Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients.

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Increased cytokine gene expression and cognition risk associated with androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment likely develops side-effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses. METHODS: Gene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database. RESULTS: A total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine-cytokine signaling with an over representation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T-cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL-17A, CCL2, IL-10, IL-6, IL-1RN, LIF/LIFR were further validated by quantitative RT-PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen-responsive prostate cancer cells, compared to no-androgen antagonist treatment. CONCLUSIONS: Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.

Systematic Review of the Management of Ureteroarterial Fistulas After Ileal Conduit Urinary Diversion.

OBJECTIVE. No studies or guidelines exist to direct management of ureteroarterial fistula (UAF) after ileal conduit urinary diversion in which the possible risks and complications associated with stent-graft infection from the conduit flora must be reconciled with those of open surgical repair. This study seeks to characterize the clinical presentation, pathogenesis, and optimal diagnostic and therapeutic management of this entity through a systematic review of the literature. MATERIALS AND METHODS. A systematic search of the English-language literature using the PubMed, Scopus, and ScienceDirect databases was performed: 264 abstracts were identified. From those abstracts, 32 studies comprising 40 patients with 43 UAFs were selected for analysis. Data points including demographics, clinical presentation, UAF specifications, procedural details, postprocedural complications, and clinical outcomes were reviewed. RESULTS. Predisposing factors included female sex, chronic ureteral stent placement, and past surgical intervention and irradiation for pelvic malignancy. Fistulization was overwhelmingly unilateral (95.0% of patients) and included the common iliac artery (90.7% of UAFs). Combined endovascular and endoureteral modalities presented similar outcomes compared with surgical approaches in terms of UAF-related mortality (7.1% vs 13.3%, respectively) and complication rates (28.6% vs 26.7%) during a similar median follow-up period (9.5 vs 14.0 months). Endovascular stent-graft infections were present in 14.3% of cases and represented a leading indication for reintervention after endovascular management (50.0%). CONCLUSION. Short- and intermediate-term outcomes of combined endovascular and endoureteral techniques compare favorably with those of surgical approaches in the treatment of UAF after ileal conduit urinary diversion. Although there is a relatively low stent-graft infection rate, close follow-up within the first year after the procedure is required given the propensity of complications to develop during this window. The use of postprocedural antibiotics is uncertain but is likely prudent.

MR Fingerprinting and ADC Mapping for Characterization of Lesions in the Transition Zone of the Prostate Gland.

BackgroundPreliminary studies have shown that MR fingerprinting-based relaxometry combined with apparent diffusion coefficient (ADC) mapping can be used to differentiate normal peripheral zone from prostate cancer and prostatitis. The utility of relaxometry and ADC mapping for the transition zone (TZ) is unknown.PurposeTo evaluate the utility of MR fingerprinting combined with ADC mapping for characterizing TZ lesions.Materials and MethodsTZ lesions that were suspicious for cancer in men who underwent MRI with T2-weighted imaging and ADC mapping (b values, 50-1400 sec/mm2), MR fingerprinting with steady-state free precession, and targeted biopsy (60 in-gantry and 15 cognitive targeting) between September 2014 and August 2018 in a single university hospital were retrospectively analyzed. Two radiologists blinded to Prostate Imaging Reporting and Data System (PI-RADS) scores and pathologic diagnosis drew regions of interest on cancer-suspicious lesions and contralateral visually normal TZs (NTZs) on MR fingerprinting and ADC maps. Linear mixed models compared two-reader means of T1, T2, and ADC. Generalized estimating equations logistic regression analysis was used to evaluate both MR fingerprinting and ADC in differentiating NTZ, cancers and noncancers, clinically significant (Gleason score ≥ 7) cancers from clinically insignificant lesions (noncancers and Gleason 6 cancers), and characterizing PI-RADS version 2 category 3 lesions.ResultsIn 67 men (mean age, 66 years ± 8 [standard deviation]) with 75 lesions, targeted biopsy revealed 37 cancers (six PI-RADS category 3 cancers and 31 PI-RADS category 4 or 5 cancers) and 38 noncancers (31 PI-RADS category 3 lesions and seven PI-RADS category 4 or 5 lesions). The T1, T2, and ADC of NTZ (1800 msec ± 150, 65 msec ± 22, and [1.13 ± 0.19] × 10-3 mm2/sec, respectively) were higher than those in cancers (1450 msec ± 110, 36 msec ± 11, and [0.57 ± 0.13] × 10-3 mm2/sec, respectively; P < .001 for all). The T1, T2, and ADC in cancers were lower than those in noncancers (1620 msec ± 120, 47 msec ± 16, and [0.82 ± 0.13] × 10-3 mm2/sec, respectively; P = .001 for T1 and ADC and P = .03 for T2). The area under the receiver operating characteristic curve (AUC) for T1 plus ADC was 0.94 for separation. T1 and ADC in clinically significant cancers (1440 msec ± 140 and [0.58 ± 0.14] × 10-3 mm2/sec, respectively) were lower than those in clinically insignificant lesions (1580 msec ± 120 and [0.75 ± 0.17] × 10-3 mm2/sec, respectively; P = .001 for all). The AUC for T1 plus ADC was 0.81 for separation. Within PI-RADS category 3 lesions, T1 and ADC of cancers (1430 msec ± 220 and [0.60 ± 0.17] × 10-3 mm2/sec, respectively) were lower than those of noncancers (1630 msec ± 120 and [0.81 ± 0.13] × 10-3 mm2/sec, respectively; P = .006 for T1 and P = .004 for ADC). The AUC for T1 was 0.79 for differentiating category 3 lesions.ConclusionMR fingerprinting-based relaxometry combined with apparent diffusion coefficient mapping may improve transition zone lesion characterization.© RSNA, 2019Online supplemental material is available for this article.

Green tea-induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase-3 suppresses prostate cancer progression through histone-modifying enzymes.

Green tea polyphenols (GTPs) and their major constituent, epigallocatechin-3-gallate (EGCG), have been reported to demonstrate many interesting biological activities, including anticancer properties. Recent studies on prostate cancer provide strong evidence that epigenetic mechanisms are major players in the regulation of matrix metalloproteinases (MMPs) and their binding partner tissue inhibitor of MMPs (TIMPs) involved in prostate cancer progression. Here we demonstrate that GTP/EGCG mediate epigenetic reactivation of TIMP-3 that plays a key role in suppressing invasiveness and cancer progression. Treatment of human prostate cancer DUPRO and LNCaP cells with 10 µg/mL GTP and 20 µM EGCG induced TIMP-3 mRNA and protein expression. This transcriptional activation of TIMP-3 was associated with the decrease in the expression of both enhancers of zeste homolog 2 (EZH2) and its catalytic product trimethylation of histone H3 at lysine 27 (H3K27me3) repressive marks at the TIMP-3 promoter with an accompanying increase in histone H3K9/18 acetylation. In addition, GTP/EGCG treatment significantly reduced class I histone deacetylase (HDAC) activity/expression and EZH2 and H3K27me3 levels in prostate cancer cells. EGCG/GTP exposure also reduced MMP-2/MMP-9 gelatinolytic activity and abrogated invasion and migration capabilities in these cells. Silencing of EZH2 and class I HDACs strikingly increased the expression of TIMP-3 independent of DNA methylation. Furthermore, clinical trials performed on patients undergoing prostatectomy consuming 800 mg EGCG (Polyphenon E) up to 6 weeks and grade-matched controls demonstrate an increase in plasma TIMP-3 levels. A marked reduction in class I HDACs activity/expression and EZH2 and H3K27me3 levels were noted in GTP-supplemented prostate tissue. Our findings highlight that TIMP-3 induction, as a key epigenetic event modulated by green tea in restoring the MMP:TIMP balance suppresses prostate cancer progression.

Variability in Prices for Erectile Dysfunction Medications-Are All Pharmacies the Same?

BACKGROUND: Variability in prices of medications is a well-known phenomenon; however, this variability has not been quantified in the realm of erectile dysfunction (ED) medications. ED medications are ideal for this quantification, because they are often not covered by insurances; therefore, the cost is the most direct reflection of price variability among pharmacies as they affect the patients. AIM: To evaluate the variability in cash prices for phosphodiesterase type 5 inhibitors (PDEIs) for ED. We also evaluated whether certain types of pharmacies consistently offer better pricing than others, and whether there was any correlation with demographic factors. METHODS: 331 pharmacies were contacted within a 25-mile radius of our institution to obtain the cash price for 4 commonly used ED medications with prespecified doses. After exclusion, 323 pharmacies were categorized as chain, independent, wholesale, or hospital-associated. Cash prices for the specified medications were evaluated. In addition, we identified demographic and socioeconomic factors to determine if these had an impact on median drug pricing within each zip code. MAIN OUTCOME MEASURE: The main outcome was the cost for patients to fill each prescription. RESULTS: Independent pharmacies provided the lowest cost for 3 of 4 of the PDEIs. The largest price difference for 10 tablets of 100 mg sildenafil between all pharmacies was 38,000%. The median cost difference between independent pharmacies and chain pharmacies for sildenafil was >900%, and >1,100% for independent pharmacies vs hospital-associated pharmacies. Demographic and socioeconomic factors had no impact on the cost. CLINICAL IMPLICATIONS: Our goal is to promote patient counseling among practitioners and to empower patients to shop for the best prices for their medications. STRENGTH AND LIMITATIONS: A strength of the study is the large cohort that was surveyed; however, a weakness is that the large majority of the cohort was comprised of chain pharmacies. Mail pharmacies could not be evaluated as they required a valid prescription before offering prices. CONCLUSION: The drastic differences in cash prices for the PDEIs give us an insight into the variability and cost-inflation of medications in the United States. These patterns hold true for other essential medications as well, and improved transparency will allow patients to make informed decisions when choosing where to purchase their medications. It may also encourage certain pharmacies to provide medications at more affordable prices. Mishra K, Bukavina L, Mahran A, et al. Variability in prices for erectile dysfunction medications-Are all pharmacies the same? J Sex Med 2018;15:1785-1791.

Comparative analysis for renal stereotactic body radiotherapy using Cyberknife, VMAT and proton therapy based treatment planning.

PURPOSE: We conducted this dosimetric analysis to evaluate the feasibility of a multi-center stereotactic body radiation therapy (SBRT) trial for renal cell carcinoma (RCC) using different SBRT platforms. MATERIALS/METHODS: The computed tomography (CT) simulation images of 10 patients with unilateral RCC previously treated on a Phase 1 trial at Institution 1 were anonymized and shared with Institution 2 after IRB approval. Treatment planning was generated through five different platforms aiming a total dose of 48 Gy in three fractions. These platforms included: Cyberknife and volumetric modulated arc therapy (VMAT) at institution 1, and Cyberknife, VMAT, and pencil beam scanning (PBS) Proton Therapy at institution 2. Dose constraints were based on the Phase 1 approved trial. RESULTS: Compared to Cyberknife, VMAT and PBS plans provided overall an equivalent or superior coverage to the target volume, while limiting dose to the remaining kidney, contralateral kidney, liver, spinal cord, and bowel. CONCLUSION: This dosimetric study supports the feasibility of a multi-center trial for renal SBRT using PBS, VMAT and Cyberknife.

Cost-effectiveness of MR Imaging-guided Strategies for Detection of Prostate Cancer in Biopsy-Naive Men.

Purpose To evaluate the cost-effectiveness of multiparametric diagnostic magnetic resonance (MR) imaging examination followed by MR imaging-guided biopsy strategies in the detection of prostate cancer in biopsy-naive men presenting with clinical suspicion of cancer for the first time. Materials and Methods A decision-analysis model was created for biopsy-naive men who had been recommended for prostate biopsy on the basis of abnormal digital rectal examination results or elevated prostate-specific antigen levels (age groups: 41-50 years, 51-60 years, and 61-70 years). The following three major strategies were evaluated: (a) standard transrectal ultrasonography (US)-guided biopsy; (b) diagnostic MR imaging followed by MR imaging-targeted biopsy, with no biopsy performed if MR imaging findings were negative; and (c) diagnostic MR imaging followed by MR imaging-targeted biopsy, with a standard biopsy performed when MR imaging findings were negative. The following three MR imaging-guided biopsy strategies were further evaluated in each MR imaging category: (a) biopsy with cognitive guidance, (b) biopsy with MR imaging/US fusion guidance, and (c) in-gantry MR imaging-guided biopsy. Model parameters were derived from the literature. The primary outcome measure was net health benefit (NHB), which was measured as quality-adjusted life-years (QALYs) gained or lost by investing resources in a new strategy compared with a standard strategy at a willingness-to-pay (WTP) threshold of $50 000 per QALY gained. Probabilistic sensitivity analysis was performed by using Monte Carlo simulations. Results Noncontrast MR imaging followed by cognitively guided MR biopsy (no standard biopsy if MR imaging findings were negative) was the most cost-effective approach, yielding an additional NHB of 0.198 QALY compared with the standard biopsy approach. Noncontrast MR imaging followed by in-gantry MR imaging-guided biopsy (no standard biopsy if MR imaging findings were negative) led to the highest NHB gain of 0.251 additional QALY compared with the standard biopsy strategy. All MR imaging strategies were cost-effective in 94.05% of Monte Carlo simulations. Analysis by age groups yielded similar results. Conclusion MR imaging-guided strategies for the detection of prostate cancer were cost-effective compared with the standard biopsy strategy in a decision-analysis model. © RSNA, 2017 Online supplemental material is available for this article.

Development of a Combined MR Fingerprinting and Diffusion Examination for Prostate Cancer.

Purpose To develop and evaluate an examination consisting of magnetic resonance (MR) fingerprinting-based T1, T2, and standard apparent diffusion coefficient (ADC) mapping for multiparametric characterization of prostate disease. Materials and Methods This institutional review board-approved, HIPAA-compliant retrospective study of prospectively collected data included 140 patients suspected of having prostate cancer. T1 and T2 mapping was performed with fast imaging with steady-state precession-based MR fingerprinting with ADC mapping. Regions of interest were drawn by two independent readers in peripheral zone lesions and normal-appearing peripheral zone (NPZ) tissue identified on clinical images. T1, T2, and ADC were recorded for each region. Histopathologic correlation was based on systematic transrectal biopsy or cognitively targeted biopsy results, if available. Generalized estimating equations logistic regression was used to assess T1, T2, and ADC in the differentiation of (a) cancer versus NPZ, (b) cancer versus prostatitis, (c) prostatitis versus NPZ, and (d) high- or intermediate-grade tumors versus low-grade tumors. Analysis was performed for all lesions and repeated in a targeted biopsy subset. Discriminating ability was evaluated by using the area under the receiver operating characteristic curve (AUC). Results In this study, 109 lesions were analyzed, including 39 with cognitively targeted sampling. T1, T2, and ADC from cancer (mean, 1628 msec ± 344, 73 msec ± 27, and 0.773 × 10-3 mm2/sec ± 0.331, respectively) were significantly lower than those from NPZ (mean, 2247 msec ± 450, 169 msec ± 61, and 1.711 × 10-3 mm2/sec ± 0.269) (P < .0001 for each) and together produced the best separation between these groups (AUC = 0.99). ADC and T2 together produced the highest AUC of 0.83 for separating high- or intermediate-grade tumors from low-grade cancers. T1, T2, and ADC in prostatitis (mean, 1707 msec ± 377, 79 msec ± 37, and 0.911 × 10-3 mm2/sec ± 0.239) were significantly lower than those in NPZ (P < .0005 for each). Interreader agreement was excellent, with an intraclass correlation coefficient greater than 0.75 for both T1 and T2 measurements. Conclusion This study describes the development of a rapid MR fingerprinting- and diffusion-based examination for quantitative characterization of prostatic tissue. © RSNA, 2017 Online supplemental material is available for this article.

Outcomes and toxicities in patients treated with definitive focal therapy for primary prostate cancer: systematic review.

AIM: This systematic review summarizes the clinical data on focal therapy (FT) when used alone as definitive therapy for primary prostate cancer (PCa). METHODS: The protocol is detailed in the online PROSPERO database, registration No. CRD42014014765. Articles evaluating any form of FT alone as a definitive treatment for PCa in adult male patients were included. RESULTS: Of 10,419 identified articles, 10,401 were excluded, and thus leaving 18 for analysis. In total, 2288 patients were treated using seven modalities. The outcomes of FT in PCa seem to be similar to those observed with whole gland therapy and with fewer side effects. CONCLUSION: Further research, including prospective randomized trials, is warranted to elucidate the potential advantages of focal radiation techniques for treating PCa. Prospero Registration Number: CRD42014014765.

Real-time in vivo dosimetry for SBRT prostate treatment using plastic scintillating dosimetry embedded in a rectal balloon: a case study.

A novel FDA approved in vivo dosimetry device system using plastic scintillating detectors placed in an endorectal balloon to provide real-time in vivo dosimetry for prostatic rectal interface was tested for use with stereotactic body radiotherapy (SBRT). The system was used for the first time ever to measure dose during linear accelerator based SBRT. A single patient was treated with a total dose of 36.25 Gy given in 5 fractions. Delivered dose was measured for each treatment with the detectors placed against the anterior rectal wall near the prostate rectal interface. Measured doses showed varying degrees of agreement with computed/ planned doses, with average combined dose found to be within 6% of the expected dose. The variance between measurements is most likely due to uncertainty of the detector location, as well as variation in the placement of a new balloon prior to each fraction. Distance to agreement for the detectors was generally found to be within a few millimeters, which also suggested that the differences in measured and calculated doses were due to positional uncertainty of the detectors during the SBRT, which had sharp dose falloff near the penumbra along the rectal wall. Overall, the use of a real time in vivo dosimeter provided a level of safety and improved confidence in treatment delivery. We are evaluating the device further in an IRB-approved prospective partial prostate SBRT trial, and believe further clinical investigations are warranted.

Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1.

The pi-class glutathione S-transferase (GSTP1) actively protect cells from carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is the most common epigenetic alteration observed in human prostate cancer. Silencing of GSTP1 can increase generation of reactive oxygen species (ROS) and DNA damage in cells. In this study we investigated whether loss of GSTP1 contributes to increased DNA damage that may predispose men to a higher risk of prostate cancer. We found significantly elevated (103%; P < 0.0001) levels of 8-oxo-2'-deoxogunosine (8-OHdG), an oxidative DNA damage marker, in adenocarcinomas, compared to benign counterparts, which positively correlated (r = 0.2) with loss of GSTP1 activity (34%; P < 0.0001). Silencing of GSTP1 using siRNA approach in normal human prostate epithelial RWPE1 cells caused increased intracellular production of ROS and higher susceptibility of cells to H2 O2 -mediated oxidative stress. Additionally, human prostate carcinoma LNCaP cells, which contain a silenced GSTP1 gene, were genetically modified to constitutively express high levels of GSTP1. Induction of GSTP1 activity lowered endogenous ROS levels in LNCaP-pLPCX-GSTP1 cells, and when exposed to H2 O2 , these cells exhibited significantly reduced production of ROS and 8-OHdG levels, compared to vector control LNCaP-pLPCX cells. Furthermore, exposure of LNCaP cells to green tea polyphenols caused reexpression of GSTP1, which protected the cells from H2 O2 -mediated DNA damage through decreased ROS production compared to nonexposed cells. These results suggest that loss of GSTP1 expression in human prostate cells, a process that increases their susceptibility to oxidative stress-induced DNA damage, may be an important target for primary prevention of prostate cancer.

The impact of recent screening recommendations on prostate cancer screening in a large health care system.

PURPOSE: The United States Preventive Services Task Force recently recommended against routine prostate cancer screening, stating that the risks of screening outweigh the benefits. We determined the impact of this recommendation on prostate cancer screening in a large health system. MATERIALS AND METHODS: We obtained data on all screening prostate specific antigen tests performed at University Hospitals Case Medical Center and affiliated hospitals in northeastern Ohio from January 2008 to December 2012. We examined the total number of prostate specific antigen tests ordered with time and adjusted for patient volume by fitting a regression line. The overall trend was examined and stratified by location (urban, suburban or rural), patient age and provider type (primary care or urology). RESULTS: A total of 43,498 screening prostate specific antigen tests were performed from January 2008 to December 2012. Most tests were ordered by specialists in internal medicine (64.9%), followed by family medicine (23.7%), urology (6.1%) and hematology/oncology (1.3%). Prostate specific antigen screening increased with time until March 2009, when initial screening trials were published. Prostate specific antigen testing then decreased significantly and continued to decrease after the task force recommendations. Similar patterns were noted in almost all subgroups. The greatest decrease in screening was observed by urologists and in patients in the intermediate age group (50 to 59 years). CONCLUSIONS: United States Preventive Services Task Force recommendations appeared to have decreased prostate cancer screening. The greatest impact was seen for urologists and patients in the intermediate age group. Further study is needed to determine the long-term effects of these recommendations on the screening, diagnosis, treatment and prognosis of this prevalent malignancy.

The true risk of blood transfusion after nephrectomy for renal masses: a population-based study.

OBJECTIVE: To examine blood transfusion rates after nephrectomy for renal masses at the population-level. PATIENTS AND METHODS: We performed a population-based, retrospective observational study using a national discharge abstract database. The study cohort consisted of 10,902 patients who were treated by radical nephrectomy (RN) or partial nephrectomy (PN) for a renal mass between 1 April 2003 and 31 March 2008. The association between blood transfusion and various explanatory variables was examined using the chi-squared test and multivariable logistic regression. RESULTS: The overall blood transfusion rate was 18.1%. Transfusions occurred after 28.2%, 12.7%, 9.2% and 8.6% of open RN, open PN, laparoscopic RN and laparoscopic PN, respectively (P < 0.001). Transfusion rates were found to be strongly associated with age and comorbidity, such that patients aged <50 years with Charlson scores of 0 were transfused 11.2% and 14.5% of the time compared to 28.2% and 40.7% in patients aged ≥80 years with Charlson scores of ≥3, respectively (P < 0.001). On multivariable logistic regression, age (P < 0.001), Charlson score (P < 0.001), procedure type (P < 0.001), surgeon (P < 0.001) and hospital volume quartile (P < 0.001) were all found to be associated with the rate of blood transfusions, whereas year of surgery, sex and income quintile were not. CONCLUSIONS: The transfusion rate after nephrectomy in general clinical practice is higher than that reported in the urological literature. Patient and provider factors appear to contribute to the considerable variability that exists in the observed transfusion rate. A more detailed understanding of these factors may help with respect to preoperative patient counselling and informed consent.

Pneumodissection: an alternative protective technique for the percutaneous cryoablation of small renal masses.

INTRODUCTION: Percutaneous cryoablation is an emerging treatment option for the small renal mass. It poses a risk of thermal injury to adjacent tissues, limiting its application. We describe pneumodissection, a novel technique for preventing thermal injury during percutaneous cryoablation. MATERIALS AND METHODS: The cases of 4 patients who underwent percutaneous renal cryoablation and pneumodissection were retrospectively reviewed. RESULTS: Pneumodissection mechanically separated four tumors from overlying bowel segments (mean distance 1.2 ± 0.4 cm), permitting successful cryoablation. There were no complications or recurrences with 7.5 months of follow-up. CONCLUSIONS: Pneumodissection is a feasible displacement technique that facilitates percutaneous cryoablation in at-risk patients. Further study is warranted.

Image-guided biopsy of small renal masses in the era of ablative therapies.

OBJECTIVE: To further evaluate the accuracy, safety, and impact of image-guided renal biopsies on clinical decision making and management of the indeterminate small renal masses. METHODS: A total of 145 patients (males 99, females 46) with small renal masses suspicious for malignancy were evaluated during the study period. The patients' mean age was 67.2 (± 11.6) years. Computed tomography guided biopsies were carried out in all cases by an experienced interventional radiologist. An experienced genitourinary pathologist reviewed all pathological specimens. Patients' demographic characteristics, tumor histology and subsequent intervention, as well as periprocedural morbidities were recorded and analyzed. RESULTS: A total of 145 renal biopsy procedures were carried out. The small renal masses mean size was 2.4 ± 1.1 cm. Biopsy was diagnostic in 126 (86.9%) cases and non-diagnostic in 19 (13.1%) cases. Of diagnostic biopsies, 107 (84.9%) were malignant, 84.1% of which were primary renal cell carcinoma. Histological subtyping and grading of tumor was possible in 100% and 52.2% of renal cell carcinomas, respectively. The major renal cell carcinoma subtype was clear cell (63.3%) followed by papillary (24.4%) and chromophobe (8.8%). Repeat biopsy was carried out in nine of 19 non-diagnostic cases, and diagnosis was possible in 66.7%. Sensitivity of percutaneous renal biopsy was 91%, and its accuracy was 85.5%. Overall, patients' age, sex, tumor size, and location were not related to non-diagnostic biopsy results and/or tumor pathology. No cases of hemorrhage, seeding of biopsy tract, infection or mortalities were observed. CONCLUSIONS: Our findings showed that image-guided biopsy of indeterminate small renal masses is safe and can provide the correct diagnosis with a high degree of accuracy. Thus, this procedure can play an important role in establishing a histopathological diagnosis before treatment of enhancing small renal masses with ablative technologies. Furthermore, repeat biopsy can alter the clinical management of non-diagnostic biopsies.

Melatonin and Prostate Cancer: Anti-tumor Roles and Therapeutic Application.

Melatonin is an endogenous indoleamine that has been shown to inhibit tumor growth in laboratory models of prostate cancer. Prostate cancer risk has additionally been associated with exogenous factors that interfere with normal pineal secretory activity, including aging, poor sleep, and artificial light at night. Therefore, we aim to expand on the important epidemiological evidence, and to review how melatonin can impede prostate cancer. More specifically, we describe the currently known mechanisms of melatonin-mediated oncostasis in prostate cancer, including those that relate to the indolamine's ability to modulate metabolic activity, cell cycle progression and proliferation, androgen signaling, angiogenesis, metastasis, immunity and oxidative cell status, apoptosis, genomic stability, neuroendocrine differentiation, and the circadian rhythm. The outlined evidence underscores the need for clinical trials to determine the efficacy of supplemental, adjunct, and adjuvant melatonin therapy for the prevention and treatment of prostate cancer.

Treatment patterns and survival of low and intermediate-risk prostate cancer in end-stage kidney disease: A retrospective population cohort study.

BACKGROUND: In accordance with guidelines, observation with or without active surveillance for low-risk prostate cancer increased in recent years in the general population. We compared treatment patterns and mortality for low- and intermediate-risk prostate cancer and mortality rates among end-stage kidney disease (ESKD) and non-ESKD patients. METHODS: This is a retrospective population-based observational cohort study of Surveillance, Epidemiology, and End Results-Medicare data of men aged 66 years and older with localized prostate cancer (2004-2015). ESKD status was determined using Medicare billing codes. Multivariable logistic regression models and Cox-proportional hazards models were used to study definitive treatment patterns and mortality, respectively. RESULTS: For low-risk prostate cancer, dialysis patients (N = 83) had lower but not statistically significant odds (OR, 0.74; 95% CI: 0.48-1.16) of receiving definitive treatment than non-ESKD patients (N = 24,935). For those with intermediate-risk prostate cancer, dialysis patients (N = 254) had lower odds to receive definitive treatment (OR, 0.54; 95% CI: 0.42-0.72) than non-ESKD patients (N = 60,883). From 2004-2010 to 2011-2015, for patients with low-risk prostate cancer, while the receipt of definitive treatment for non-ESKD patients trended down from 72% to 48%, it trended up for dialysis patients from 55% to 65%. Kidney transplant patients (N = 33 for low-risk and N = 91 for intermediate-risk) had lower rates of definitive treatment for low-risk and similar rates of treatment for intermediate-risk prostate cancer compared to non-ESKD patients. CONCLUSIONS: The disparity in definitive treatment rates for low-risk prostate cancer among dialysis patients exists despite their high mortality, compared to the general population.

Five-Year Patient-Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score. RESULTS: The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.