Can nomograms improve our ability to select candidates for active surveillance for prostate cancer?

BACKGROUND: Our goal was to compare the ability of active surveillance (AS) criteria and preoperative nomograms to identify patients with pathologically low-risk prostate cancer. METHODS: The study cohort consisted of 402 radical prostatectomy patients with Gleason 6 prostate cancer on at least 10-core biopsy. In this group, we analyzed the ability of Kattan and Truong nomograms to select patients with Gleason 3+3 or 3+4 organ-confined prostate cancer, and compared it with that of AS criteria of John Hopkins (JH) and University of California at San Francisco (UCSF) medical centers, and Prostate Cancer Research International: Active Surveillance (PRIAS) study. The performance of each tool was evaluated with respect to discrimination and predictive accuracy. RESULTS: About 30% of patients were upgraded and 8% were upstaged in the final pathology. The nomograms demonstrated slightly higher discrimination in detecting organ-confined Gleason 3+3 and 3+4 disease. The predictive accuracy of the nomograms in selecting patients with low-grade organ-confined prostate cancer was superior to that of JH and UCSF criteria but not to PRIAS criteria. Furthermore, the nomograms were unable to select larger subgroups of patients with the same prevalence of Gleason 3+3 organ-confined prostate cancer as in men who met the PRIAS criteria. No difference was seen between the studied nomograms and AS criteria in their ability to identify patients with Gleason 3+4 organ-confined prostate cancer. CONCLUSIONS: PRIAS criteria demonstrate optimal balance between sensitivity and specificity and are not inferior to the available pathological nomograms in selecting patients with low-grade organ-confined prostate cancer.

Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation.

Hypoxia inducible factor-2α (HIF-2α) has a critical role in renal tumorigenesis. HIF-2α is stabilized in von Hippel-Lindau (VHL)-deficient renal cell carcinoma through mechanisms that require ongoing mRNA translation. Mammalian target of rapamycin (mTOR) functions in two distinct complexes: Raptor-associated mTORC1 and Rictor-associated mTORC2. Rictor-associated mTORC2 complex has been linked to maintaining HIF-2α protein in the absence of VHL; however, the mechanisms remain to be elucidated. Although Raptor-associated mTORC1 is a known key upstream regulator of mRNA translation, initiation and elongation, the role of mTORC2 in regulating mRNA translation is not clear. Complex assembly of the mRNA cap protein, eukaryotic translation initiation factor 4 (eIF4)E, with activators (eIF4 gamma (eIF4G)) and inhibitors (eIF4E-binding protein 1 (4E-BP1)) are rate-limiting determinants of mRNA translation. Our laboratory has previously demonstrated that reactive oxygen species, mediated by p22(phox)-based Nox oxidases, are enhanced in VHL-deficient cells and have a role in the activation of Akt on S473, a site phosphorylated by the mTORC2 complex. In this study, we examined the role of Rictor-dependent regulation of HIF-2α through eIF4E-dependent mRNA translation and examined the effects of p22(phox)-based Nox oxidases on TORC2 regulation. We demonstrate for the first time that mTORC2 complex stability and activation is redox sensitive, and further defined a novel role for p22(phox)-based Nox oxidases in eIF4E-dependent mRNA translation through mTORC2. Furthermore, we provide the first evidence that silencing of p22(phox) reduces HIF-2α-dependent gene targeting in vitro and tumor formation in vivo. The clinical relevance of these studies is demonstrated.

Kidney pericytes: a novel therapeutic target in interstitial fibrosis.

Chronic Kidney Disease affects approximately 8% of the population and contributes considerably to premature morbidity and mortality. Recently reported studies have highlighted an important role for resident microvascular pericytes in the pathogenesis of kidney fibrosis. Pericytes are emerging as the predominant source of the activated, matrix depositing, stromal cell population seen in progressive fibrosis. Further, pericyte activation leads to their detachment from the vasculature, triggers unstable microvasculature and leads to rarefaction. Strategies to modulate pericyte function in these processes are therefore therapeutically attractive. In this review we will first describe our current understanding of the structure and function of the pericyte and the role these cells play in angiogenesis and the pathogenesis of renal fibrosis. Novel therapeutic approaches targeting pericytes in murine models of renal disease will then be considered.

Health related quality of life assessment after radical prostatectomy in men with prostate specific antigen only recurrence.

PURPOSE: The health related quality of life assessment is becoming increasingly important among patients with prostate cancer. Meanwhile, treatment of patients with increasing prostate specific antigen (PSA) after radical retropubic prostatectomy remains controversial. We attempt to define the impact of PSA recurrence on the health related quality of life of patients after radical retropubic prostatectomy. MATERIALS AND METHODS: Of 604 consecutive patients who underwent radical retropubic prostatectomy between March 1991 and September 1998, 510 (84%) were available for followup. Each patient was mailed the RAND 36-Item Health Survey and University of California, Los Angeles, Prostate Cancer Index questionnaire. A total of 348 (70%) questionnaires were returned. Health related quality of life scores were then compared between patients with and without PSA recurrence. A multivariate analysis was also performed to elucidate further the cause of differences between the groups. RESULTS: Overall, 88 (25%) patients had PSA recurrence. In regard to health related quality of life there were small (less than 10%) but statistically significant differences in 2 of 4 physical health domains (RAND 36-Item Health Survey). There was a significant decrease in only 1 category of the mental health domain for patients with PSA recurrence. Only sexual function was statistically lower on the University of California, Los Angeles, Prostate Cancer Index. This result reflects the lower incidence of nerve sparing in these patients, as confirmed by the multivariate analysis. Overall patient satisfaction was similar between those with and without PSA recurrence (76% and 79%, respectively). CONCLUSIONS: Our study demonstrates small health related quality of life differences in patients with biochemical PSA recurrence versus those without. These findings provide a baseline assessment of general and disease specific health related quality of life domains among these patients. Future studies should focus on differences in the measure of cancer anxiety before and after administration of adjuvant therapy in these asymptomatic patients.

The use of radiography, urodynamic studies and cystoscopy in the evaluation of voiding dysfunction.

PURPOSE: Children with dysfunctional voiding disorder often undergo radiological, cystoscopic or urodynamic evaluation to identify an anatomical or organic cause. We determined the role of these studies in the evaluation, management and ultimate outcome of a large patient population with voiding dysfunction at a single institution. MATERIALS AND METHODS: We retrospectively evaluated the records of 1, 153 children with dysfunctional voiding disorder treated from 1990 to 1999. A thorough history and physical examination with specific emphasis on voiding patterns were done and urinalysis was performed in all cases. Ultrasound of the urinary system and excretory urography were done in 1,050 (91%) and 24 (2%) patients, respectively, while voiding cystourethrography was performed in 672 (58%), including 564 with a history of nonfebrile urinary tract infection. Cystoscopy and a formal urodynamic study were performed in 61 (5%) and 40 (3.5%) cases, respectively. RESULTS: Mean patient age at referral was 6 years (range 3 to 14). Of the children 74% were girls and 26% were boys. Physical examination of the abdomen, back, genitalia and neurological system was unremarkable in all cases. Ultrasound of the upper urinary system was normal in 1,018 patients (97%) and showed insignificant pyelectasis in 32 (3%). All 24 excretory urography studies were normal and voiding cystourethrography was normal in 470 of 672 cases (70%). Unilateral and bilateral low grade, and unilateral high grade reflux was present in 108, 19 and 3 patients, respectively. Urodynamic studies were performed in 40 children who did not respond to standard treatment. We noted detrusor instability in 16 patients, detrusor-sphincter dyssynergia in 6 and sensory abnormality in 3, while the study was completely normal in 10. Cystoscopy revealed normal findings in 17 cases, trabeculations in 21, inflammation in 20 and type 1 posterior urethral valves in 2. CONCLUSIONS: The incidence of upper tract changes and positive anatomical findings in children with voiding dysfunction is too low to justify routine radiological evaluation and cystoscopy. However, in those who present with a nonfebrile urinary tract infection there remains an important role for voiding cystourethrography. We do not recommend routine urodynamics in children with voiding disorder because this study does not change therapy or influence the final outcome. Thorough history and physical examination lead to the correct diagnosis and treatment in the majority of children. A focus on correcting faulty voiding behavior with the judicious administration of antibiotics and anticholinergic therapy leads to a favorable outcome in most cases.

The role of hypercalciuria in a subgroup of dysfunctional voiding syndromes of childhood.

PURPOSE: Idiopathic hypercalciuria is believed to be the cause of a variety of urinary tract complaints in clinical pediatrics, including urinary frequency, urgency, and/or dysuria, often associated with gross or microscopic hematuria. In children noncalculous manifestations of idiopathic hypercalciuria are reportedly more common than urolithiasis. We determine the use of the calcium-to-creatinine ratio for the evaluation of different subsets of functional voiding disorders. MATERIALS AND METHODS: We retrospectively evaluated 288 patients with functional voiding disorders during the last 8 years. Patients presenting with isolated urinary tract infection were not included in the study. A thorough history with emphasis on voiding patterns was elicited and a routine urinalysis was performed in all patients. Patients were divided into 5 groups of 22 with total gross hematuria and dysfunctional voiding pattern, 102 with microhematuria and dysfunctional voiding pattern, 66 with isolated childhood daytime frequency, 45 with the isolated dysuria syndrome and 53 with combined childhood frequency-urgency-dysuria syndrome. The season at presentation was noted to determine a seasonal pattern. In 149 patients urine was evaluated for a spot calcium-to-creatinine ratio. RESULTS: Mean age of the 95 (33%) males and 193 (67%) females was 6.1 years (range 2 to 14) and mean duration of symptoms was 10 months (1 week to 10 years). The incidence of idiopathic hypercalciuria was 28% in cases with gross hematuria and dysfunctional voiding, 30% with microscopic hematuria and dysfunctional voiding, 21% with pure childhood daytime frequency, 22% with pure dysuria, and 28% with frequency, urgency and dysuria. The patients were treated predominantly with behavioral therapy, correction of faulty voiding habits, anticholinergics and minor diet modification in some. Mean followup of 6.5 months (range 1 month to 10 years) was available for 153 patients (53%). Resolution of symptoms along with marked improvement in voiding habits was noted in 136 (89%) patients, moderate improvement in 10 (6.5%) and persistent symptoms with minimal improvement in 7 (4.5%). Treatment with thiazides was used in only 6 (2%) patients who had intractable symptoms and a markedly elevated urine calcium-to-creatinine ratio of whom 5 responded favorably. CONCLUSIONS: Idiopathic hypercalciuria may have a significant role in cases of functional voiding disorders. It affects the different subsets of voiding disorders with remarkable consistency but the exact mechanism remains unknown. Although a significant number of patients with voiding dysfunction have an elevated calcium-to-creatinine ratio, the majority respond to standard behavioral therapy and pharmacotherapy in the form of anticholinergics, and treatment directed toward hypercalciuria is not required in most cases.

Continent urinary reconstruction versus ileal conduit: a contemporary single-institution comparison of perioperative morbidity and mortality.

OBJECTIVES: To compare postoperative morbidity and mortality in a concurrent and contemporary series of patients who underwent radical cystectomy with ileal conduit versus orthotopic neobladder. METHODS: The data of 198 patients were reviewed, 117 with orthotopic reconstruction and 81 with ileal conduit during a 5-year time frame. Thirty-day morbidity, mortality, reoperative rates, and parameters associated with the surgical procedures were obtained from chart review. RESULTS: No perioperative or postoperative deaths occurred in either group. The median operative time for the ileal conduit was 201 minutes (range 140 to 373), and for the orthotopic neobladder, it was 270 minutes (range 230 to 425). The median blood loss was 389 and 474 mL, respectively. The median length of hospitalization was 8 days for the ileal conduit group and 7 days for the orthotopic neobladder group. Diversion-related complications recognized within 30 days that ultimately required a return to the operating room occurred in 3.4% of those with a neobladder and 1.2% of those with an ileal conduit. CONCLUSIONS: The orthotopic neobladder is a longer and technically more complex procedure than the ileal conduit procedure. However, no demonstrable difference in morbidity or perioperative complications were found between the two procedures in our review.

Functional lower urinary tract voiding outcomes after cystectomy and orthotopic neobladder.

PURPOSE: We reviewed our experience with orthotopic continent urinary reconstruction after radical cystectomy to determine the functional voiding patterns and compare different methods of reservoir construction. MATERIALS AND METHODS: The study included 100 consecutive patients who underwent cystectomy and orthotopic neobladder. Reservoir construction consisted of a W-shaped ileal reservoir in 40 patients, ileal reservoir with afferent limb in 26, a Padua ileal reservoir in 18, right colon in 14 and sigmoid colon in 2. The functional voiding outcome was determined by a detailed patient interview and chart review. RESULTS: There were no perioperative deaths. All patients regained good daytime urinary control and none required protective pads, although 18% used protective padding at night because of nocturnal leakage. Eight patients (8%) performed self-intermittent catheterization because of poor reservoir emptying. There were no substantial differences in outcomes among the various methods of reservoir construction. CONCLUSIONS: Excellent functional voiding outcomes are obtained with radical cystectomy and orthotopic bladder reconstruction. Comparable results can be achieved with use of either large bowel or ileum and with various methods of bowel folding as long as principles of preservation of the periurethral sphincter muscle, and construction of an adequate capacity and low pressure reservoir are maintained.