Diagnostic miRNA Signatures in Paired Tumor, Plasma, and Urine Specimens From Renal Cell Carcinoma Patients.

BACKGROUND: The incidence of patients diagnosed with renal cell carcinoma (RCC) is increasing. There are no approved biofluid biomarkers for routine diagnosis of RCC patients. This retrospective study aims to identify cell-free microRNA (cfmiR) signatures in urine samples that can be utilized as biomarkers for early diagnosis of sporadic RCC patients. METHODS: Tissue, plasma, and urine samples (n = 221) from 56 sporadic RCC patients and respective normal healthy donors were profiled for 2083 microRNAs (miRs) using the next-generation sequencing-based HTG EdgeSeq miR Whole Transcriptome Assay. DESeq2 (FC |1.2|, false discovery rate <0.05) was performed to identify differentially expressed miRs. Data from RCC tissue samples of The Cancer Genome Atlas database were used for miR validation. RESULTS: We found a 10-miR signature that distinguished RCC tissues from remote normal kidney tissue or benign kidney lesion samples. Additionally, we identified subtype-specific miRs (miR-122-5p, miR-210-3p, and miR-21-3p) and miRs specific for all RCC subtypes (miR-106b-3p, miR-629-5p, and miR-885-5p). We observed that miR-155-5p was associated with tumor size. Using The Cancer Genome Atlas data sets, we validated the miRs found in RCC tissue samples. In plasma or urine analysis, we found cfmiRs that were consistently and significantly upregulated in RCC tissue samples. A 15-cfmiR signature was proposed in urine samples of RCC patients, of which miR-1275 was consistently upregulated in tissue, plasma, and urine samples. CONCLUSIONS: This integrative study found diagnostic miRs/cfmiRs for RCC patients, which were validated using The Cancer Genome Atlas data sets. Distinctive cfmiR signatures found in urine may have clinical utility for the diagnosis of RCC.

Feasibility of optical coherence tomography imaging to characterize renal neoplasms: limitations in resolution and depth of penetration.

UNLABELLED: What's known on the subject? and What does the study add? Optical coherence tomography has been used for the diagnosis of retinal disease and has been used experimentally for imaging of vascular plaques, gastrointestinal pathology, bladder cancer, prostate cancer, and recently to examine benign kidney microanatomy. It has not been previously used to image kidney cancer. This study presents the first data on the utility of OCT in the imaging for renal neoplasms. It found that OCT was most successful in distinguishing AML and TCC from normal parenchyma. OCT had more limited success at differentiating oncocytoma. Clear cell tumors and other renal cancer subtypes had a more heterogenous appearance, precluding reliable identification using OCT. The study shows that higher resolution versions of OCT, such as OCM, will be needed to allow optical coherence imaging to reach clinical utility in the assessment of renal neoplasms. OBJECTIVES: • To determine the appearance of normal and neoplastic renal tissue when imaged with optical coherence tomography (OCT). • To preliminarily assess the feasibility of using OCT to differentiate normal and neoplastic renal tissue. PATIENTS AND METHODS: • After radical or partial nephrectomy in 20 subjects, normal renal parenchyma and neoplastic tissue samples were obtained. • The tissue was evaluated with light microscopy and using a bench-top laboratory OCT system with a lateral resolution of 10 µm. • OCT images were compared with histological slides to evaluate the ability of OCT to differentiate renal neoplasms. RESULTS: • Pathological subtypes included eight clear-cell, three papillary and two chromophobe renal carcinomas; two oncocytomas; one angiomyolipoma (AML); two transitional cell carcinomas (TCCs); and one haematoma. • Using OCT, benign renal parenchyma showed recognizable glomeruli and tubules. • TCC had a distinctive appearance on OCT whereas AML showed a unique identifiable signature because of its fat content. Oncocytomas had a lobulated appearance, which appeared subtly different from renal carcinoma. • Renal carcinoma lacked recognizable anatomical elements and had a heterogeneous appearance making differentiation from normal parenchyma at times difficult. • Subtypes of renal cancer appeared to vary on OCT imaging although discrimination was unreliable. CONCLUSIONS: • OCT imaging for renal neoplasms was most successful in distinguishing AML and TCC from normal parenchyma and malignant tumours. Oncocytoma differed subtly from renal carcinoma, making distinction more challenging. • Clear-cell tumours and other renal carcinoma subtypes had a heterogeneous appearance on OCT, which precluded reliable differentiation from normal parenchyma and between renal carcinoma subtypes. • Higher resolution versions of optical coherence imaging, such as optical coherence microscopy, will be necessary to achieve clinical utility.

Kidney cancer: the new landscape.

PURPOSE OF REVIEW: The approach to treatment of renal cancer has shifted dramatically from radical surgery to a current emphasis on nephron-sparing treatment. We review the changes in renal cancer presentation and our understanding of its clinical behavior that have driven this shift in treatment philosophy. RECENT FINDINGS: Renal cancer incidence has increased progressively in the USA. In Europe, incidence trends have been variable. Renal cancers are increasingly being diagnosed incidentally. Increasing utilization of abdominal imaging will likely continue this trend. Renal cancer size at presentation has decreased. Fewer cases are presenting with metastasis. Mean age at diagnosis has increased slightly. Experience with active surveillance suggests that a significant percentage of small renal masses are indolent and possess a low metastatic risk. SUMMARY: The presentation of renal cancer has evolved. There has been an increase in the incidence of cases in the USA and several European countries and at the same time a shift to incidentally diagnosed, smaller, localized tumors in a slightly older population. This new landscape of renal cancer patients can be offered an expanded list of treatment options, including focal therapies, with an increased treatment priority on preservation of renal function and minimization of treatment morbidity.

Emerging Utility of Urinary Cell-free Nucleic Acid Biomarkers for Prostate, Bladder, and Renal Cancers.

CONTEXT: By 2020 the estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. Given the utility of blood-based cell-free nucleic acid (cfNA) biomarkers, the development of urinary cfNA biomarkers may improve the sensitivity of urine assays utilizing urine sediment for GU cancers. This review of urinary cfNA in GU cancers identifies the current stage of research, potential clinical utility, and the next steps needed to enter clinical use. OBJECTIVE: To critically evaluate the literature of urinary cfNA in GU cancers for clinical utility in diagnosis, screening, and precision medicine. Furthermore, the strategy for future efforts to discover potential new urinary cfNA biomarkers will be described. EVIDENCE ACQUISITION: A PubMed database (2006 to current) search was performed according to Preferred Reporting Items for Systemic Review and Meta-analysis using key Medical Subject Headings terms. Additional studies were obtained by cross-referencing from the literature. EVIDENCE SYNTHESIS: The collective research publications in urinary cfNA of GU cancers present a promising alternative liquid biopsy approach compared with blood biopsies and urine sediment, particularly for early-stage GU diseases. CONCLUSIONS: Urinary cfNA as a liquid biopsy holds potential for a more sensitive alternative to blood biopsies and urine sediment-based tests for clinical use in GU cancers. Not only does urinary cfNA offer advantages including the potential for more frequent testing, monitoring, and home use, but also has applications in early-stage GU cancers. PATIENT SUMMARY: In this review, we evaluated the current status of urinary cell-free nucleic acid in genitourinary cancers. We identified the potential advantages of urinary cell-free nucleic acid over blood and urine sediment and its clinical use in genitourinary cancer.

Detoxification of the polyamine analogue N1-ethyl-N11-[(cycloheptyl)methy]-4,8-diazaundecane (CHENSpm) by polyamine oxidase.

PURPOSE: Analogues of the naturally occurring polyamines, alkylated on both terminal amines, are being developed as anticancer drugs. Because bisalkylated derivatives of putrescine (1,4-diaminobutane) are potent inhibitors of the flavin adenine dinucleotide-dependent polyamine oxidase (PAO), we asked whether PAO could detoxify synthetic bisalkylated polyamines with chain lengths longer than putrescine. EXPERIMENTAL DESIGN: We investigated the effects of one polyamine analogue in Chinese hamster ovary (CHO) and HCT116 human colon tumor-derived cells, which express dramatically different levels of PAO activity, and in these same cells treated with an inhibitor of PAO. RESULTS: Concentrations of N1-ethyl-N11-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm), ranging from 0.3 to 10 microM, caused growth arrest and reduced cell survival in HCT116 cells but not in CHO cells. This cell line-specific difference in CHENSpm toxicity was not attributable to differences in analogue uptake, because intracellular levels of the drug were similar in CHO and HCT116 cells treated with equivalent concentrations of CHENSpm in the presence of MDL 72,527, a specific inhibitor of PAO. The PAO inhibitor, in combination with CHENSpm, caused a significant increase in intracellular CHENSpm levels and increased growth inhibition and cell damage in CHO cells but not in HCT116 cells. CHO cells, but not HCT116 cells, produced two primary amine-containing metabolites from CHENSpm that were suppressed by MDL 72,527. CONCLUSIONS: These data demonstrate that CHENSpm is detoxified in PAO-expressing CHO cells, but not in PAO-deficient HCT116 cells, by a mechanism yielding products containing free primary amine groups and implicate PAO as the detoxification enzyme. Because other studies suggest that PAO may be self-regulated in some tumors, differential expression of PAO may be the basis for selective toxicity of CHENSpm and other N-substituted polyamine analogues in certain cancers.

Standardized analysis of frequency and severity of complications after robot-assisted radical cystectomy.

BACKGROUND: Comprehensive and standardized reporting of adverse events after robot-assisted radical cystectomy (RARC) and urinary diversion for bladder cancer is necessary to evaluate the magnitude of morbidity for this complex operation. OBJECTIVE: To accurately identify and assess postoperative morbidity after RARC using a standardized reporting system. DESIGN, SETTING, AND PARTICIPANTS: A total of 241 consecutive patients underwent RARC, extended pelvic lymph node dissection, and urinary diversion between 2003 and 2011. In all, 196 patients consented to a prospective database, and they are the subject of this report. Continent diversions were performed in 68% of cases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All complications within 90 d of surgery were defined and categorized by a five-grade and 10-domain modification of the Clavien system. Univariable and multivariable logistic regression analyses were used to identify predictors of complications. Grade 1-2 complications were categorized as minor, and grade 3-5 complications were categorized as major. All blood transfusions were recorded as grade ≥2. RESULTS AND LIMITATIONS: Eighty percent of patients (156 of 196 patients) experienced a complication of any grade ≤90 d after surgery. A total of 475 adverse events (113 major) were recorded, with 365 adverse events (77%) occurring ≤30 d after surgery. Sixty-eight patients (35%) experienced a major complication within the first 90 d. Other than blood transfusions given (86 patients [43.9%]), infectious, gastrointestinal, and procedural complications were the most common, at 16.2%, 14.1%, and 10.3%, respectively. Age, comorbidity, preoperative hematocrit, estimated blood loss, and length of surgery were predictive of a complication of any grade, while comorbidity, preoperative hematocrit, and orthotopic diversion were predictive of major complications. The 90-d mortality rate was 4.1%. The main limitation is lack of a control group. CONCLUSIONS: Analysis of postoperative morbidity following RARC demonstrates a considerable complication rate, though the rate is comparable to contemporary open series that followed similar reporting guidelines. This finding reinforces the need for complete and standardized reporting when evaluating surgical techniques and comparing published series.

Evaluation of polyethylene glycol based hydrogel for tissue sealing after laparoscopic partial nephrectomy in a porcine model.

PURPOSE: Polyethylene glycol (PEG) based hydrogel is available as a tissue sealant and hemostatic aid. We determined the long-term safety and efficacy of its use as a tissue sealant for laparoscopic partial nephrectomy in a porcine model. MATERIALS AND METHODS: A total of 16 swine were cycled to 1 control group and 3 treatment groups, which underwent laparoscopic partial nephrectomy with hemostasis achieved only with application of a biodegradable PEG based hydrogel. The 3 treatment groups were sacrificed at 2, 6 and 12 weeks, respectively. Humoral immune response to the hydrogel used in the porcine abdomen was examined using enzyme-linked immunosorbent assay to detect antibodies in the serum at 0, 2, 6 and 12 weeks. Cell mediated immune response was examined using a lymphocyte proliferation assay to measure the response of leukocytes to various mitogens and antigens, including the polymerized hydrogel, at the same intervals. RESULTS: Hemostasis was satisfactory after hydrogel application. No adverse effects in the immediate and delayed periods were noted. At 2, 6 and 12 weeks there were no significant differences in hemoglobin or creatinine levels, or in the humoral immune response by enzyme-linked immunosorbent assay. There was no significant difference between test and control pig reactivity to hydrogel as an antigen in the lymphocyte proliferation assay at any time point. Histologically by 6 weeks the animals had almost absorbed the hydrogel with acute inflammation and foreign body reaction resolving by 6 to 12 weeks. No deleterious effect to renal tubules was seen. CONCLUSIONS: Biodegradable PEG based hydrogel is effective for long-term use as an agent for hemostasis. There was no detectable humoral immune response and no cell mediated immune response to sealant after 2 weeks. This represents promising sealant technology and it should be further investigated for human use.