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www.hezarkhani.blogfa.com 21 April 2014
Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma
Kunyoo Shin1, Agnes Lim2, Justin I. Odegaard3, Jared D. Honeycutt4, Sally Kawano1, Michael H. Hsieh5, Philip A. Beachy1, 2, 6, 7, Journal name:Nature Cell Biology/Year published:(2014) DOI:doi:10.1038/ncb2956 20 April 2014
Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression.
Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium.
These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma in situ. Shh-expressing basal cells within this precursor lesion become tumour-initiating cells, although Shh expression is lost in subsequent carcinomas.
We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.
www.Hezarkhani.blogfa.com 21 April 2014
Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial
Bora Gurel1, M. Scott Lucia7, Ian M. Thompson Jr8, Phyllis J. Goodman10, Catherine M. Tangen10,Alan R. Kristal11, Howard L. Parnes6, Ashraful Hoque9, Scott M. Lippman12, Siobhan Sutcliffe13,Sarah B. Peskoe4, Charles G. Drake2,3,5, William G. Nelson1,3,5, Angelo M. De Marzo1,3,5, and Elizabeth A. Platz3,4,5 Departments of 1Pathology and 2Immunology; 3The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine; 4Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; 5Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore; 6Division of Cancer Prevention, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland; 7University of Colorado School of Medicine, Aurora, Colorado; 8Department of Urology, University of Texas Health Sciences Center San Antonio, San Antonio; 9Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas; 10SWOG Statistical Center; 11Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; 12Moores Cancer Center, University of California San Diego, La Jolla, California; and 13Division of Public Health Sciences and The Alvin J. Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
Background: Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.
Methods: Prostate cancer cases (N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin–stained sections. Logistic regression was used to estimate associations.
Results: Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04–3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N = 94; OR, 2.24; 95% CI, 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (<2 ng/mL at biopsy).
Conclusion: Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias.
Cancer Epidemiol Biomarkers Prev; 23(5); 1–10. ©2014 AACR. February 17, 2014.
©2014 American Association for Cancer Research.
Urology news 21 April 2014
Cranberry Extract Supplementation Eases Bladder Discomfort and Infection following Radiotherapy for Prostate Cancer
Bonetta A, Di Pierro F. Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer Manag Res. 2012;4:281-286.
Cranberry (Vaccinium macrocarpon) preparations have long been used for medicinal purposes, especially to treat urinary tract infections. The berries contain complex proanthocyanidins with A-type bonds. Several recent studies have demonstrated the clinical efficacy of cranberry preparations in patients with lower urinary tract infections (LUTIs).1 Because LUTI is a frequent adverse event in patients with cancer who are being treated with external beam radiotherapy (EBRT) to the pelvis, the authors conducted a nonrandomized, single-center study to determine whether enteric-coated tablets containing highly standardized cranberry (ecVM) could prevent LUTIs and moderate the bladder irritation associated with the treatment.
From July 6, 2007 to September 3, 2010, 370 patients were enrolled at the Unità Operativa di Radioterapia Oncologica of Cremona Hospital in Cremona, Italy. The patients, diagnosed with prostatic adenocarcinoma, were treated with radiotherapy to the prostatic area (and to the pelvis in cases with a high risk of lymph node involvement). Only patients treated with radical, adjuvant, or salvage radiotherapy were enrolled in the study. Of the 370 patients, 186 had undergone surgery.
The patients were sorted into 2 groups: those treated with ecVM (n=184) and those serving as controls (n=186).
The patients in the ecVM group took 1 enteric-coated tablet daily of VO370® or MonoSelect Macrocarpon® (PharmExtracta; Pontenure, Italy), containing 200 mg of a highly standardized cranberry extract titered at 30% proanthocyanidins.
During the 6-7 weeks of treatment, all patients underwent weekly examinations to record their urinary symptoms and their use of nonsteroidal anti-inflammatory drugs. Urine cultures were performed at weeks 3 and 6 and in cases of intense dysuria. Urinary tract infection was diagnosed when bacteriuria exceeded 100,000 u/mL and specific symptoms of cystitis were present.
Compliance in the ecVM group was excellent; only 1 patient discontinued treatment for 10 days during the study. Two patients with chronic gastritis in the ecVm group complained of gastric pain and required treatment. No other unwanted effects or allergies were observed. All patients completed their planned EBRT.
In the control group, 45 (24.2%) patients suffered LUTIs; 8 (4.3%) had recurrent infection. In the ecVM group, 16 (8.7%) experienced urinary infections with no recurrence. The difference between the percent of patients that suffered LUTIs in each group was statistically significant.
Of the bacteria found in the urine cultures, Escherichia coli and bacteria of enteric origin were the most common, with a higher prevalence of coliform bacteria in the control group (21 cases) than in the ecVM group (5 cases).
Of the 8 relapses observed in the control group, 5 were caused by E. coli, 2 by enterococci, and 1 by a hemolytic staphylococcal strain.
Analysis of urinary symptomology, conducted in all but 2 patients independent of the presence of an infectious process, revealed a lower incidence of dysuria and milder symptoms in the ecVM group than in the control group. Absence of symptoms was observed in 62% of patients in the ecVM group and in 36% of those in the control group. Other degrees of dysuria (occasional burning, frequent burning, and constant pain) were significantly higher in the control group (P<0.0001).
Overall, the urinary symptoms due to radiotherapy were milder in the ecVM group than in the control group, with statistically significant differences in terms of nocturia (31% vs. 54% increase, P<0.001); urgency (31% vs. 54% increase, P<0.0001); and urine flow (14% vs. 21.5% decrease, P=0.0066). Daily urination frequency increased from 5.33 to 8.74 in the control group, and from 5.85 to only 7.55 in the treatment group (P=0.0006).
These results suggest that, "The benefits of cranberry extract in prevention of LUTIs can be observed also in nonphysiologic situations, such as the acute bladder damage associated with high-dose irradiation," say the authors.
According to the authors, only 2 studies have been reported on the use of cranberry extract in supportive cancer care. The first study, in 128 female patients treated with radiotherapy or a combination of radiotherapy and chemotherapy for uterine cancer, showed only a tendency toward reduced LUTI frequency in the treatment group compared with placebo, with the difference not statistically significant.2 The second study3 also used cranberry juice to prevent bladder symptoms in patients undergoing pelvic radiotherapy; no significant differences were reported between the cranberry-treated group and the controls. Both studies had design limitations.
Acknowledging the lack of randomization in their study, the authors conclude that the incidence of LUTIs and bladder discomfort associated with pelvic irradiation was lower with the use of cranberry extract compared with placebo, with statistically significant differences in dysuria, nocturia, and urinary frequency. "It is possible that, because of its strong antioxidant properties, cranberry could attenuate actinic damage to the bladder mucosa, reducing the inflammatory process and, as a consequence, its symptoms," they explain. The authors fail to make a compelling case for their rationale of the use of an enteric coating in the formulation, which may have weakened the study outcome significantly.American Botanical Council
1Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2008;(1):CD001321. doi: 10.1002/14651858.CD001321.pub4.
2Cowan CC, Hutchison C, Cole T, et al. A randomised double-blind placebo-controlled trial to determine the effect of cranberry juice on decreasing the incidence of urinary symptoms and urinary tract infections in patients undergoing radiotherapy for cancer of the bladder or cervix. Clin Oncol (R Coll Radiol). 2012;24(2):e31-e38.
3Campbell G, Pickles T, D'yachkova Y. A randomised trial of cranberry versus apple juice in the management of urinary symptoms during external beam radiation therapy for prostate cancer. Clin Oncol (R Coll Radiol). 2003;15(6):322-328.
Urology news 19 April 2014
Hypermethylation of the GABRE∼miR-452∼miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy
Departments of 1Molecular Medicine and 2Urology and 3Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark; 4Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; 5Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; 6Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland; Departments of 7Oncology and Pathology and 8Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
Purpose: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE∼miR-452∼miR-224 genomic locus.
Experimental Design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE∼miR-452∼miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE∼miR-452∼miR-224 methylation was evaluated by ROC, Kaplan–Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data.
Results: GABRE∼miR-452∼miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high GABRE∼miR-452∼miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2.
Conclusion: The GABRE∼miR-452∼miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE∼miR-452∼miR-224 may be selected for in prostate cancer.
Clin Cancer Res; 20(8); 2169–81. ©2014 AACR. February 5, 2014. ©2014 American Association for Cancer Research.
Urology news 19 April 2014
UK NICE guidance recommends FIRMAGON only in people with spinal metastases who present with signs or symptoms of impending spinal cord compression
Radical treatment for advanced prostate cancer may herald major survival advantage over conventional treatment
A quarter of men drop out of prostate cancer monitoring, casting doubt on safety of "active surveillance
Urology news 17 April 2014
Perioperative chemotherapy for muscle-invasive bladder cancer: A population-based outcomes study
Christopher M. Booth MD1,2,*, D. Robert Siemens MD2,3, Gavin Li MD1, Yingwei Peng PhD1,4, Ian F. Tannock MD, PhD5, Weidong Kong MD1, David M. Berman MD, PhD6 andWilliam J. Mackillop MB, ChB1,2,/14 APR 2014/DOI: 10.1002/cncr.28510
Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute,Department of Oncology, Queen's University, Kingston, Ontario, Canada,Department of Urology, Queen's University, Kingston, Ontario, Canad,Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canad,Princess Margaret Hospital, Toronto, Ontario, Canada,Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
Practice guidelines recommend neoadjuvant chemotherapy (NACT) for bladder cancer. However, the evidence in support of adjuvant chemotherapy (ACT) is less robust. Here we describe whether the evidence of efficacy for NACT/ACT was sufficient to change clinical practice and whether the efficacy demonstrated in clinical trials was translated into effectiveness in the general population.
Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients with bladder cancer treated with cystectomy in Ontario 1994-2008. Utilization of NACT/ACT was compared across 1994-1998, 1999-2003, and 2004-2008. Logistic regression was used to analyze factors associated with NACT/ACT. Cox model and propensity score analyses were used to explore the association between ACT and survival.
Two thousand forty-four patients underwent cystectomy for muscle-invasive bladder cancer (MIBC). Use of NACT remained stable (mean, 4%), whereas utilization of ACT increased over time (16%, 18%, 22%; P = .001). Advanced stage (T3/T4; OR, 1.83; 95% CI, 1.38-2.46) and node-positive disease (OR, 8.10; 95% CI, 6.20-10.7) were associated with greater utilization of ACT. Five-year overall survival (OS) and cancer-specific survival (CSS) for all patients was 29% (95% CI, 28%-31%) and 33% (95% CI, 31%-35%), respectively. Utilization of ACT was associated with improved OS (HR, 0.71; 95% CI, 0.62-0.81) and CSS (HR, 0.73; 95% CI, 0.64-0.84). Results were consistent in propensity score analyses.
NACT remains substantially underutilized in routine clinical practice. Our results suggest that perioperative chemotherapy is associated with a substantial survival benefit in the general population. Patients who are planning to undergo cystectomy for bladder cancer should be reviewed by a multidisciplinary team. Cancer 2013. © 2013 American Cancer Society.
10 Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer British Journal of Cancer, April 14, 2014
15 Effect of perioperative electroacupuncture as an adjunctive therapy on postoperative analgesia with tramadol and ketamine in prostatectomy: a randomised sham-controlled single-blind trial Acupuncture in Medicine, April 14, 2014
17 Blood type influences prostate cancer relapse, study shows, Prostate Cancer News,Healthcare Industry Today by EIN Newsdesk
18 Gene linked to pediatric kidney cancer suggests new strategies for kidney regeneration,Journal reference: Genes & Development
14 Apr 2014 MNT
20 Ejaculatory Problems Linked to BPH Drugs , Renal&Urology news
Urology news 13 April 2014
Penile traction therapy reduced curvature and significantly improved function and hardness. Penile traction therapy (PTT) is an effective treatment for the acute phase of Peyronie's disease (PD).
Juan Martínez-Salamanca, MD, PhD, of the Department of Urology at the Autonomous University of Madrid and colleagues studied 55 patients who underwent PTT, a novel penile extender device therapy, for 6 months for acute phase (AP) of Peyronie's. These patients were compared with 41 patients in the acute phase of Peyronie's disease who received no active treatment.
From baseline, mean curvature in patients treated with PTT had decreased from 33° to 15° at 6 months and 13° at 9 months, with a mean decrease of 20°. Erectile function and hardness improved significantly, and the proportion of patients unable to achieve penetration decreased from 62% to 20%.
The need for surgery was reduced in 40% of patients who would otherwise have been eligible, and the complexity of surgical procedures was further simplified in 1 out of 3 patients. PTT was associated with the removal of sonographic plaques in 48% of patients treated.The non-active treatment group had a significant increase in penile deformity, where function and hardness worsened and stretched flaccid penile length had decreased.“PTT seems an effective treatment for the AP of PD in terms of pain reduction, penile curvature decrease, and improvement in sexual function,” the authors concluded.
The Journal of Sexual Medicine (2014;11:506-515).