Prevalence and bother of patient-reported lower urinary tract symptoms in the muscular dystrophies.

INTRODUCTION: Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) are characterized by progressive muscle weakness and eventual loss of ambulation, and result from mutations in the dystrophin gene. Dystrophin is essential for skeletal muscle functioning but its role in smooth muscle function is not as well established. In a retrospective review, our group previously demonstrated that roughly half of these patients have at least one documented urologic diagnosis, most commonly being lower urinary tract symptoms (LUTS) and nephrolithiasis. To better understand the frequency of LUTS and the degree to which they impact quality of life in this patient population, we performed a cross-sectional evaluation. METHODS AND MATERIALS: Following IRB approval, a survey modified from multiple validated surveys was distributed to DMD and BMD patients. The survey contained questions derived from multiple validated questionnaires, including the American Urological Association Symptom Score and the Dysfunctional Voiding Symptoms Score, which assessed both the frequency of lower urinary tract symptoms (i.e. urinary urgency, frequency, enuresis, dysuria, and bowel function) as well as how bothersome patients found these symptoms. RESULTS: Of the 56 respondents (mean age 15.3; range 4-33), 40 (71.4%) reported at least one LUTS, most commonly urgency (n = 31, 55%) and hesitancy of stream (n = 32, 57%) (Figure). Although the majority of the patients reported being happy with their symptoms, 16% (n = 9) expressed dissatisfaction. We did not find any correlation between LUTS and disease progression, as measured by years non-ambulatory, on chi-square analysis. CONCLUSIONS: In this cross-sectional study of the frequency and degree of bother of LUTS in D/BMD patients, we found that a high percentage experience LUTS. Despite this high prevalence, the majority report that they are not especially bothered by these symptoms; however, over 16% express dissatisfaction with their current LUTS. With this patient population now living longer, this may become even more prevalent. Screening for bothersome LUTS in patients with DMD and BMD should be a part of disease management, with appropriate treatment or referral to a urologist for those bothered by their symptoms to positively impact their quality of life.

Cell cycle progression score predicts metastatic progression of clear cell renal cell carcinoma after resection.

BACKGROUND: The outcome of surgically resected, apparently localized, clear cell renal carcinoma (ccRCC) is uncertain. OBJECTIVE: To evaluate if cell cycle progression (CCP) gene expression can predict future metastasis. METHODS: Pathologic T2a-T3b tumors at University of Iowa were reviewed. Patients with known or suspected metastasis, lymph node involvement or who received neoadjuvant or adjuvant radiation, chemotherapy or immunotherapy were excluded. Case and control cohorts were defined as those who did or did not develop metastatic disease within 5 years. Measured levels of 31 cell cycle genes and 15 control genes from the tumor were calculated as a CCP score. Additionally, gene expression data for a separate ccRCC cohort was downloaded from The Cancer Genome Atlas (TCGA). RESULTS: Univariate analysis of 26 cases and 38 controls revealed that the CCP score predicted progression to metastasis (OR 2.65, p = 0.0091). In multivariate logistic regression modeling, CCP expression remained a significant independent predictor for progression (p = 0.026). The CCP score was also significantly associated with distant metastasis in the TCGA renal cancer cohort in both univariate (p = 1.0 × 10-9) and multivariate (p = 5.6 × 10-3) analysis. CONCLUSION: The CCP score has prognostic value in predicting metastatic progression after resection of organ-confined ccRCC.

Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma.

BACKGROUND: Dystroglycan (DG) is a cell-surface laminin receptor that links the cytoskeleton to the extracellular matrix in a variety of epithelial tissues. Its function as a matrix receptor requires extensive glycosylation of its extracellular subunit αDG, which involves at least 13 distinct genes. Prior work has shown loss of αDG glycosylation in an assortment of carcinomas, including clear cell renal cell carcinoma (ccRCC) though the cause (s) and functional consequences of this loss are still unclear. METHODS: Using The Cancer Genome Atlas (TCGA) database, we analyzed the DG glycosylation pathway to identify changes in mRNA expression and correlation with clinical outcomes. We validated our findings with a cohort of 65 patients treated with radical nephrectomy by analyzing DG glycosylation via immunohistochemistry and gene expression via qRT-PCR. RESULTS: Analysis of TCGA database revealed frequent dysregulation of a subset of DG glycosyltransferases. Most notably, there was a frequent, significant downregulation of GYLTL1B (LARGE2) and ISPD. DG glycosylation is frequently impaired in ccRCC patient samples and most strongly associates with downregulation of GYLTL1B. CONCLUSIONS: Reduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of αDG hypoglycosylation in ccRCC.

Urinalysis: case presentations for the primary care physician.

Urinalysis is useful in diagnosing systemic and genitourinary conditions. In patients with suspected microscopic hematuria, urine dipstick testing may suggest the presence of blood, but results should be confirmed with a microscopic examination. In the absence of obvious causes, the evaluation of microscopic hematuria should include renal function testing, urinary tract imaging, and cystoscopy. In a patient with a ureteral stent, urinalysis alone cannot establish the diagnosis of urinary tract infection. Plain radiography of the kidneys, ureters, and bladder can identify a stent and is preferred over computed tomography. Asymptomatic bacteriuria is the isolation of bacteria in an appropriately collected urine specimen obtained from a person without symptoms of a urinary tract infection. Treatment of asymptomatic bacteriuria is not recommended in nonpregnant adults, including those with prolonged urinary catheter use.

Morbidity and mortality of octogenarians following open radical cystectomy using a standardized reporting system.

INTRODUCTION: Recent evidence suggests that radical cystectomy may be underutilized in elderly patients, despite literature supporting acceptable morbidity/mortality in this population. However, there is a paucity of literature reporting complications in a standardized manner. Therefore, we evaluated the morbidity and mortality of octogenarians treated with radical cystectomy using the modified Clavien complication reporting system. MATERIALS AND METHODS: We retrospectively reviewed 443 consecutive patients undergoing radical cystectomy at our institution between January 2000 and April 2010. Patients who underwent cystectomy for benign conditions were excluded, leaving 359 for analysis. Baseline demographic and perioperative data were reviewed and all complications were graded. We compared the outcomes of our octogenarian population (n = 43) against our younger population (n = 316). RESULTS: There was no difference between octogenarians and the younger cohort for overall complication rates (86% versus 83%, p = 0.91), or major (33% versus 30%, p = 0.93) or minor (81% versus 80%, p = 0.91) complications. The younger group was more likely to encounter a late complication (41.5% versus 23.3%, p = 0.03). Those 80 years and older trended toward more intraoperative complications (21% versus 10%, p = 0.07). The older group also had a greater propensity for neurological complications (26% versus 11%, p = 0.02), but there was no difference in CVA (2% versus 3%, p = 0.22). There was no difference in mortality rates between the older and younger cohort (2.3% versus 0.9%, p = 0.95). CONCLUSIONS: Radical cystectomy is a morbid procedure regardless of patient age. Age alone should not preclude radical cystectomy in the elderly.

Urological manifestations of Duchenne muscular dystrophy.

PURPOSE: Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. MATERIALS AND METHODS: We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. RESULTS: Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. CONCLUSIONS: As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists.

Bladder Cancer Immunotherapy: BCG and Beyond.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1) immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.

Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth.

Obesity is a mounting health concern in the United States and is associated with an increased risk for developing several cancers, including renal cell carcinoma (RCC). Despite this, little is known regarding the impact of obesity on antitumor immunity. Because dendritic cells (DC) are critical regulators of antitumor immunity, we examined the combined effects of obesity and tumor outgrowth on DC function. Using a diet-induced obesity (DIO) model, DC function was evaluated in mice bearing orthotopic RCC and in tumor-free controls. Tumor-free DIO mice had profoundly altered serum cytokine and chemokine profiles, with upregulation of 15 proteins, including IL-1α, IL-17, and LIF. Tumor-free DIO mice had elevated percentages of conventional splenic DC that were impaired in their ability to stimulate naive T cell expansion, although they were phenotypically similar to normal weight (NW) controls. In DIO mice, intrarenal RCC tumor challenge in the absence of therapy led to increased local infiltration by T cell-suppressive DC and accelerated early tumor outgrowth. Following administration of a DC-dependent immunotherapy, established RCC tumors regressed in normal weight mice. The same immunotherapy was ineffective in DIO mice and was characterized by an accumulation of regulatory DC in tumor-bearing kidneys, decreased local infiltration by IFN-γ-producing CD8 T cells, and progressive tumor outgrowth. Our results suggest that the presence of obesity as a comorbidity can impair the efficacy of DC-dependent antitumor immunotherapies.

Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation.

Iron (Fe) is an essential micronutrient for virtually all organisms and serves as a cofactor for a wide variety of vital cellular processes. Although Fe deficiency is the primary nutritional disorder in the world, cellular responses to Fe deprivation are poorly understood. We have discovered a posttranscriptional regulatory process controlled by Fe deficiency, which coordinately drives widespread metabolic reprogramming. We demonstrate that, in response to Fe deficiency, the Saccharomyces cerevisiae Cth2 protein specifically downregulates mRNAs encoding proteins that participate in many Fe-dependent processes. mRNA turnover requires the binding of Cth2, an RNA binding protein conserved in plants and mammals, to specific AU-rich elements in the 3' untranslated region of mRNAs targeted for degradation. These studies elucidate coordinated global metabolic reprogramming in response to Fe deficiency and identify a mechanism for achieving this by targeting specific mRNA molecules for degradation, thereby facilitating the utilization of limited cellular Fe levels.