Robotic-assisted laparoscopic pyeloplasty for the treatment of ureteropelvic junction obstruction - How should success be determined?

BACKGROUND: Ureteropelvic junction obstruction (UPJO) is characterised by stenosis of the ureteral lumen at the level of the renal pelvis and proximal ureter. At Haukeland University Hospital, robotic-assisted laparoscopic pyeloplasty (RLP) for UPJO has been performed since 2014. The aim of this study was to evaluate the results of the treatment and consider what determines treatment success. MATERIALS AND METHODS: Retrospective review was performed of consecutive patients undergoing RLP between 2014-2022. Outcomes of interest included symptom relief, complication rates and renographic findings at follow-up. Treatment success was defined in terms of symptom improvement and/or improvement as well as relief of obstruction on renography. RESULTS: In total, 95 RLPs were performed in 54 women and 41 men, with a mean age of 40 years (IQR: 21-58). Flank pain was the most frequent presenting complaint (n = 81, 85%) followed by infection (n = 33, 35%). More than one indication for surgery was present in 1/3 of the patients. Urodynamic relevant obstruction on renography was found in 62 patients (65%) preoperatively. Mean operative time was 123 minutes (range 60-270). Two patients experienced minor intraoperative complications. At three months follow-up, 91% of patients had symptom relief, and no obstruction on renography was recorded in 64%. There was no significant association between improvement in symptoms and renography findings at follow-up, p = 1. CONCLUSIONS: RLP can deliver a high success rate in terms of symptom relief and few complications. There was no association between renography findings and symptom relief at follow-up. Success after surgery should be determined by symptom relief rather than renography findings.

A preoperative magnetic resonance imaging can aid in staging and treatment choice for upper tract urothelial carcinoma.

Objectives: The aim was to investigate the predictive abilities of a preoperative diffusion-weighted MRI (dwMRI) among patients with surgically treated upper tract urothelial carcinoma (UTUC). Materials and methods: Written consent was obtained from all participants in this prospective and ethically approved study. Thirty-five UTUC patients treated with radical surgery were examined with a preoperative dwMRI and prospectively included during 2017-2022. Two radiologists examined the CT scans and dwMRIs for radiological stage, and the apparent diffusion coefficient (ADC) in the tumours at the dwMRI was registered. The radiologists were blinded for patient history, final histopathology and the readings of the other radiologist. The radiological variables were analysed regarding their abilities to predict muscle-invasive disease (MID, T2-T4) and tumour grade at final pathology after radical surgery. The predictive abilities were assessed using chi-square tests, Student's t-test and calculating the area under the curve in a receiver operating characteristic (ROC) curve. Correlation between the two radiologists was quantified calculating the intra-class correlation coefficient. P-values <0.05 were considered statistically significant. Results: Mean age was 72 years, 20 had high-grade tumour, and 13 patients had MID. The ADC values at the dwMRI were significantly lower among patients with MID compared to patients with non-muscle-invasive disease (930 vs 1189, p = <0.001). The area under the ROC curve (AUC) in an ROC curve to predict MID was 0.88 (CI 0.77-0.99, p = <0.001). The ADC values were significantly lower among patients with high-grade tumours compared to low-grade tumours (1005 vs 1210, p = 0.002). The correlation of the ADC measurements between the two radiologists was of 0.93 (CI 0.85-0.96, p < 0.001). Conclusion: Tumour ADC at the MRI emerges as a potential biomarker for aggressive disease. The results are promising but should be validated in a larger, multicentre study.

Current status of the adjustable transobturator male system (ATOMSTM) for male stress urinary incontinence.

Male stress urinary incontinence is a debilitating condition, which can occur after prostate surgery. In persistent cases, surgery is indicated and a number of options are available. This includes one of the male slings, Adjustable transobturator male system (ATOMSTM, A.M.I, Austria). There are now an increasing number of studies published. This review provides an overview of the current status of this implant device including technical considerations, surgical outcomes and potential advantages and disadvantages compared to alternatives such as the artificial urinary sphincter.

Outcomes with the Adjustable Transobturator Male System (ATOMS) for the Treatment of Male Stress Urinary Incontinence After Prostate Surgery and the Impact of Previous Radiotherapy.

Background and objective: The adjustable transobturator male system (ATOMS) is an established treatment for patients with urinary incontinence after prostate surgery. Our objective was to evaluate the efficacy and the complication burdens associated with ATOMS with a focus on exploring the potential impact on previous radiotherapy (RT). Methods: We performed a retrospective analysis for consecutive patients who underwent ATMOS implantation procedure at a tertiary center over an 11-yr study period. Outcomes of interest were dryness at 3-mo follow up, postoperative complications (≤30 d), and late treatment failures (>30 d). Key findings and limitations: A total of 118 patients underwent ATOMS surgery performed by five different surgeons. Median follow-up was 67 mo (interquartile range 41-95). The mean 24-h pad count after surgery was 1.1 (range 0-8) and the mean reduction in pad weight was 179 g (range 0-1080). There was no significant difference in the reduction in pad use between groups with and without RT (-1.7 vs -2.4; p = 0.13). Multivariable analysis revealed that RT, degree of incontinence, and age were not risk factors for reoperation. Conclusions and clinical implications: ATOMS implantation is feasible in patients who have undergone prostate RT and patients with severe stress urinary incontinence after prostate surgery. We found that RT was not a risk factor for reoperation and there was no significant difference in pad weight reduction by RT status. This study offers new insight into potential incontinence surgery for male patients with stress urinary incontinence and previous RT. Patient summary: We assessed outcomes for patients who had an ATOMS (adjustable transobturator male system) device implanted to control stress urinary incontinence after prostate surgery. After implantation, 52.5% of the patients reported zero leakage and 39.9% reported only mild incontinence. Our results show that this device can improve continence after prostate surgery and is also suitable in patients who underwent radiotherapy.

Prediction of clinically significant recurrence after partial nephrectomy. Data from the Cancer Registry of Norway with more than five years of follow-up.

OBJECTIVE: To determine recurrence incidence after partial nephrectomy (PN) for renal cell carcinoma and identify predictors for local recurrence (LR) and metastasis. MATERIAL AND METHODS: We retrospectively evaluated a cohort of 524 patients from the Cancer Registry of Norway, who underwent PN between January 2014 and December 2015 and were followed-up for >6 years. Patient demographics and pathological characteristics were correlated with recurrence and progression-free survival using Kaplan-Meier and Cox regression analyses. RESULTS: Median patient age was 64 years, and the median tumour size was 2.6 cm. A positive surgical margin (PSM) was observed in 11% of the cases, while the LR and metastasis rates were 3.4% and 3.2%, respectively. PSM (hazard ratio [HR], 55.4; 95% confidence interval [CI], 12.55-244.6), tumour number (HR, 45.4; 95% CI, 6.5-316.1) and stage (HR, 33.5; 95% CI, 5.4-205.3) were independent predictors for LR. Undetermined margin status was also a risk factor for LR. Tumour stage (HR, 41.05; 95% CI, 8.52-197.76), tumour necrosis (HR, 1.3; 95% CI, 0.4-4.31) and age (HR, 1.07; 95% CI, 1.01-1.14) were predictors for metastasis. CONCLUSIONS: Both local and distant recurrences after PN were rare, and the pT stage was a common predictor. PSM or indeterminate surgical margin and tumour number were LR predictors, while age at surgery and the presence of tumour necrosis predicted metastasis.

Management of Bladder Pain Syndrome (BPS): A Practical Guide.

Bladder pain syndrome (BPS) is a prevalent and pervasive disease. The physical and psychological sequelae can be very burdensome for the patient, and the condition represents a real challenge for the clinician as well. With no simple pathognomonic test, finding harmony in navigating patient care can be demanding. Diagnosis and management rely upon a multidisciplinary and holistic approach. Treatment options include conservative measures and pharmacotherapies as well as bladder instillation therapies. Ultimately, surgery may be offered but only in cases of refractory disease. This article offers a pragmatic guide for clinicians managing this challenging disease.

Current Status of Intravesical Therapies for Bladder Pain Syndrome (BPS): A Narrative Review of Emerging Evidence.

Bladder pain syndrome (BPS) is a complex condition, which can have debilitating sequelae for patients. Many elements of BPS remain poorly understood including pathophysiology, diagnosis and treatment. Navigating patient care can therefore be challenging for the clinician. Management mandates a multidisciplinary and symptom-based approach. Intravesical treatments such as instillation therapies remain a cornerstone of most treatment algorithms and there are a range of agents that can be selected. This review offers an up-to-date evaluation of the evidence for these intravesical treatments.

The levels of IL-6 and soluble IL-33R are increased in the renal vein during surgery for clear cell renal cell carcinoma.

PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.

Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).

PURPOSE: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. METHODS: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. RESULTS: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. CONCLUSIONS: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

The Biological Context of C-Reactive Protein as a Prognostic Marker in Renal Cell Carcinoma: Studies on the Acute Phase Cytokine Profile.

High serum levels of the acute phase protein C-reactive protein (CRP) are associated with an adverse prognosis in renal cancer. The acute phase reaction is cytokine-driven and includes a wide range of inflammatory mediators. This overall profile of the response depends on the inducing event and can also differ between patients. We investigated an extended acute phase cytokine profile for 97 renal cancer patients. Initial studies showed that the serum CRP levels had an expected prognostic association together with tumor size, stage, nuclear grading, and Leibovich score. Interleukin (IL)6 family cytokines, IL1 subfamily mediators, and tumor necrosis factor (TNF)α can all be drivers of the acute phase response. Initial studies suggested that serum IL33Rα (the soluble IL33 receptor α chain) levels were also associated with prognosis, although the impact of IL33Rα is dependent on the overall cytokine profile, including seven IL6 family members (IL6, IL6Rα, gp130, IL27, IL31, CNTF, and OSM), two IL1 subfamily members (IL1RA and IL33Rα), and TNFα. We identified a patient subset characterized by particularly high levels of IL6, IL33Rα, and TNFα alongside an adverse prognosis. Thus, the acute phase cytokine reaction differs between renal cancer patients, and differences in the acute phase cytokine profile are associated with prognosis.

Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial.

BACKGROUND: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. METHODS: We did a randomised, controlled, phase 2-3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen-A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18-80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30-40 sessions, 100% oxygen, breathed at a pressure of 240-250 kPa, for 80-90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6-8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. FINDINGS: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210-262) in the hyperbaric oxygen therapy group and 217 days (195-237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2-18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1-2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. INTERPRETATION: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. FUNDING: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.

Real-life use of diagnostic biopsies before treatment of kidney cancer: results from a Norwegian population-based study.

OBJECTIVE: Interest in renal mass biopsies (RMBs) has increased in recent years. However, most publications are low-volume and/or single-center studies, so their generalizability is questionable. The aim of this study was to describe population-based, real-life use of diagnostic RMBs for localized and advanced kidney cancer (KC). MATERIALS AND METHODS: All KC patients diagnosed during 2008-2013 extracted from the database at the Cancer Registry of Norway were included. Relationships with outcome were analyzed using multivariate logistic regression and competing risks analyses. RESULTS: Of patients treated radically for localized KC, a pretreatment RMB was used in 8.4%. For similar patients treated by observation only, the rate increased from 29.3% to 60.7% during the study period. Tumor size ≤4 cm, another malignancy, multiple tumors, old age (≥ 80 years) and second study half were independent RMB predictors. Competing risks analysis showed that among radically treated patients with localized KC, those who had undergone an RMB had a higher risk of dying of other diseases. In patients with advanced KC, biopsy was used in 54.5%, and is increasing. Study limitations include a lack of data on benign tumors, comorbidity and performance status. CONCLUSIONS: For localized KC, the use of RMBs in Norway is in line with current guidelines. Because real-world data on RMB use are scarce, this study is useful for benchmarking in future studies. Furthermore, the study shows that fewer patients with advanced KC are treated without histopathological verification, and biopsies seem to have an increasing role in tailoring treatment.

National Norwegian Practice Patterns for Surgical Treatment of Kidney Cancer Tumors ≤7cm: Adherence to Changes in Guidelines May Improve Overall Survival.

BACKGROUND: Guidelines on surgical treatment for kidney cancer (KC) have changed over the last 10 yr. We present population-based data for patients with KC tumors ≤7cm from 2008 to 2013 to investigate whether surgical practice in Norway has changed according to guidelines. OBJECTIVE: To assess the predictors of treatment and survival after KC surgery. DESIGN, SETTING, AND PARTICIPANTS: We identified all surgically treated KC patients with tumors ≤7cm without metastasis diagnosed during 2008-2013 (2420 patients) from the Cancer Registry of Norway. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcomes were analyzed using joinpoint regression, multivariate logistic regression, Kaplan-Meier survival estimates, Cox regression, relative survival (RS), and competing-risk analyses. RESULTS AND LIMITATIONS: The mean follow-up was 5.2 yr. There was a 28% increase in the number of patients undergoing surgical treatment over the study period. Joinpoint regression revealed a significant annual increase in partial nephrectomy (PN) and a small reduction in radical nephrectomy (RN). PN increased from 43% to 66% for tumors ≤4cm and from 10% to 18% for tumors of 4.1-7cm. Minimally invasive (MI) RN increased from 53% to 72% and MI PN from 25% to 64%, of which 55% of procedures were performed with robotic assistance in 2013. The geographical distribution of treatment approaches differed significantly. Both PN and MI approaches were more frequent in high-volume hospitals. Cox regression analysis revealed that PN, age, and Fuhrman grade and stage were independent predictors of survival. There were no significant differences in cancer-specific survival (p=0.8). The 5-yr RS for T1a disease was higher after PN than after RN. CONCLUSIONS: The rate of PN for tumors ≤7cm increased in the 6-yr study period. MI approaches increased for both RN and PN. This treatment shift coincides with the new guideline recommendations in 2010. The possible better survival for patients undergoing PN compared to RN indicates the importance of following evidence-based guidelines. PATIENT SUMMARY: The use of partial nephrectomy and minimally invasive surgery for kidney cancer tumors increased in Norway from 2008 to 2013 according to population-based data, coinciding with guideline changes. The study illustrate that adherence to guidelines may improve patient outcomes.

Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.

Postoperative 30-day Mortality Rates for Kidney Cancer Are Dependent on Hospital Surgical Volume: Results from a Norwegian Population-based Study.

BACKGROUND: To improve cancer care in Norway, the government introduced surgical volume requirements for hospitals in 2015. To treat kidney cancer (KC) in Norway, the lower limit is 20 surgical procedures per year. OBJECTIVES: To compare the impact of hospital volume on outcome with regard to 30-d mortality (TDM) following KC surgery. DESIGN, SETTING, AND PARTICIPANTS: We identified all KC patients from the Cancer Registry of Norway diagnosed during 2008-2013 whose surgical treatment involved partial or radical nephrectomy. Hospitals were divided into three volume groups: low (LVH), intermediate (IVH), and high (HVH) volume. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analysed using multivariate logistic regression. RESULTS AND LIMITATIONS: In total, 3273 patients were identified. The TDM rate was 0.89% overall, 0.73% for localised KC, and 2.6% for metastatic KC. The mean (median, interquartile range) numbers of procedures for LVH, IVH and HVH were 5.2 /yr (3, 1.3-8.7), 27 /yr (26, 23-30) and 53 /yr (53, 48-58), with TDM rates of 2.2%, 0.83%, and 0.39%, respectively (p=0.001). In a multivariate logistic regression model, tumour stage, age, and hospital volume remained independent TDM predictors. The odds ratio for TDM was 4.98 (confidence interval 1.72-14.4) for LVH compared to HVH (p=0.003). Study limitations include a lack of data for surgical complications and other possible confounders. CONCLUSIONS: TDM is associated with age, stage, and hospital volume. The study supports the new regulation for hospital volume introduced in Norway. PATIENT SUMMARY: The risk of dying within 30 d following kidney cancer surgery is low. Advanced disease and older age are risk factors for higher mortality. In this study, we also showed that more patients die within 30 d in hospitals performing fewer operations per year than in hospitals performing many operations.

Development and confirmation of potential gene classifiers of human clear cell renal cell carcinoma using next-generation RNA sequencing.

OBJECTIVE: A previous study by this group demonstrated the feasibility of RNA sequencing (RNAseq) technology for capturing disease biology of clear cell renal cell carcinoma (ccRCC), and presented initial results for carbonic anhydrase-9 (CA9) and tumor necrosis factor-α-induced protein-6 (TNFAIP6) as possible biomarkers of ccRCC (discovery set) [Eikrem et al. PLoS One 2016;11:e0149743]. To confirm these results, the previous study is expanded, and RNAseq data from additional matched ccRCC and normal renal biopsies are analyzed (confirmation set). MATERIALS AND METHODS: Two core biopsies from patients (n = 12) undergoing partial or full nephrectomy were obtained with a 16 g needle. RNA sequencing libraries were generated with the Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using linear modeling (voom/Limma; R Bioconductor). RESULTS: The formalin-fixed and paraffin-embedded discovery and confirmation data yielded 8957 and 11,047 detected transcripts, respectively. The two data sets shared 1193 of differentially expressed genes with each other. The average expression and the log2-fold changes of differentially expressed transcripts in both data sets correlated, with R² = .95 and R² = .94, respectively. Among transcripts with the highest fold changes were CA9, neuronal pentraxin-2 and uromodulin. Epithelial-mesenchymal transition was highlighted by differential expression of, for example, transforming growth factor-ß1 and delta-like ligand-4. The diagnostic accuracy of CA9 was 100% and 93.9% when using the discovery set as the training set and the confirmation data as the test set, and vice versa, respectively. These data further support TNFAIP6 as a novel biomarker of ccRCC. TNFAIP6 had combined accuracy of 98.5% in the two data sets. CONCLUSIONS: This study provides confirmatory data on the potential use of CA9 and TNFAIP6 as biomarkers of ccRCC. Thus, next-generation sequencing expands the clinical application of tissue analyses.

Nephron Sparing Surgery Associated With Better Survival Than Radical Nephrectomy in Patients Treated for Unforeseen Benign Renal Tumors.

OBJECTIVE: To evaluate the role of the surgical technique used for the treatment of benign renal tumors, with regard to renal function and overall survival (OS) in patients without cancer-related mortality. PATIENTS AND METHODS: The study included 506 patients, mean age of 63.3 years, with histologically proven benign renal lesions originating from 5 European centers. Retrospective data from each hospital were retrieved and merged into a common database for analyses. OS, American Society of Anesthesiology score, and renal functions were measured in relation to surgical technique. The Mann-Witney U-test, the paired t-test, and Cox's multivariate analysis were used. RESULTS: Patients treated with radical nephrectomy had significantly reduced renal function postoperatively compared with nephron sparing surgery (NSS). OS was significantly reduced after radical nephrectomy compared with NSS (P = .012), a survival difference that remained significant [hazard ratio (HR) 0.042, 95% confidence interval (CI) 0.221-0.972, P = .042] in multivariate analysis, together with age at diagnosis (HR 1.065, 95% CI 1.026-1.106, P = .001) and American Society of Anesthesiology score (HR 2.361, 95% CI 1.261-4.419, P = .007). Also renal function assessed by estimated glomerular filtration rate significantly correlated to survival in univariate analysis, but did not remain independent after multivariate analysis. Oncocytoma was the most frequent benign lesion, followed by angiomyolipoma. CONCLUSION: The present study in patients with benign renal tumors shows that the remaining renal function and OS correspond to the choice of surgical procedure. Our results support the recommendation to perform NSS whenever possible when surgery is performed for patients with renal masses. The limitations of the study are the retrospective design and the selection bias for the surgical approach.

Transcriptome Sequencing (RNAseq) Enables Utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development.

Formalin-fixed, paraffin-embedded (FFPE) tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany) stored samples from clear cell renal cell carcinoma (ccRCC) patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®. RNA sequencing libraries were generated applying the new Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using voom/Limma R-package. The analysis of the FFPE and RNAlater® datasets yielded similar numbers of detected genes, differentially expressed transcripts and affected pathways. The FFPE and RNAlater datasets shared 80% (n = 1106) differentially expressed genes. The average expression and the log2 fold changes of these transcripts correlated with R2 = 0.97, and R2 = 0.96, respectively. Among transcripts with the highest fold changes in both datasets were carbonic anhydrase 9 (CA9), neuronal pentraxin-2 (NPTX2) and uromodulin (UMOD) that were confirmed by immunohistochemistry. IPA revealed the presence of gene signatures of cancer and nephrotoxicity, renal damage and immune response. To simulate the feasibility of clinical biomarker studies with FFPE samples, a classifier model was developed for the FFPE dataset: expression data for CA9 alone had an accuracy, specificity and sensitivity of 94%, respectively, and achieved similar performance in the RNAlater dataset. Transforming growth factor-ß1 (TGFB1)-regulated genes, epithelial to mesenchymal transition (EMT) and NOTCH signaling cascade may support novel therapeutic strategies. In conclusion, in this proof of concept study, RNAseq data obtained from FFPE kidney biopsies are comparable to data obtained from fresh stored material, thereby expanding the utility of archival tissue specimens.