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Parkinson's disease (PD) is a common, progressive neurodegenerative disease, which typically presents itself with a range of motor symptoms, like resting tremor, bradykinesia, and rigidity, but also non-motor symptoms such as fatigue, constipation, and sleep disturbance. Neuropathologically, PD is characterized by loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and Lewy bodies, neuronal inclusions containing α-synuclein (α-syn). Mutations and copy number variations of SNCA , the gene encoding α-syn, are linked to familial PD and common SNCA gene variants are associated to idiopathic PD. Large-scale genome-wide association studies have identified risk variants across another 40 loci associated to idiopathic PD. These risk variants do not, however, explain all the genetic contribution to idiopathic PD. The rat Vra1 locus has been linked to neuroprotection after nerve- and brain injury in rats. Vra1 includes the glutathione S -transferase alpha 4 ( Gsta4 ) gene, which encodes a protein involved in clearing lipid peroxidation by-products. The DA.VRA1 congenic rat strain, carrying PVG alleles in Vra1 on a DA strain background, was recently reported to express higher levels of Gsta4 transcripts and to display partial neuroprotection of SNpc dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) induced model for PD. Since α-syn expression increases the risk for PD in a dose-dependent manner, we assessed the neuroprotective effects of Vra1 in an α-syn-induced PD model. Human wild-type α-syn was overexpressed by unilateral injections of the rAAV6-α-syn vector in the SNpc of DA and DA.VRA1 congenic rats. Gsta4 gene expression levels were significantly higher in the striatum and midbrain of DA.VRA1 compared to DA rats at 3 weeks post surgery, in both the ipsilateral and contralateral sides. At 8 weeks post surgery, DA.VRA1 rats suffered significantly lower fiber loss in the striatum and lower loss of dopaminergic neurons in the SNpc compared to DA. Immunofluorescent stainings showed co-expression of Gsta4 with Gfap at 8 weeks suggesting that astrocytic expression of Gsta4 underlies Vra1 -mediated neuroprotection to α-syn induced pathology. This is the second PD model in which Vra1 is linked to protection of the nigrostriatal pathway, solidifying Gsta4 as a potential therapeutic target in PD.

Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis‑variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to α-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on α-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress α-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system and behavioral deficits after α-syn overexpression. We report that allelic variants of Mhc2ta differently modified the microglial activation in response to overexpression of human α-syn in rats. Overexpression of α-syn led to a larger denervation of the nigro-striatal system and significant behavioral deficits in DA.VRA4 congenic rats with lower Mhc2ta expression compared to DA rats. These results indicate that Mhc2ta is a key upstream regulator of the inflammatory response in PD pathology., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: To compare outcomes following laparoscopic renal surgery (LRS) and open renal surgery (ORS) in the treatment of pathologic T3a (pT3a) renal cell carcinoma (RCC) using a propensity matched analysis., Materials and Methods: The Canadian Kidney Cancer Information System is a prospectively maintained database for patients diagnosed with RCC from 15 Canadian institutions. Patients treated for nonmetastatic pT3a RCC between 2008 and 2015 were included. Propensity score matching for age, gender, tumor size, grade, histology, and surgical approach was performed to compare laparoscopic radical and partial nephrectomy (LRN or LPN) with open radical or partial nephrectomy (ORN or OPN). The primary endpoint was recurrence-free survival (RFS)., Results: Two hundred twenty-six (45%) patients underwent LRS (88% LRN and 12% LPN), and 275 (55%) underwent ORS (75% ORN and 25% OPN). After a median follow-up of 21.1 months, 155 (72 LRS and 83 ORS) patients experienced recurrence. The 3-year RFS was 63% and 50% for the LRS and ORS groups, respectively, p = 0.36. On subgroup analysis, there was no significant difference in RFS among patients who underwent radical nephrectomy (3-year RFS 61% in LRN compared with 46% in ORN group, p = 0.32) or partial nephrectomy (77% in LPN compared with 79% in OPN group, p = 0.82)., Conclusions: This study is the largest matched analysis comparing LRS and ORS for pT3a RCC. In matched patients, LRS showed no difference in oncologic outcomes compared with ORS and should be considered when technically feasible.

Idiopathic Parkinson's disease (PD) is a complex disease caused by multiple, mainly unknown, genetic and environmental factors. The Ventral root avulsion 1 ( Vra1 ) locus on rat chromosome 8 includes the Glutathione S-transferase alpha 4 ( Gsta4 ) gene and has been identified in crosses between Dark Agouti (DA) and Piebald Virol Glaxo (PVG) rat strains as being associated to neurodegeneration after nerve and brain injury. The Gsta4 protein clears lipid peroxidation by-products, a process suggested to being implicated in PD. We therefore investigated whether PVG alleles in Vra1 are neuroprotective in a toxin-induced model of PD and if this effect is coupled to Gsta4 . We performed unilateral 6-hydroxydopamine (6-OHDA) partial lesions in the striatum and compared the extent of neurodegeration in parental (DA) and congenic (DA.VRA1) rats. At 8 weeks after 6-OHDA lesion, DA.VRA1 rats displayed a higher density of remaining dopaminergic fibers in the dorsolateral striatum compared to DA rats (44% vs. 23%, p < 0.01), indicating that Vra1 alleles derived from the PVG strain protect dopaminergic neurons from 6-OHDA toxicity. Gsta4 gene expression levels in the striatum and midbrain were higher in DA.VRA1 congenic rats compared to DA at 2 days post-lesion ( p < 0.05). The GSTA4 protein co-localized with astrocytic marker GFAP, but not with neuronal marker NeuN or microglial marker IBA1, suggesting astrocyte-specific expression. This is the first report on Vra1 protective effects on dopaminergic neurodegeneration and encourages further studies on Gsta4 in relation to PD susceptibility., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Survival in patients with bladder cancer has only moderately improved over the past 2 decades. A potential reason for this is nonadherence to clinical guidelines and best practice, leading to wide variations in care. Common quality indicators (QIs) are needed to quantify adherence to best practice and provide data for benchmarking and quality improvement., Objective: To produce an evidence- and consensus-based list of QIs for the management of bladder cancer., Methods: A modified Delphi method was used to develop the indicator list. Candidate indicators were extracted from the literature and rated by a 27-member Canadian expert panel in several rounds until consensus was reached on the final list of indicators. In rounds with numeric ratings, a frequency analysis was performed., Results: A total of 86 indicators were rated, 52 extracted from the literature and 34 suggested by the panel. After iterative rounds of ratings and discussion, a final list of 60 QIs spanning several disciplines and phases of the cancer care continuum was developed., Conclusions: This is the first study to comprehensively produce common QIs representing structure, process, and outcome measures in bladder cancer management. Though developed in Canada, these indicators can be used in other countries with slight modifications to track performance and improve care., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction and Objective: Patients who undergo surgical management of renal cell carcinoma (RCC) are at risk for chronic kidney disease and its sequelae. This study describes the natural history of renal function after radical and partial nephrectomy and explores factors associated with postoperative decline in renal function., Methods: This is a multi-institutional cohort study of patients in the Canadian Kidney Cancer Information System who underwent partial or radical nephrectomy for RCC. Estimated glomerular filtration rate (eGFR) and stage of chronic kidney disease were determined preoperatively and at 3, 12, and 24 months postoperatively. Linear regression was used to determine the association between postoperative eGFR and type of surgery (radical vs. partial), duration of ischemia, ischemia type (warm vs. cold), and tumor size., Results and Limitations: With a median follow-up of 26 months, 1,379 patients were identified from the Canadian Kidney Cancer Information System database including 665 and 714 who underwent partial and radical nephrectomy, respectively. Patients undergoing radical nephrectomy had a lower eGFR (mean = 19ml/min/1.73m 2 lower) at 3, 12, and 24 months postoperatively (P<0.001). Decline in renal function occurred early and remained stable throughout follow-up. A lower preoperative eGFR and increasing age were also associated with a lower postoperative eGFR (P<0.01). Ischemia type and duration were not predictive of postoperative decline in eGFR (P>0.05). Severe renal failure (eGFR<30ml/min/1.73m 2 ) developed postoperatively in 12.5% and 4.1% of radical and partial nephrectomy patients, respectively (P<0.001)., Conclusions: After the initial postoperative decline, renal function remains stable in patients undergoing surgery for RCC. Patients undergoing radical nephrectomy have a greater long-term reduction in renal function compared with those undergoing partial nephrectomy. Ischemia duration and type are not predictive of postoperative renal function when adhering to generally short ischemia durations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response., Patients and Methods: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201)., Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type., Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Apart from an invasive biopsy, currently no tools are available to confirm the diagnosis of clear cell renal cell carcinoma (ccRCC); this resulted in approximately 30% of patients being diagnosed with metastatic disease., Objective: To determine whether urinary microRNAs (miRNAs) can serve as biomarkers to confirm the diagnosis of ccRCC., Design, Setting, and Participants: Global miRNA expression was assessed in 28 preoperative urine samples from patients with ccRCC and 18 healthy participants. The independent validation set consisted of 81 ccRCC patients, 24 patients with benign lesions, and 33 healthy participants. We extracted both cell-free and exosomal RNA for miRNA expression analysis using miRNA-specific polymerase chain reaction assays. We also investigated exosomal miRNA secretion in cell line models and performed exosome transfer between RCC and endothelial cell types., Outcome Measurements and Statistical Analysis: Receiver operating characteristic analysis was applied to identify the discrimination power of miRNAs., Results and Limitations: Overall, miR-126-3p combined with miR-449a or with miR-34b-5p could significantly distinguish ccRCC patients from healthy participants (miR-126-3p-miR-449a: area under the curve [AUC]: 0.84; 95% confidence interval [CI], 0.7620-0.9151; p<0.001; miR-126-3p-miR-34b-5p: AUC: 0.79; 95% CI, 0.7013-0.8815; p<0.001). The combination of miR-126-3p and miR-34b-5p was also able to distinguish small renal masses (pT1a, ≤4cm) from healthy controls (AUC: 0.79; 95% CI, 0.6848-0.8980; p<0.001). Using miR-126-3p and miR-486-5p in combination, we were able to differentiate between benign lesions and ccRCC (AUC: 0.85; 95% CI, 0.7295-0.9615; p<0.01). The expression of a number of miRNAs returned to a level comparable with health after surgery. Kidney cancer cell lines were found to secrete exosomal miR-126-3p, miR-17-5p, miR-21-3p, and miR-25-3p, and these miRNAs were found to be internalized by other cell types., Conclusions: We identified exosomal miRNAs as potential noninvasive diagnostic urinary biomarkers for ccRCC and provided evidence that miRNAs are secreted by the tumor and can function as a tool for intercellular communication., Patient Summary: We identified urinary microRNAs that can serve as diagnostic biomarkers for clear cell renal cell carcinoma., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence., Methods: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898., Findings: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity., Interpretation: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis., Funding: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype and can be further classified as type 1 (pRCC1) or 2 (pRCC2). There is currently minimal understanding of pRCC1 pathogenesis, and treatment decisions are mostly empirical. The aim of this study was to identify biological pathways that are involved in pRCC1 pathogenesis using an integrated genomic approach. By microarray analysis, we identified a number of significantly dysregulated genes and microRNAs (miRNAs) that were unique to pRCC1. Integrated bioinformatics analyses showed enrichment of the focal adhesion and extracellular matrix (ECM) pathways. We experimentally validated that many members of these pathways are dysregulated in pRCC1. We identified and experimentally validated the downregulation of miR-199a-3p in pRCC1. Using cell line models, we showed that miR-199a-3p plays an important role in pRCC1 pathogenesis. Gain of function experiments showed that miR-199a-3p overexpression significantly decreased cell proliferation (p = 0.013). We also provide evidence that miR-199a-3p regulates the expression of genes linked to the focal adhesion and ECM pathways, such as caveolin 2 (CAV2), integrin beta 8 (ITGB8), MET proto-oncogene and mammalian target of rapamycin (MTOR). Using a luciferase reporter assay, we further provide evidence that miR-199a-3p overexpression decreases the expression of MET and MTOR. Using an integrated gene/miRNA approach, we provide evidence linking miRNAs to the focal adhesion and ECM pathways in pRCC1 pathogenesis. This novel information can contribute to the development of effective targeted therapies for pRCC1, for which there is none currently available in the clinic., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Purpose: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents., Experimental Design: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE)., Results: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups., Conclusions: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population., (©2015 American Association for Cancer Research.)

Purpose: To test the hypothesis that qualitative and quantitative features of contrast material-enhanced ultrasonography (US) can be used to differentiate benign from malignant small renal masses., Materials and Methods: This is an institutional review board approved, HIPAA-compliant prospective study with written informed consent. Patients with histologically characterized solid small renal masses, excluding lipid-rich angiomyolipomas, underwent qualitative contrast-enhanced US with a combination of three different US machines. A subgroup of patients underwent quantitative contrast-enhanced US. Patients received a bolus injection of 0.2 mL of contrast material for qualitative and quantitative evaluations and were followed for 3 minutes. Two radiologists independently reviewed videotaped qualitative contrast-enhanced US examinations and were blinded to the final diagnoses. Features that were evaluated included lesion vascularity relative to the adjacent cortex in the arterial phase, the presence of a capsule, homogeneity, the pattern of vascularity, and washout. One radiologist separately reviewed a subset of contrast-enhanced US examinations that were performed with all three machines. Parameters of a first-pass time intensity curve were calculated for quantitative analysis. The Mann-Whitney test was used for quantitative parameters, the χ(2) or Fisher exact test was used for qualitative parameters, and κ statistics and Fleiss methodology were used to determine interobserver and intermachine agreement., Results: The study population consisted of 91 patients (35 women and 56 men) with 94 lesions. The mean age was 62 years ± 14 (range, 21-91). Three patients had two lesions each, which were evaluated at two different sessions. There were 26 benign small renal masses (including 18 oncocytomas, seven lipid-poor angiomyolipomas, and one hemangioblastoma) and 68 malignant masses (including 41 clear cell, 20 papillary, and seven chromophobe renal cell carcinomas [RCCs[) that were 1.1-4.0 cm in diameter (mean, 2.7 cm ± 0.9). All patients underwent contrast-enhanced US on the same one machine, and 68 patients were imaged on all three machines. Vascularity was present in all lesions (n = 94) at contrast-enhanced US. Lesion hypovascularity relative to the adjacent cortex in the arterial phase was seen in only malignant lesions by both reviewers; reviewer 1 saw hypovascularity in 24 of 94 lesions (P = .0001), and reviewer 2 saw hypovascularity in 21 of 94 lesions (P = .0006), for a specificity of 100% (95% confidence interval [CI]: 84, 100). This feature had κ values of 0.91 (95%CI: 0.82, 1.00) between the two reviewers and 0.85 (95% CI: 0.72, 0.99) between the three machines. Eighteen of 20 papillary RCCs were hypovascular. Quantitative parameters of area under the receiver operating characteristics curve, peak intensity, wash-in slope of 10%-90% and 5%-45%, and washout slope of 100%-10% and 50%-10% were significantly higher in malignant renal masses (P = .018, P = .002, P = .036, P = .016, P = .001, and P = .005, respectively) than in benign lesions., Conclusion: Excluding lipid-rich angiomyolipoma, hypovascularity-which has high interobserver and intermachine agreement-of solid small renal masses relative to the cortex in the arterial phase has 100% specificity (95% CI: 84, 100) for detecting malignancy, most often papillary RCC.

Objective: The purpose of this study was to evaluate the diagnostic performance of chemical-shift MRI in the differentiation of clear cell renal cell carcinoma (RCC) from minimal-fat angiomyolipoma (AML) and non-clear cell RCC., Materials and Methods: In this retrospective study, 97 patients with solid renal tumors without macroscopic fat and with a pathologic diagnosis of clear cell RCC (n = 40), non-clear cell RCC (n = 31), or minimal-fat AML (n = 26) who had undergone renal chemical-shift MRI were included. Size, location, morphology, and signal intensity (SI) of the tumors and the contralateral normal kidneys on T2-weighted and in-phase and opposed-phase images were recorded by readers blinded to the pathology. Percentage tumor-to-renal parenchymal SI drop (percentage SI drop) was calculated and correlated to tumor histology. The statistical analysis was done using Kruskal-Wallis, one-way ANOVA, chi-square, and Fisher exact tests., Results: The percentage SI drop was significantly higher in clear cell RCC compared with non-clear cell RCC and minimal-fat AML (p < 0.001). Percentage SI drop of greater than 20% had 57.5% sensitivity, 96.5% specificity, and 92% positive predictive value (PPV); and percentage SI drop greater than 29% had 40% sensitivity and 100% specificity for diagnosis of clear cell RCC within the cohort of clear cell RCC, minimal-fat AML, and non-clear cell RCC. A significant proportion of minimal-fat AML (46.2%) displayed homogeneous low T2-weighted SI as opposed to clear cell RCC (5%) and non-clear cell RCC (29%) (p < 0.001)., Conclusion: The percentage SI drop on chemical-shift MRI had high specificity and moderate sensitivity in predicting clear cell RCC over non-clear cell RCC and minimal-fat AML. A percentage SI drop greater than 20% in a renal mass without macroscopically visible fat has high PPV for clear cell RCC over minimal-fat AML and non-clear cell RCC. Among morphologic features, homogeneous low T2 SI favors minimal-fat AML over RCC.

The western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), recently expanded its range from the western United States into the Great Lakes region of the United States and Canada, threatening eastern dry bean production. Our objectives were to better understand the relationship between cutworm infestation and damage in dry beans, and to determine the best method and timing of insecticide application to reduce pick. Infesting with at least one egg mass per 1.5 m, or as few as two larvae per 0.3 m, of row resulted in significantly more pod damage and pick than in uninfested plots. By 14 d after hatch, larvae were no longer on plants during the daytime; direct observations revealed that fifth instars climbed plants to feed between 2100 and 0600 hours, illustrating the impractically of using larval counts to make management decisions. There was a strong linear relationship between pod damage and percent pick, making scouting for pod damage a viable alternative to egg or larval scouting. Aldicarb soil insecticide or thiamethoxam-treated seed did not reduce cutworm damage. Instead, plots treated with these insecticides had significantly more pick than control plots, perhaps related to increased canopy growth or fewer natural enemies. The pyrethroid λ-cyhalothrin provided excellent control of cutworm when sprayed up to 18 d after infestation. Pick was similar among plots sprayed once up to 18 d after infestation or sprayed four separate times. In a field study, λ-cyhalothrin residue on field-treated foliage was 100% effective at controlling caterpillars up to 14 d after application., (© The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC) platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell markers.

Background: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor outcome in various tumours. Its prognostic utility in patients with urothelial carcinoma of the bladder (UCB) undergoing radical cystectomy (RC) is yet to be fully elucidated., Methods: A cohort of patients undergoing RC for UCB in a tertiary referral centre between 1992 and 2012 was analysed. Neutrophil-to-lymphocyte ratio was computed using complete blood counts performed pre-RC, or before neo-adjuvant chemotherapy where applicable. Time-dependent receiver operating characteristic curves were used to determine the optimal cutoff point for predicting recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The predictive ability of NLR was assessed using Kaplan-Meier analyses and multivariable Cox proportional hazards models. The likelihood-ratio test was used to determine whether multivariable models were improved by including NLR., Results: The cohort included 424 patients followed for a median of 58.4 months. An NLR of 3 was determined as the optimal cutoff value. Patients with an NLR⩾3.0 had significantly worse survival outcomes (5y-RFS: 53% vs 64%, log-rank P=0.013; 5y-CSS: 57% vs 75%, log-rank P<0.001; 5y-OS: 43% vs 64%, log-rank P<0.001). After adjusting for disease-specific predictors, an NLR ⩾3.0 was significantly associated with worse RFS (HR=1.49; 95% CI=1.12-2.0, P=0.007), CSS (HR=1.88; 95% CI=1.39-2.54, P<0.001) and OS (average HR=1.67; 95% CI=1.17-2.39, P=0.005). The likelihood-ratio test confirmed that prognostic models were improved by including NLR., Conclusions: Neutrophil-to-lymphocyte ratio is an inexpensive prognostic biomarker for patients undergoing RC for UCB. It offers pre-treatment prognostic value in addition to established prognosticators and may be helpful in guiding treatment decisions.

Introduction: Most small renal masses (SRMs) are diagnosed incidentally and have a low malignant potential. As more elderly patients and infirm patients are diagnosed with SRMs, there is an increased interest in active surveillance (AS) with delayed intervention. Patient and tumour characteristics relating to aggressive disease have not been well-studied. The objective was to determine predictors of growth of SRMs treated with AS., Methods: A multicentre prospective phase 2 clinical trial was conducted on 207 SRMs in 169 patients in 8 institutions in Canada from 2004 to 2009; in these patients treatment was delayed until disease progression. Patient and tumour characteristics were evaluated to determine predictors of growth of SRMs by measuring rates of change in growth (on imaging) over time. All patients underwent AS for presumed renal cell carcinoma (RCC) based on diagnostic imaging. We used the following factors to develop a predictive model of tumour growth with binary recursive partitioning analysis: patient characteristics (age, symptoms at diagnosis) and tumour characteristics (consistency [solid vs. cystic] and maximum diameter at diagnosis., Results: With a median follow-up of 603 days, 169 patients (with 207 SRMs) were followed prospectively. Age, symptoms at diagnosis, tumour consistency and maximum diameter of the renal mass were not predictors of growth. This cohort was limited by lack of availability of patient and tumour characteristics, such as sex, degree of endophytic component and tumour location., Conclusion: Slow growth rates and the low malignant potential of SRMs have led to AS as a treatment option in the elderly and infirm population. In a large prospective cohort, we have shown that age, symptoms, tumour consistency and maximum diameter of the mass at diagnosis are not predictors of growth of T1a lesions. More knowledge on predictors of growth of SRMs is needed.

Objective: To examine the management and outcomes of patients with stage I seminoma and to relate these to overall treatment burden., Patients and Methods: A total of 764 patients with stage I seminoma underwent surveillance or adjuvant radiation therapy (RT) at a single institution. First relapse on surveillance was managed with RT alone, or with combination chemotherapy (ChT) for more extensive recurrence. Second relapse was managed with ChT. Relapse after adjuvant RT was treated with ChT. The treatment burden was measured, according to the specific treatment undertaken after orchiectomy, by defining treatment episodes as follows: surgery - one episode; one course of RT - one episode; one course of ChT - one episode., Results: In all, 484 patients underwent surveillance and 280 received adjuvant RT. The 5- and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant RT. A total of 72 (15%) patients in the surveillance group relapsed; treatment for relapse was RT (n = 56), ChT (n = 15) and surgery (n = 1). Second relapse occurred in six patients; these patients were treated with ChT. Of the patients in the adjuvant RT group, 14 (5%) relapsed: salvage treatment was 10 - ChT (n = 10) surgery (n = 1) and further RT (n = 3). The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant RT group., Conclusions: Surveillance reduces the overall treatment burden in patients with stage I seminoma and is the preferred management option. The selective use of RT at first relapse for patients on surveillance leads to a similar requirement for subsequent ChT to that for patients on adjuvant RT., (© 2013 The Authors. BJU International © 2013 BJU International.)

MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.

Purpose: Optimal quality of care is needed for ideal outcomes. In renal cell carcinoma (RCC), there is a lack of information defining optimal care. This is particularly important in RCC, with increased complexity of care and a need for coordination among providers. The goal of this study was to identify quality indicators (QIs) and measures of quality care across the RCC disease spectrum., Materials and Methods: A modified Delphi technique was used to select QIs that are relevant and practical to RCC care. This technique involved an expert panel of 13 urologic and medical oncologists who participated in two e-mail questionnaires and an in-person meeting to review and prioritize potential QIs. These potential QIs were identified from a systematic literature review or were suggested by panel members., Results: From 233 literature citations, 34 possible QIs were identified; 24 additional potential QIs were suggested. A final set of 23 QIs was established. These are distributed across the RCC disease spectrum as follows (number of QIs in parentheses): screening (n=1), diagnosis/prognosis (n=3), surgical for localized disease (n=6), surgery for advanced disease (n=3), systemic therapy (n=6), and follow-up (n=2). In addition, two QIs related to survival outcomes (overall and progression-free survival) were selected., Conclusion: A systematic, consensus-based approach was used to determine relevant QIs in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes in patients. The next step will be to establish a means of measuring each QI based on defined or yet-to-be-defined benchmarks.

Objective: The purpose of this study is to evaluate the interval growth, tumor recurrence, and metastatic disease occurrence of cystic renal cell carcinoma (RCC)., Materials and Methods: Pre-and posttreatment imaging of 47 histologically proven cystic RCCs, with at least 6 months of pretreatment imaging monitoring or at least 2 years of posttreatment imaging follow-up, or both, was retrospectively reviewed. Tumor morphologic features, preoperative growth, histologic typing and grading, and the incidence of tumor recurrence or metastasis were evaluated. Growth rate of tumors were compared among various histologic subtypes and Fuhrman grades., Results: Of 47 tumors, 27 (57.5%) were clear cell RCCs, 12 (25.5%) were multilocular RCCs, and eight (17%) were papillary cystic RCCs. Overall, 26 (55.3%) tumors were graded as Fuhrman grade 2, 17 (36.1%) were Fuhrman grade 1, and one tumor was Fuhrman grade 3. Of the 26 tumors with a minimum of 6 months of pretreatment imaging monitoring, 19 (73%) did not show a significant increase in tumor size. The differences in mean growth among the Fuhrman grades and different subtypes were not statistically significant. The average duration of posttreatment follow-up was 51 months. There were no local recurrences among the 43 patients who underwent posttreatment imaging, except for one patient who had metastasis at preoperative clinical presentation., Conclusion: Cystic RCCs exhibit slow indolent growth, if any, and show no significant metastatic or recurrence potential, with excellent clinical outcomes. We raise the need for revisiting current imaging protocols that may involve frequent pre-and posttreatment imaging in cystic RCCs.

Objective: In this study, we examine the oncologic outcomes of men with low, intermediate and high preoperative risk for prostate cancer treated with radical prostatectomy prior to and during the active surveillance era., Methods: We analyzed records from patients who underwent radical prostatectomy at our Canadian tertiary care facility from 2000 to 2012. Patients were stratified by D'Amico preoperative risk category and by year of treatment. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method., Results: We included 2643 consecutive patients in our analysis. The proportion of men with low-risk disease undergoing radical prostatectomy decreased from 2007 onwards coincident with the implementation of an active surveillance strategy in our institution. Men with low-risk and high-risk disease showed significantly worse biochemical outcomes from 2007 to 2012 compared to 2000 to 2006 (p < 0.05), while men with intermediate-risk prostate cancer showed no significant differences (p = 0.27). Within the low-risk cohort, the later treatment group displayed significantly lower age, pre-treatment prostate specific antigen and tumour volume and significantly higher testosterone and body mass index., Conclusions: The time period corresponding with the implementation of active surveillance at our institution corresponded with significant deterioration of biochemical outcomes in the low- and high-risk groups. This suggests that the men with most favourable disease deferred treatment, whereas men with worse preoperative disease characteristics were increasingly treated with radical prostatectomy in the past 6 years perhaps to their benefit.

Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.

Background: The serum tumor markers α-fetoprotein (AFP), β-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) are often measured as part of surveillance protocols in patients with stage I seminoma. In this study, the authors evaluated the utility of routine measurement of these markers in the detection of disease relapse., Methods: Data were gathered from a prospectively maintained database of patients who underwent surveillance for stage I testicular seminoma diagnosed between 1982 and 2005 at Princess Margaret Hospital. Patients were followed on a predefined schedule with physical examination (PE), serum tumor markers, abdominopelvic computed tomography, and chest x-rays. The records of patients who relapsed were examined for details of imaging and serum tumor markers throughout the period of follow-up until the time of relapse., Results: Of the 527 patients who were managed by surveillance, 75 patients (14%) relapsed at a median follow-up of 72 months. Of these, 65 patients relapsed within the first 3 years and had routine serum tumor markers measured. In total, 11 patients had abnormal tumor markers at the time of relapse (AFP, 0 patients; HCG, 6 patients; LDH, 4 patients; and HCG and LDH, 1 patient). Only 1 patient had an elevated tumor marker (LDH) before relapse, as defined by an abnormal imaging study (n = 64) or physical examination (n = 1), for which the treatment and outcome were not affected., Conclusions: Serum tumor marker levels did not aid in the early diagnosis of disease relapse in patients with stage I seminoma who were managed with surveillance. The current results indicated that routine measurement of serum tumor markers can be discontinued safely in seminoma surveillance schedules., (Copyright © 2012 American Cancer Society.)

Purpose: Deformable registration of histology to MRI is an essential tool to validate in vivo prostate cancer imaging. However, direct registration of histology to in vivo MR is prone to error due to geometric differences between the tissue sections and the in vivo imaging planes. To increase the accuracy of registration, an ex vivo high resolution MRI is acquired to compensate for the direct registration difficulties. A novel intensity-based deformable registration algorithm based on local variation in image intensities is proposed to register the histology to ex vivo MRI of prostatectomy specimens., Methods: Four sets of ex vivo MR and whole mount pathology images from four patients were used to investigate and validate the technique. In addition, 9 synthetically deformed ex vivo MR images were used. The standard deviation in local windows within the images was calculated to generate intermediate images based on both MR and histology. The intermediate images were registered using the Drop package (Munich, Germany). To further increase the accuracy, a final refinement of the registration was performed using Drop with a finer B-spline rid. The registration parameters were tuned to achieve a visually acceptable registration. Magnitude of Differences (MOD) and Angular Error (AE) were used to validate the synthetic data, and the Target Registration Error (TRE) of manually indicated landmarks was used for the clinical data., Results: MOD of 0.6mm and AE of 8.3 degrees showed the efficacy of using intermediate images, compared to 0.8mm and 10.0 degrees achieved with Drop without the intermediate images. The average mean±std TRE among the four patients was 1.0±0.6 mm using the proposed method compared to 1.6±1.1 mm using Elastix (Utrecht, The Netherlands)., Conclusions: An intensity-based deformable registration algorithm which uses intermediate images was evaluated on prostatectomy specimens and synthetically deformed clinical data, indicating improvement in overall accuracy and robustness. OICR, Terry Fox Ultrasound for Cancer Therapy. Dr. Brock is a Cancer Care Ontario Research Chair in Cancer Imaging and has financial interest in deformable registration technology through the licensing of Morfeus to RaySearch Laboratories., (© 2012 American Association of Physicists in Medicine.)

Urachal cancer is a rare form of bladder cancer that arises from the urachus, a vestigial musculofibrous band that extends from the dome of the bladder to the umbilicus. Urachal cancer often presents at an advanced stage and has a dismal prognosis. We present a case of a young woman with urachal cancer that recurred rapidly post-partial cystectomy. The patient was treated with up to 6 different chemotherapy regimens, including an oral antiangiogenic drug as part of a clinical trial. Our case illustrates the aggressive nature of this disease, the difficulty in accessing drugs for the treatment of rare cancers and the lack of late stage clinical trials to help guide therapeutic decisions.

Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The 5-year survival rate for metastatic RCC is ≤10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer., Method: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared with primary RCCs. We validated our results by quantitative real-time PCR. We performed experimental and bioinformatic analyses to explore the involvement of miR-215 in RCC progression and metastasis., Results: We identified 65 miRNAs that were significantly altered in metastatic compared with primary RCCs. We validated our results by examining the expression of miR-10b, miR-126, miR-196a, miR-204 and miR-215, in two independent cohorts of patients. We showed that overexpression of miR-215 decreased cellular migration and invasion in an RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumour metastasis., Conclusion: Our analysis showed that miRNAs are altered in metastatic RCCs and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.

Traditionally, overall survival (os) has been considered the "gold standard" for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of the increasing crossover and contamination of trials. As a result, the approval of promising new therapies may be delayed.Many clinicians believe that progression-free survival (pfs) is a more viable option for evaluating new therapies in metastatic and advanced renal cell carcinoma. As with all endpoints, pfs has inherent biases, and those biases must be addressed to ensure that trial results are not compromised and that they will be accepted by regulatory authorities. In this paper, we examine the issues surrounding the use of pfs as a clinical trial endpoint, and we suggest solutions to ensure that data integrity is maintained.

Background and Objectives: To evaluate the long-term prognostic value of the combination of the EORTC risk calculator and proapoptotic, antiapoptotic, proliferation, and invasiveness molecular markers in predicting the outcome of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) treated with intravesical Bacille Calmette-Guérin (BCG) therapy., Materials and Methods: This study included 42 patients accrued prospectively presenting with intermediate- to high-risk NMIBC (high-grade T1 tumors or multiple rapidly recurrent tumors refractory to intravesical chemotherapy) treated with transurethral resection (TUR) and BCG. TUR samples were analyzed for the molecular markers p53, p21 waf1/cip, Bcl-2, CyclinD1, and metallothionein 9 (MMP9) using immunohistochemistry. Frequency of positivity, measured as a percentage, was assessed alone or in combination with EORTC risk calculator, for interaction with outcome in terms of recurrence and progression using univariate analysis and Kaplan-Meier survival curves., Results: Median follow-up was 88 months (mean, 99; range, 14-212 months). The overall recurrence rate was 61.9% and progression rate was 21.4%. In univariate analysis, CyclinD1 and EORTC risk groups were significantly associated with recurrence (P value 0.03 and 0.02, respectively), although none of the markers showed a correlation to progression. In combining EORTC risk groups to markers expression status, high-risk group associated with positive MMP9, Bcl-2, CyclinD1, or p21 was significantly correlated to tumor recurrence (log rank P values <0.001, 0.03, 0.02, and 0.006, respectively) and when associated with positive MMP9 or p21, it was significantly correlated to progression (log rank P values 0.01 and 0.04, respectively)., Conclusion: Molecular markers have a long-term prognostic value when combined with EORTC scoring system and they may be used to improve the predictive accuracy of currently existing scoring system. Larger series are needed to confirm these findings.

Purpose: Renal cell carcinoma develops in renal transplant recipients 30 or more times more commonly than in the general population. We assessed the prevalence, histology and outcome of renal cell carcinoma in a large, single center recipient population., Materials and Methods: We examined outcomes in patients who underwent renal transplantation at our center to determine the prevalence, histology and outcome of those in whom renal cell carcinoma developed., Results: A total of 3,568 patients received a renal allograft at our institution between 1966 and 2009. A total of 45 renal cell carcinomas were diagnosed in the native kidney of 39 patients (1.1%) and in 8 (0.2%) renal cell carcinoma developed in the allograft kidney. Mean age at diagnosis was 51.6 and 48.2 years in patients with native kidney and allograft tumors, respectively. The mean interval between transplantation and the native or allograft renal cell carcinoma diagnosis was 10.6 and 12.1 years, respectively. Clear cell renal cell carcinoma was the most common tumor histology in native kidneys, diagnosed in 21 cases, while papillary renal cell carcinoma was diagnosed in 20. Five allograft tumors were papillary renal cell carcinoma and 3 were clear cell renal cell carcinoma. Native kidney tumors were managed by radical nephrectomy in 44 or by observation after biopsy. Allograft tumors were managed by transplant nephrectomy in 3 cases, radio frequency ablation in 3 and partial nephrectomy in 2. At a mean 6.6-year followup 32 patients with native kidney renal cell carcinoma were alive while 7 with allograft tumors were alive at a mean 3.6-year followup., Conclusions: Renal cell carcinoma is more prevalent in patients with renal transplantation than the general population, although the subtype distribution differs. Excellent survival is seen at more than 6 years after treatment., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: • To investigate androgen receptor (AR) expression in a large series of patients with bladder cancer (BC) because data on a limited number of patients showed that loss of AR expression was associated with invasive BC., Patients and Methods: • A total of 472 patients with urothelial bladder carcinoma (UBC) from two institutional centres (Toronto and Dallas) were analysed. Tissue microarrays comprising both non-muscle-invasive UBC (n= 167) and muscle-invasive UBC (n= 305) were accrued and immunohistochemical staining for AR was performed. • We used bright-field microscopy imaging coupled with advanced colour detection software to detect, classify and count stained cellular objects and manual scoring. • Results obtained in Dallas were blindly reviewed and validated in Toronto and samples randomly chosen were further analysed in Rochester, NY, USA., Results: • The AR were positively expressed in 61/472 (12.9%) bladder tumours. No statistically significant difference in AR expression between men and women was observed. • Only 9.0% of non-muscle-invasive BC expressed the AR compared with 15.1% of muscle-invasive tumours (P= 0.059). The highest percentage of AR positivity (28.9% of cases) was found in T2 tumours. • There was no statistically significant difference in death from BC, time to death, or time to recurrence between AR-positive and AR-negative cases., Conclusion: • In contrast to previous reports, based on our large BC series, we did not observe a decrease in AR protein expression in bladder tumours with increased pathological stage. Our data do not suggest that loss of AR expression is gender-related nor is it associated with invasive BC., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Purpose: The American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial comparing radical prostatectomy (RP) and brachytherapy (BT) closed after 2 years due to poor accrual. We report health-related quality of life (HRQOL) at a mean of 5.3 years for 168 trial-eligible men who either chose or were randomly assigned to RP or BT following a multidisciplinary educational session., Patients and Methods: After initial lack of accrual, a multidisciplinary educational session was introduced for eligible patients. In all, 263 men attended 47 sessions. Of those, 34 consented to random assignment, 62 chose RP, and 94 chose BT. Five years later, these 190 men underwent HRQOL evaluation by using the cancer-specific 50-item Expanded Prostate Cancer Index Composite, the Short Form 12 Physical Component Score, and Short Form 12 Mental Component Score. Response rate was 88.4%. The Wilcoxon rank sum test was used to compare summary scores between the two interventions., Results: Of 168 survey responders, 60.7% had BT (9.5% randomly assigned) and 39.3% had RP (9.5% randomly assigned). Median age was 61.4 years for BT and 59.4 for RP (P = .05). Median follow-up was 5.2 years (range, 3.2 to 6.5 years). For BT versus RP, there was no difference in bowel or hormonal domains, but men treated with BT scored better in urinary (91.8 v 88.1; P = .02) and sexual (52.5 v 39.2; P = .001) domains, and in patient satisfaction (93.6 v 76.9; P < .001)., Conclusion: Although treatment allocation was random in only 19%, all patients received identical information in a multidisciplinary setting before selecting RP, BT, or random assignment. HRQOL evaluated 3.2 to 6.5 years after treatment showed an advantage for BT in urinary and sexual domains and in patient satisfaction.

A biomechanical model-based deformable image registration incorporating specimen-specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration.

Background: Device implant pocket hematoma is a recognized complication after permanent pacemaker (PM) and implantable cardioverter-defibrillator (ICD) implantation. Pocket hematoma is associated with local discomfort, an increased risk of infection, and may require surgical intervention or lead to lengthier hospital stays. The purpose of the study was to identify the clinical factors associated with hematoma formation after PM or ICD device implantation., Methods and Results: The subjects of this prospective observational study were 935 consecutive patients at Beaumont Hospital who underwent implantation of a PM or an ICD. Clinical characteristics and anticoagulant/antiplatelet drug use were recorded. A pocket hematoma was documented in 89 of 935 patients. Significant predictors of device pocket hematoma included ongoing clopidogrel therapy (18.3% on therapy, 10.5% recently discontinued, and 7.9% off therapy; P<0.001) and use of intravenous heparin (22.0% on therapy versus 8.2%; P<0.0001). Patients in whom clopidogrel was discontinued >4 days before device implantation had no hematoma. Hematomas occur more frequently in patients receiving ICDs than those receiving PMs. Device pocket hematoma was associated with an increased median length of hospital stay (4 days [interquartile range, 1 to 9] days with versus 2 days [ interquartile range, 1 to 6] days without hematoma; P=0.004) and increased late complications or surgical intervention., Conclusions: The use of clopidogrel or intravenous heparin significantly increased the risk of hematoma at the time of PM or ICD implantation. By withholding clopidogrel before surgery, the excess risk of bleeding complications may be reduced.

After orchidectomy and staging, patients with clinical stage I (CS I) non-seminomatous testicular cancer (NSTC) may be offered chemotherapy, surgery or active surveillance. The optimal postoperative approach is undefined. Therefore, a systematic review was carried out to assess these management approaches. Eligible studies, systematic reviews and clinical practice guidelines included patients with CS I NSTC or a mixed seminoma/non-seminoma diagnosis. The primary outcomes of interest included cancer cure, long-term toxicity and quality of life. In total, 32 unique reports met the selection criteria. Cancer cure rates were excellent regardless of the management option selected. Overall and disease-free survival rates were over 95% for all management approaches; recurrence rates were higher in the patients managed by surveillance. In conclusion, patients with CS I NSTC should be assessed and managed at multidisciplinary centres by health care professionals experienced in the treatment of testicular cancer. On the basis of the available evidence, the Genitourinary Disease Site Group recommended primary surveillance for all patients with CS I NSTC, with treatment if relapse occurs. As cancer cure rates are similar with primary surveillance, adjuvant chemotherapy and retroperitoneal lymphadenectomy, patient preference with respect to the risk of recurrence and the timing and toxicities of treatment must be considered. For patients who prefer immediate treatment, or who are unsuitable for primary surveillance, adjuvant chemotherapy with two cycles of bleomycin, etoposide (500mg/m(2)/cycle) and cisplatin was recommended. Surgeons involved in the development of this guideline suggested that retroperitoneal lymphadenectomy may be a useful option for patients at high risk of relapse. There is currently insufficient evidence from prospective trials to support or refute this position., (Copyright (c) 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Positive surgical margins have a negative impact on disease outcomes after radical prostatectomy, yet their prognostic value may vary depending on specific pathological characteristics. We examined the relationship of positive surgical margins to biochemical progression according to several clinicopathological features., Materials and Methods: We analyzed data from 1,268 patients who underwent radical prostatectomy for clinically localized prostate cancer at our center between 1992 and 2008, and did not receive any neoadjuvant or adjuvant treatment. We examined the relation of age, pretreatment prostate specific antigen, pathological T stage, radical prostatectomy Gleason score, disease risk group and surgical margin status to biochemical progression-free survival., Results: The overall positive surgical margin rate was 20.8% and median followup was 79 months. The impact of positive surgical margins was dependent on risk group. Biochemical progression-free survival was 99.6% for the negative surgical margin group vs 94.9% for the positive surgical margin group in low risk disease (log rank p = 0.53), 93.5% for the negative surgical margin group vs 83% for the positive surgical margin group in intermediate risk disease (log rank p <0.001) and 78.5% for the negative surgical margin group vs 57.1% for the positive surgical margin group in high risk disease (log rank p = 0.003). These differences remained significant in a multivariate Cox regression model adjusting for other clinicopathological features., Conclusions: Positive surgical margins are an independent predictor of biochemical progression in patients with intermediate and high risk prostate cancer. Patients with low risk disease have a favorable long-term outcome regardless of margin status and may be candidates for expectant management even with positive surgical margins, sparing them the side effects and costs of treatment.

Purpose: Laparoscopic or robot assisted laparoscopic radical prostatectomy is often performed via a transperitoneal approach for prostate cancer, in contrast to open retropubic radical prostatectomy. Theoretically transgressing the peritoneum may introduce small bowel loops into the pelvis, increasing the risk of small bowel injury with adjuvant radiotherapy. We compared the incidence of small bowel within the planning target volume for radiotherapy to the prostate bed in patients who underwent open retropubic and laparoscopic radical prostatectomy., Materials and Methods: A total of 25 patients recently treated with laparoscopic radical prostatectomy prospectively provided consent to undergo radiotherapy planning computerized tomography simulation to assess the incidence of small bowel within the prostate bed planning target volume. These studies were compared to radiotherapy planning computerized tomography in 50 patients who underwent open retropubic radical prostatectomy and received adjuvant or salvage radiotherapy for prostate cancer. For all computerized tomography images 1 blinded observer delineated the distal small bowel loops and 1 blinded radiation oncologist delineated the superior extent of clinical and planning target volumes., Results: The overlap rate between small bowel and planning target volume was 16% in the laparoscopic and open radical prostatectomy groups (p = 0.579)., Conclusions: There is no difference between transperitoneal laparoscopic and open retropubic radical prostatectomy in the incidence of small bowel within the planning target volume for radiotherapy to the prostate bed. Thus, patients who undergo transperitoneal laparoscopic radical prostatectomy do not face a higher risk of toxicity or compromise due to adjuvant or salvage radiotherapy should they require it.

Purpose: To define a population-based pelvic lymph node clinical target volume (CTV) for radiotherapy treatment planning using magnetic resonance (MR) imaging and the ultrasmall superparamagnetic iron oxide lymph node contrast agent ferumoxtran-10., Methods and Materials: A total of 55 eligible patients with endometrial, cervical, prostate, or bladder cancer underwent MR imaging sessions before and after contrast administration on 2 consecutive days. Ferumoxtran-10 was administered immediately after the first scan. The three-dimensional spatial distribution of the pelvic lymph nodes was determined in relation to adjacent vessels and other musculoskeletal landmarks, from which guidelines for determining a nodal CTV in individual patients were developed., Results: On average, 30 lymph nodes (range, five to 62 nodes) were identified in each patient. The distribution of nodal distances to the closest artery or vein was observed to vary in different anatomic regions. Symmetrical three-dimensional margins of expansion around the distal para-aortic (12 mm), common iliac (10 mm), external iliac (9 mm), and internal iliac (10 mm) vessels, drawn in continuity with a 12-mm expansion anterior to the sacrum and a 22-mm expansion medial to the pelvic sidewall, were shown to encompass the majority of detectable lymph nodes in most patients., Conclusion: Use of MR lymphography with ferumoxtran-10 provides an objective description of lymph node locations for radiotherapy planning. Use of this nodal CTV model in clinical practice could ensure a high probability of encompassing the regions at risk of harboring metastatic disease while minimizing the dose to adjacent normal tissues.