the general population.

PURPOSE: We characterized variation in the clinical presentation between older and younger first time symptomatic stone formers in the general population. MATERIALS AND METHODS: We studied a random sample of Olmsted County, Minnesota residents with their first diagnostic code for urolithiasis between 1984 and 2003. Chart validated symptomatic stone formers had a confirmed stone by imaging or stone passage. Clinical presentation characteristics were compared between age groups. RESULTS: Among the 3,473 charts reviewed there were 1,590 validated incident symptomatic stone formers (mean age 43 years, range 18 to 96). Older individuals were more likely to present with atypical or no pain, fever, diarrhea, pyuria, urinary tract infections and bacteremia (p <0.001). Stone size and location did not differ by patient age. Calcium phosphate stone disease was associated with younger age, while uric acid stone and atypical stone composition was associated with older age (p <0.001). Older individuals were less likely to pass the stone spontaneously and were more likely to require surgical intervention (p <0.001). Surgical intervention was required in 516 (32.5%) individuals. Younger individuals were more likely to undergo ureteroscopy while older individuals were more likely to undergo shock wave lithotripsy, temporizing stent placement and percutaneous nephrolithotomy. CONCLUSIONS: The detection of stone disease in older individuals can be challenging due to atypical pain or absence of pain, as well as the presence of other comorbid conditions such as urinary tract infections and diarrhea. A higher index of suspicion for urolithiasis may be needed in the elderly for a more timely diagnosis and intervention to prevent morbidity.

The impact of clinical stage on prostate cancer survival following radical prostatectomy.

PURPOSE: Clinical stage has been incorporated into multiple risk stratification models for patients with newly diagnosed prostate cancer. However, the independent prognostic value of this variable remains open to debate. In this study we evaluated the association of clinical stage with death from prostate cancer in men who underwent radical prostatectomy and assessed for changes in its prognostic value over time. MATERIALS AND METHODS: We reviewed the records of 14,842 consecutive patients who underwent radical prostatectomy at our institution between 1970 and 2008 without having received preoperative hormone or radiation therapy. Postoperative disease recurrence was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariate Cox proportional hazard regression models were used to analyze the association of clinical stage with outcome. RESULTS: A total of 5,725 (38.6%) men were classified as having cT1 tumors, 8,160 (55.0%) cT2 tumors and 957 (6.4%) cT3 disease. On univariate analysis clinical stage was significantly associated with postoperative biochemical recurrence, systemic progression and death from prostate cancer (p <0.001 for each). Moreover on multivariate analysis clinical stage was significantly associated with death from cancer for patients treated before (1.45, p = 0.006) and those treated during (1.96, p <0.001) the prostate specific antigen era. Furthermore, the incorporation of clinical stage into contemporary risk stratification improved the prediction of cancer specific survival (c statistic 0.782 without and 0.802 with clinical stage). CONCLUSIONS: Clinical stage is significantly associated with systemic progression and death from prostate cancer. Inclusion of this variable in multivariate prediction models improves the prediction of systemic progression and cancer specific survival.

Risk stratification of patients with extraprostatic extension and negative lymph nodes at radical prostatectomy: identifying optimal candidates for adjuvant therapy.

PURPOSE: Randomized trials demonstrate a benefit to adjuvant radiation therapy after radical prostatectomy in patients with pathologically locally advanced tumors. However, limited data exist on natural history, specifically in men with extraprostatic extension, and wide variability in outcomes has been reported. We evaluated long-term outcomes in patients with pT3aN0 disease and determined predictors of recurrence in these men. MATERIALS AND METHODS: We evaluated 20,744 patients who underwent radical prostatectomy at our clinic between 1987 and 2011. Of these men 1,073 with pT3aN0 disease were identified who did not receive neoadjuvant or adjuvant therapy. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method. Multivariate stepwise selection was used to develop a prognostic model for biochemical recurrence. RESULTS: Median followup after radical prostatectomy was 10.9 years, during which 449 patients experienced biochemical recurrence. On stepwise selection preoperative prostate specific antigen (HR 1.3, p=0.0003), clinical tumor stage (HR 1.2, p=0.001), pathological Gleason score (HR 1.9, p<0.0001), surgical margin status (HR 1.6, p<0.0001) and detectable first postoperative prostate specific antigen (HR 2.2, p<0.0001) were significantly associated with biochemical recurrence. Cumulative weighted scores of these variables were used to stratify patients into quintiles according to biochemical recurrence risk. The 15-year biochemical recurrence-free survival rate in the lowest to the highest risk group was 70%, 56%, 44%, 34% and 25%, respectively (p<0.0001). The c-index for this model was 0.69. CONCLUSIONS: We present a model to individualize the estimation of biochemical recurrence in men with pT3aN0 disease at radical prostatectomy. These data may be used for patient counseling, specifically in regard to risk stratification when discussing secondary therapy.

Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population.

PURPOSE: Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. MATERIALS AND METHODS: A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. RESULTS: The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001). CONCLUSIONS: Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer.

Interaction of adjuvant androgen deprivation therapy with patient comorbidity status on overall survival after radical prostatectomy for high-risk prostate cancer.

BACKGROUND: To evaluate the impact of adjuvant hormonal therapy after radical prostatectomy on overall survival in high-risk prostate cancer patients, stratified by comorbidity status. METHODS: We identified 1247 patients who underwent radical prostatectomy from 1988 to 2004 for high-risk prostate cancer, as defined by National Comprehensive Cancer Network classification. Comorbidity status was stratified by Charlson Comorbidity Index as 0, 1 or >2, as well as by the presence or absence of cardiovascular disease. Overall survival was estimated by the Kaplan-Meier method, and compared within each comorbidity category/adjuvant hormonal therapy strata with the log-rank test. RESULTS: Median patient age was 65 years, and the median postoperative follow up was 11.2 years. In total, 419 patients (34%) received adjuvant hormonal therapy. The distribution of Charlson Comorbidity Index was 0, 1 and ≥ 2 in 861 (69%), 244 (20%) and 142 (11%) patients, respectively. The 10-year overall survival for patients who received adjuvant hormonal therapy versus those who did not was 75% versus 82% (P=0.54) for patients with Charlson Comorbidity Index=0, 72% versus 76% (P=0.83) with Charlson Comorbidity Index=1, and 70% versus 68% (P=0.33) with Charlson Comorbidity Index ≥ 2. Meanwhile, 155 (12%) patients had cardiovascular disease, and the 10-year overall survival for patients with cardiovascular disease who received adjuvant hormonal therapy was 72%, compared with 76% without adjuvant hormonal therapy (P=0.97). On multivariate analysis, receipt of adjuvant hormonal therapy was not associated with non-prostate cancer mortality (P=0.24). CONCLUSIONS: Adjuvant hormonal therapy after radical prostatectomy for high-risk prostate cancer does not increase non-prostate cancer mortality, even among patients with multiple comorbidities. Additional studies are warranted to determine optimal multimodal treatment approach for high-risk patients.

Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.

BACKGROUND: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation. METHODS: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides. RESULTS: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls. CONCLUSIONS: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.

Temporal trends in incidence of kidney stones among children: a 25-year population based study.

PURPOSE: We conducted a population based pediatric study to determine the incidence of symptomatic kidney stones during a 25-year period and to identify factors related to variation in stone incidence during this period. MATERIALS AND METHODS: The Rochester Epidemiology Project was used to identify all patients younger than 18 years who were diagnosed with kidney stones in Olmsted County, Minnesota from 1984 to 2008. Medical records were reviewed to validate first time symptomatic stone formers with identification of age appropriate symptoms plus stone confirmation by imaging or passage. The incidence of symptomatic stones by age, gender and study period was compared. Clinical characteristics of incident stone formers were described. RESULTS: A total of 207 children received a diagnostic code for kidney stones, of whom 84 (41%) were validated as incident stone formers. The incidence rate increased 4% per calendar year (p = 0.01) throughout the 25-year period. This finding was due to a 6% yearly increased incidence in children 12 to 17 years old (p = 0.02 for age × calendar year interaction) with an increase from 13 per 100,000 person-years between 1984 and 1990 to 36 per 100,000 person-years between 2003 and 2008. Computerized tomography identified the stone in 6% of adolescent stone formers (1 of 18) from 1984 to 1996 vs 76% (34 of 45) from 1997 to 2008. The incidence of spontaneous stone passage in adolescents did not increase significantly between these 2 periods (16 vs 18 per 100,000 person-years, p = 0.30). CONCLUSIONS: The incidence of kidney stones increased dramatically among adolescents in the general population during a 25-year period. The exact cause of this finding remains to be determined.

Natural history of biochemical recurrence after radical prostatectomy with adjuvant radiation therapy.

PURPOSE: We evaluated the long-term outcome of patients with biochemical recurrence following radical prostatectomy with adjuvant radiation therapy and determined predictors of systemic progression in these men. MATERIALS AND METHODS: We identified 134 men with biochemical recurrence following radical prostatectomy plus adjuvant radiation therapy for pT(any)N0M0 disease. Median followup was 13.1 years. Survival after biochemical recurrence was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to analyze clinicopathological variables associated with systemic progression after biochemical recurrence. RESULTS: Overall, 41 patients (31.5%) with biochemical recurrence experienced systemic progression and 57 (42.5%) died, including 19 (14.2%) of prostate cancer. Median systemic progression-free and cancer specific survival were not attained at 15 years of followup after biochemical recurrence. Median time from prostatectomy to recurrence was 3.3 years. Ten-year cancer specific survival was not significantly different for patients who experienced biochemical recurrence less and greater than 3.3 years after radical prostatectomy (83% and 83%, respectively, p = 0.39). Moreover, on multivariate analysis increased pathological Gleason score (HR 1.78, p = 0.02) and rapid prostate specific antigen doubling time (less than 6-month doubling time HR 11.39, p <0.0001) were significantly associated with the risk of systemic progression. CONCLUSIONS: The natural history of biochemical recurrence after radical prostatectomy plus adjuvant radiation therapy is heterogeneous with only a minority of these men experiencing systemic progression and death from prostate cancer. The decision to begin additional therapies in such patients must balance the risk of disease progression, based on pathological Gleason score and postoperative prostate specific antigen doubling time, against the cost and morbidity of treatment.

Somatostatin analog therapy for severe polycystic liver disease: results after 2 years.

BACKGROUND: We showed in a randomized double-blinded placebo-controlled clinical trial that octreotide long-acting repeatable depot.® (OctLAR(®)) for 12 months reduces kidney and liver growth in autosomal dominant polycystic kidney patients with severe polycystic liver disease (PLD) and liver growth in patients with severe isolated PLD. We have now completed an open-label extension for one additional year to assess safety and clinical benefits of continued use of OctLAR for 2 years (O → O) and examined drug effect in the placebo group who crossed over to OctLAR in Year 2 (P → O). METHODS: The primary end point was change in total liver volume (TLV) measured by magnetic resonance imaging (MRI); secondary end points were changes in total kidney volume (TKV) measured by MRI, glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs and laboratory parameters. RESULTS: Forty-one of 42 patients received OctLAR (n = 28) or placebo (n = 14) in Year 1 and received OctLAR in Year 2 (maximum dose 40 mg). Patients originally randomized to placebo (P → O) showed substantial reduction in TLV after treatment with OctLAR in Year 2 (Δ% -7.66 ± 9.69%, P = 0.011). The initial reduction of TLV in the OctLAR group (O → O) was maintained for 2 years (Δ% -5.96 ± 8.90%), although did not change significantly during Year 2 (Δ% -0.77 ± 6.82%). OctLAR inhibited renal enlargement during Year 1 (Δ% +0.42 ± 7.61%) in the (O → O) group and during Year 2 (Δ% -0.41 ± 9.45%) in the (P → O) group, but not throughout Year 2 (Δ% +6.49 ± 7.08%) in the (O → O) group. Using pooled analyses of all individuals who received OctLAR for 12 months, i.e. in Year 1 for O → O patients and Year 2 for P → O patients, average reduction in TLV was -6.08 ± 7.58% (P = 0.001) compared to net growth of 0.9 ± 8.35% in the original placebo group. OctLAR-treated individuals continued to experience improvements in QOL in Year 2, although overall physical and mental improvements were not significant during Year 2 compared to Year 1. Changes in GFR were similar in both groups. CONCLUSION: Over 2 years, OctLAR significantly reduced the rate of increase in TLV and possibly the rate of increase in TKV.