A. Bosio

Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years. Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3). Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.

Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy.

Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32–0.94); rs76507 adjHR 0.48 (95%CI 0.27–0.84); rs2854501 adjHR 0.25 (95%CI 0.12–0.52); rs2854509 adjHR 0.21 (95%CI 0.09–0.46); rs3213255 adjHR 0.46 (95%CI 0.26–0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of “risky” alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy.

Proteomic identification of Reticulocalbin 1 as potential tumor marker in renal cell carcinoma.

UNLABELLED Renal cell carcinoma (RCC) biomarkers are necessary for diagnosis and prognosis. They serve to monitor therapy response and follow-up, as drug targets, and therapy predictors in personalized treatments. Proteomics is a suitable method for biomarker discovery. Here we investigate differential protein expression in RCC, and we evaluate Reticulocalbin 1 (RCN1) use as a new potential marker. Neoplastic and healthy tissue samples were collected from 24 RCC patients during radical nephrectomy. Seven specimens were firstly processed by proteomic analysis (2-DE and MALDI-TOF) and 18 differentially expressed proteins from neoplastic and healthy renal tissues were identified. Among them, RCN1 was over-expressed in all cancer specimens analyzed by proteomics. Consequently RCN1 use as a potential marker was further evaluated in all 24 donors. RCN1 expression was verified by Western blotting (WB) and immunohistochemistry (IHC). WB analysis confirmed RCN1 over-expression in 21 out of 24 tumor specimens, whereas IHC displayed focal or diffuse expression of RCN1 in all 24 RCC tissues. Thus RCN1 appears as a potential marker for clinical approaches. A larger histopathological trial will clarify the prognostic value of RCN1 in RCC. BIOLOGICAL SIGNIFICANCE The present work aimed at finding new biomarkers for RCC - a life-threatening disease characterized by high incidence in Western countries - by performing differential proteomic analysis of neoplastic and normal renal tissues obtained from a small cohort of RCC patients. Some of the identified proteins have been previously associated to renal cancer however data confirming the possible use of these proteins in clinical practice are not available to date. By IHC we demonstrated that RCN1 could be easily employed in clinical practice, confirming RCN1 over-expression in RCC tissues of all examined patients, and weak protein expression in healthy renal tissues only in correspondence to the renal tubule section. These data indicate a promising role of RCN1 as a possible marker in RCC and indicate the proximal convoluted renal tubule as a putative origin point for RCC. Since IHC staining displayed different grades of intensity in tested tissues, we hypothesized that RCN1 could also be employed as a prognostic marker or as a response predictor for RCC-targeted therapy. To test such a hypothesis, a larger retrospective trial on paraffin-embedded tissues obtained from radical or partial nephrectomy of RCC patients is planned to be performed by our group.

Induction of hepatic drug metabolizing enzymes and interaction with carbon tetrachloride in rats after a single oral exposure to atrazine.

A single oral dose (430 mg/kg) of atrazine, a widely employed s-triazine herbicide, was administered to young male rats. There was a significant increase of the in vivo elimination of hexobarbital and a significant induction of the activity of 7-pentoxyresorufin-O-dealkylase, while cytochrome P-450 content and other mixed function oxidase activities remained unaltered. The administration of carbon tetrachloride (CCl4) to atrazine pretreated rats did not substantially augment the impairment of drug metabolizing enzymes brought about by CCl4 alone. Results suggest that atrazine behaves like a relatively weak inducer of phenobarbital-inducible families of cytochrome P-450.

Phosphodiesterase Type 5 Inhibitor Treatment for Erectile Dysfunction in Patients with End-Stage Renal Disease Receiving Dialysis or After Renal Transplantation

INTRODUCTION The phosphodiesterase type 5 (PDE5) inhibitors are generally well tolerated and effective for treating erectile dysfunction (ED), including in patients with significant comorbidity. Because of this benign safety profile, investigators have used PDE5 inhibitors to treat patients with ED and severe renal disease or those who have received renal transplants. AIM To assess safety and efficacy of PDE5 inhibitors in patients receiving dialysis or renal transplants. MAIN OUTCOME MEASURES Erectile function as assessed by the International Index of Erectile Function (IIEF) and Global Assessment Questions; adverse events (AEs). METHODS We reviewed published studies of PDE5 inhibitors in patients receiving dialysis or renal transplants. RESULTS In double-blind, placebo-controlled studies in patients receiving dialysis or renal transplants, sildenafil significantly improved erectile function as assessed by the IIEF, and 75-85% of patients reported improved erectile function on Global Assessment Questions; efficacy was more variable in less well-controlled studies. In >260 patients undergoing dialysis who received sildenafil in clinical studies, there were only six reported discontinuations because of AEs (headache [N=3], headache and nausea [N=1], gastrointestinal [N=1], and symptomatic blood pressure decrease [N=1]). In approximately 400 patients with renal transplants who received sildenafil, only three patients discontinued because of AEs. Vardenafil improved IIEF scores of up to 82% of renal transplant recipients in randomized, controlled studies (N=59, total), with no reported discontinuations because of AEs. Limited data also suggest benefit with tadalafil. CONCLUSIONS ED is common in patients undergoing renal dialysis or postrenal transplant and substantially affects patient quality of life. Sildenafil and vardenafil appear to be efficacious and well tolerated in patients receiving renal dialysis or transplant.

Evidence of Abnormal Tyrosine Phosphorylated Proteins in the Urine of Patients With Bladder Cancer: The Road Toward a New Diagnostic Tool?

PURPOSE Since changes in protein phosphorylation are a common feature of cancer cells, we analyzed phosphoproteins in the tissue and urine of patients with bladder cancer and assessed the diagnostic relevance of abnormally phosphorylated proteins as tumor markers. MATERIALS AND METHODS Enrolled in this study were 66 patients and 82 healthy volunteers. From the first 14 patients with bladder cancer we obtained samples of malignant and normal bladder tissue. All patients and volunteers provided a urine sample. Protein extracts of tissue specimens were separated by 2-dimensional gel electrophoresis for comparative analysis of neoplastic and normal tissue. Phosphoproteins were studied by Western blot and characterized by mass spectrometry. Urine samples were analyzed by 1-dimensional gel electrophoresis. Phosphoproteins were measured by affinity dot blotting. RESULTS Profound changes in the pattern of protein tyrosine phosphorylation were consistently, reproducibly observed in bladder cancer tissues. A total of 24 phosphorylated proteins were differentially expressed in cancer tissue and identified by mass spectrometry. Phosphoproteins were fairly stable in urine samples, leading to accumulation. Urinary tyrosine phosphoproteins showed the most remarkable changes in patients with cancer with an approximately 5-fold increase compared to levels in healthy controls. CONCLUSIONS To our knowledge we investigated for the first time the diagnostic potential of tissue and urinary tyrosine phosphoproteins for bladder carcinoma. Results indicate that phosphorylated proteins may represent a new, valuable class of urinary biomarkers for bladder cancer.

Leiomyomata of the genitourinary tract: A case series from the “rare urological neoplasm” registry

Abstract Objective. Leiomyomata are benign neoplasms that are rarely encountered in the genitourinary tract outside the uterus. Pathological confirmation is always needed for definitive diagnosis, in order to rule out malignancies such as leiomyosarcoma. In cases of small leiomyomata, a surveillance strategy can be suggested, although the preferred approach is complete resection. Prognosis seems to be excellent, but available data are based on few, inconsistent series, as is often the case with rare neoplasms. This article presents long-term follow-up data from the most heterogeneous series, in terms of anatomical location, currently available. Material and methods. The present series of 33 genitourinary leiomyomata was retrieved after joining the “rare urogenital neoplasm” registry of two Italian regions. Two pathologists jointly reviewed all pathological slides and confirmed the diagnosis of leiomyoma. Results. Sixteen cases were localized to the scrotum, eight to the bladder, five to the kidney, two to the prostate, one to the urethra and one to the penis. Mean patient age was 58.4 (range 32–80) years. Mean follow-up was 15.5 (range 2–20) years. Conclusions. In this highly heterogeneous series, the disease showed excellent long-term recurrence- and progression-free interval. The accuracy of pathological diagnosis, along with the indolent long-term course, make the role of active surveillance amenable for asymptomatic cases, particularly where surgery may result in overtreatment.

Prostate Cancer Treatment in Renal Transplant Recipients: A Systematic Review

The aim of this review was to summarize the current evidence and to highlight the main issues future research needs to address regarding prostate cancer (PCa) treatment in renal transpant recipients (RTRs). We conducted a search of AMED, Medline and Embase up to 17 November 2016 to investigate oncological and functional outcomes of PCa treatment in RTR. Type and use/protocols of immunosuppression and peri‐operative antibiotic drugs were also assessed. The search was implemented manually. Exclusion criteria were absence of full text or absence of information that allowed us to differentiate oncological and/or functional outcomes of each therapeutic approach used. We included 241 patients from 27 retrospective studies published between 1991 and 2016; seven of the studies were case–control and 20 were case series. We also considered nine case reports published between 1999 and 2016. Follow‐up ranged from 1 to 120 months. PCa was organ‐confined, with Gleason score ≤6 in 75.2% and 60.4% of patients. Surgery was the most frequent treatment used (n = 186), for which cancer‐specific (CSS) and overall survival (OS) rates were both 96.8%. Functional outcomes, including continence and erectile function, and complications were less frequently reported and were generally similar to those reported for radical prostatectomy (RP) in non‐RTRs. Other treatment methods in the patients included in the review were radiotherapy (RT) ± androgen deprivation therapy (ADT; n = 34; OS 88.2%; CSS 88.2%), ADT alone (n = 14; OS 42.9%; CSS 64.3%), brachytherapy (BT; n = 11; OS and CSS 100%), watchful waiting (n = 4) and active surveillance (n = 1). Overall no treatment‐related graft loss occurred. Immunosuppression and antibiotic schemes were poorly reported and inconsistent. Outcomes of PCa treatment in RTRs are encouraging and do not appear to be inferior to those of non‐RTR. RP was the most commonly assessed approach, whilst RT, BT and ADT were less frequent. Immunosuppression and antibiotic use were poorly reported and highly variable. High‐quality studies are needed because the current level of evidence is low, and our results should therefore be interpreted with caution.

Radiofrequency Ablation for Renal Cancer in Von Hippel–Lindau Syndrome Patients: A Prospective Cohort Analysis

Introduction Management of renal‐cell carcinoma (RCC) in patients with Von Hippel–Lindau syndrome (VHL) represents a clinical dilemma: the oncologic outcomes must be weighed against preservation of renal function. Radiofrequency ablation (RFA) is currently used in selected cases for treatment of small‐size RCC. The aim of this study was to evaluate the safety, complications, and functional and oncologic outcomes of RFA in the treatment of RCC in VHL patients. Patients and Methods RCCs were treated with ultrasound‐guided RFA or with laparoscopic RFA. Clinical and radiologic response, disease recurrence, and survival outcomes were evaluated during follow‐up. Early and late complications were recorded and graded. Results Nine RCC patients underwent RFA. The median number of RCCs per patient was 3 (interquartile range, 2‐4). Among these 9 patients, a total of 20 RCCs were treated by RFA (19 ultrasound‐guided RFA and 1 laparoscopic procedure). Median RCC size was 2.5 cm (interquartile range, 2.0‐3.0). RFA did not impair renal function (P = .35). In 2 cases disease persisted, and in 1 case disease recurred after 18 months. These patients were retreated with ultrasound‐guided RFA with complete response and no renal function impairment. RFA treatment was overall well tolerated and safe. No complications were recorded. Postoperative stay was no longer than 1 day. Conclusion RCC occurred in about two‐thirds of VHL patients, who had young age at presentation; it was frequently multifocal and recurrent. The use of RFA, with extended indications, could represent a tailored treatment for VHL patients, reducing the risk of renal failure and resulting in satisfying oncologic results. Micro‐Abstract Management of renal‐cell carcinoma (RCC) in Von Hippel–Lindau syndrome (VHL) patients represents a clinical challenge. Radiofrequency ablation (RFA) is currently used in selected cases for treatment of small‐size RCC. The aim of this study was to evaluate the safety and complication rate of RFA in treating RCC in VHL patients. The treatment did not impair renal function and resulted in complete oncologic control.

Treatment of multiple synchronous misdiagnosed renal cell cancers in a young patient affected by a “de novo” Von Hippel-Lindau syndrome

Introduction Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited syndrome occurring in one out of 36,000 live births. Diagnosis could be a challenge in patients with no familial VHL history. Renal cancer (RCC) represents one of the most important manifestations. RCC is usually recurrent and multifocal. Actually treating RCC in VHL patients represent a clinical dilemma: the oncological outcomes must be balanced against renal function preservation. Case Presentation A young man with a negative familial history was referred to our department with seven misdiagnosed renal masses. VHL disease was determined through genetic test. The multiple RCCs were treated by surgery and percutaneous thermal ablation by radiofrequency ablation (RFA) with complete control of RCC and no impairment of renal function. Conclusions This case history confirms that VHL disease has to be suspected in young patients with evidence of synchronous multiple renal masses and in presence of specific clinical criteria. RFA appears to be safe in terms of oncological radicalism and in renal function preservation. In hereditary RCC, we should purpose, whenever it is possible, minimally invasive treatment in terms of low hospital stay and a minimal loss of renal tissue.