Ex vivo Study of Partial Bladder Resection in a Porcine ModelEx vivo Study of Partial Bladder Resection in a Porcine Model.

INTRODUCTION: Partial cystectomy aims to preserve bladder function, yet its urodynamic impacts remain unclear. We investigate these effects using an ex-vivo porcine model, evaluating bladder volume, compliance, and wall thickness, alongside with thermal damage after bi- and monopolar resection. METHODS: Within an artificial human pelvis, we conducted partial bladder wall resections (5 cm2, 10 cm2). Urodynamic tests and sonography assessed volume, compliance, and thickness changes. Traction force for catheter retrieval and thermal collagen destruction were measured. RESULTS: Bladder compliance decreased by 1.12 and 1.5 after 5 cm2 and 10 cm2 resections respectively, with volume reductions of 3-6% and 10-18%. Wall thickness decreased by 20% and 30% post-resection. Comparable thermal damage was observed with mono- and bipolar resection methods. CONCLUSION: Our study outlines urodynamic impacts and technical considerations of partial cystectomy, affirming its endoscopic feasibility while highlighting potential bladder dysfunction risks.

Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation.

Solute carrier (SLC) transport proteins are fundamental for the translocation of endogenous compounds and drugs across membranes, thus playing a critical role in disease susceptibility and drug response. Because only a limited number of transporter substrates are currently known, the function of a large number of SLC transporters is elusive. Here, we describe the proof-of-concept of a novel strategy to identify SLC transporter substrates exemplarily for the proton-coupled peptide transporter (PEPT) 2 (SLC15A2) and multidrug and toxin extrusion (MATE) 1 transporter (SLC47A1), which are important renal transporters of drug reabsorption and excretion, respectively. By combining metabolomic profiling of mice with genetically-disrupted transporters, in silico ligand screening and in vitro transport studies for experimental validation, we identified nucleobases and nucleoside-derived anticancer and antiviral agents (flucytosine, cytarabine, gemcitabine, capecitabine) as novel drug substrates of the MATE1 transporter. Our data confirms the successful applicability of this new approach for the identification of transporter substrates in general, which may prove particularly relevant in drug research.

Head-to-head comparison of biparametric versus multiparametric MRI of the prostate before robot-assisted transperineal fusion prostate biopsy.

PURPOSE: Prostate biparametric magnetic resonance imaging (bpMRI) including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) might be an alternative to multiparametric MRI (mpMRI, including dynamic contrast imaging, DCE) to detect and guide targeted biopsy in patients with suspected prostate cancer (PCa). However, there is no upgrading peripheral zone PI-RADS 3 to PI-RADS 4 without DCE in bpMRI. The aim of this study was to evaluate bpMRI against mpMRI in biopsy-naïve men with elevated prostate-specific antigen (PSA) scheduled for robot-assisted-transperineal fusion-prostate biopsy (RA-TB). METHODS: Retrospective single-center-study of 563 biopsy-naïve men (from 01/2015 to 09/2018, mean PSA 9.7 ± 6.5 ng/mL) with PI-RADSv2.1 conform mpMRI at 3 T before RA-TB. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥ 2 in any core. Two experienced readers independently evaluated images according to PI-RADSv2.1 criteria (separate readings for bpMRI and mpMRI sequences, 6-month interval). Reference standard was histology from RA-TB. RESULTS: PI-RADS 2 was scored in 5.1% of cases (3.4% cancer/3.4% csPCa), PI-RADS 3 in 16.9% (32.6%/3.2%), PI-RADS 4 in 57.6% (66.1%/58.3%) and PI-RADS 5 in 20.4% of cases (79.1%/74.8%). For mpMRI/bpMRI test comparison, sensitivity was 99.0%/97.1% (p < 0.001), specificity 47.5%/61.2% (p < 0.001), PPV 69.5%/75.1% (p < 0.001) and NPV 97.6%/94.6% (n.s.). csPCa was considered gold standard. 35 cases without cancer were upgraded to PI-RADS 4 (mpMRI) and six PI-RADS 3 cases with csPCa were not upgraded (bpMRI). CONCLUSION: In patients planned for RA-TB with elevated PSA and clinical suspicion for PCa, specificity was higher in bpMRI vs. mpMRI, which could solve constrains regarding time and contrast agent.

T2 mapping for the characterization of prostate lesions.

PURPOSE: Purpose of this study is to evaluate the diagnostic accuracy of quantitative T2/ADC values in differentiating between PCa and lesions showing non-specific inflammatory infiltrates and atrophy, features of chronic prostatitis, as the most common histologically proven differential diagnosis. METHODS: In this retrospective, single-center cohort study, we analyzed 55 patients suspected of PCa, who underwent mpMRI (3T) including quantitative T2 maps before robot-assisted mpMRI-TRUS fusion prostate biopsy. All prostate lesions were scored according to PI-RADS v2.1. Regions of interest (ROIs) were annotated in focal lesions and normal prostate tissue. Quantitative mpMRI values from T2 mapping and ADC were compared using two-tailed t tests. Receiver operating characteristic curves (ROCs) and cutoff were calculated to differentiate between PCa and chronic prostatitis. RESULTS: Focal lesions showed significantly lower ADC and T2 mapping values than normal prostate tissue (p < 0.001). PCa showed significantly lower ADC and T2 values than chronic prostatitis (p < 0.001). ROC analysis revealed areas under the receiver operating characteristic curves (AUCs) of 0.85 (95% CI 0.74-0.97) for quantitative ADC values and 0.84 (95% CI 0.73-0.96) for T2 mapping. A significant correlation between ADC and T2 values was observed (r = 0.70; p < 0.001). CONCLUSION: T2 mapping showed high diagnostic accuracy for differentiating between PCa and chronic prostatitis, comparable to the performance of ADC values.

Versatility and clinical effectiveness of a synthetic sealing hemostatic patch as alternative to parenchyma suturing in laparoscopic partial nephrectomy.

BACKGROUND: Improvements in laparoscopic partial nephrectomy (LPN) in order to minimize perioperative warm ischemia time (WIT), complications, and consequently patient outcome are desirable. Veriset™ is a ready-to-use hemostatic patch of absorbable oxidized cellulose and hydrogel components that has earlier been implemented in vascular and hepatic surgery. We report our experience using this device in LPN. METHODS: Patients with a solitary malignant renal mass suspicious for renal cancer underwent LPN with either the use of Veriset™ hemostatic patch (n = 40) or conventional suture technique (n = 40). Patient characteristics, operation time and WIT, postoperative course and complications were recorded retrospectively. Tumor complexity was calculated according to the R.E.N.A.L. score. Outcome was determined according to the "trifecta" criteria (negative surgical margin, WIT < 25 min, no complications within 30 days). RESULTS: No significant differences with regard to clinical parameters and median R.E.N.A.L. score (6) were observed between both groups. Operation time (mean 127.1 min vs. 162. 8 min; p = 0.001) and WIT were both lower in the Veriset™ group (14.6 min vs. 20.6 min; p = 0.01). No differences in surgical margins (p = 0.602) and overall complication rates at 30 (p = 0.599) and 90 days (p = 0.611) postoperatively were noticed. The surgical outcome according to "trifecta" was achieved in 65% of patients using Veriset™ and in 57.5% of patients by suture closure, respectively. CONCLUSION: The hemostatic Veriset™ patch can successfully be implemented in LPN. Handling and application appear favorable, thereby reducing operation time and WIT. The present results suggest that the device may represent an alternative to parenchyma suturing in LPN.

Robotic Transrectal Computed Tomographic Ultrasound with Artificial Neural Network Analysis: First Validation and Comparison with MRI-Guided Biopsies and Radical Prostatectomy.

INTRODUCTION: There is still a lack of availability of high-quality multiparametric magnetic resonance imaging (mpMRI) interpreted by experienced uro-radiologists to rule out clinically significant PC (csPC). Consequently, we developed a new imaging method based on computed tomographic ultrasound (US) supported by artificial neural network analysis (ANNA). METHODS: Two hundred and two consecutive patients with visible mpMRI lesions were scanned and recorded by robotic CT-US during mpMRI-TRUS biopsy. Only significant index lesions (ISUP ≥2) verified by whole-mount pathology were retrospectively analyzed. Their visibility was reevaluated by 2 blinded investigators by grayscale US and ANNA. RESULTS: In the cohort, csPC was detected in 105 cases (52%) by mpMRI-TRUS biopsy. Whole-mount histology was available in 44 cases (36%). In this subgroup, mean PSA level was 8.6 ng/mL, mean prostate volume was 33 cm3, and mean tumor volume was 0.5 cm3. Median PI-RADS and ISUP of index lesions were 4 and 3, respectively. Index lesions were visible in grayscale US and ANNA in 25 cases (57%) and 30 cases (68%), respectively. Combining CT-US-ANNA, we detected index lesions in 35 patients (80%). CONCLUSIONS: The first results of multiparametric CT-US-ANNA imaging showed promising detection rates in patients with csPC. US imaging with ANNA has the potential to complement PC diagnosis.

Simultaneous whole-body PET/MRI with integrated multiparametric MRI for primary staging of high-risk prostate cancer.

PURPOSE: Whole-body positron emission tomography/magnetic resonance imaging (wbPET/MRI) is a promising diagnostic tool of recurrent prostate cancer (PC), but its role in primary staging of high-risk PC (hrPC) is not well defined. Thus, the aim was to compare the diagnostic accuracy for T-staging of PET-blinded reading (PBR) and PET/MRI. METHODS: In this prospective study, hrPC patients scheduled to radical prostatectomy (RPx) with extended lymphadenectomy (eLND) were staged with wbPET/MRI and either 68Ga-PSMA-11 or 11C-choline including simultaneous multiparametric MRI (mpMRI). Images were assessed in two sessions, first as PBR (mpMRI and wbMRI) and second as wbPET/MRI. Prostate Imaging Reporting and Data System criteria (PIRADS v2) were used for T-staging. Results were correlated with the exact anatomical localization and extension as defined by histopathology. Diagnostic accuracy of cTNM stage according to PBR was compared to pathological pTNM stage as reference standard. RESULTS: Thirty-four patients underwent wbPET/MRI of 68Ga-PSMA-11 (n = 17) or 11C-choline (n = 17). Twenty-four patients meeting the inclusion criteria of localized disease ± nodal disease based on imaging results underwent RPx and eLND, whereas ten patients were excluded from analysis due to metastatic disease. T-stage was best defined by mpMRI with underestimation of tumor lesion size by PET for both tracers. N-stage yielded a per patient sensitivity/specificity comparable to PBR. CONCLUSION: MpMRI is the primary modality for T-staging in hrPC as PET underestimated T-stage in direct comparison to final pathology. In this selected study, cohort MRI shows no inferiority compared to wbPET/MRI considering N-staging.

Can contrast-enhanced ultrasound and acoustic radiation force impulse imaging characterize CT-indeterminate renal masses? A prospective evaluation with histological confirmation.

PURPOSE: To prospectively characterize computed tomography (CT)-indeterminate renal masses (CTIRM) using acoustic radiation force impulse (ARFI) elastography and contrast-enhanced ultrasound (CEUS) and to correlate quantitative imaging findings with histopathology or interim follow-up (FU). METHODS: 123 patients with CTIRM (longest diameter < 4 cm) underwent ARFI and CEUS with CT image fusion (IF). Exclusion criteria included all contraindications for CEUS and IF. Shear wave velocity (SWV), shear wave ratio (SWR), peak intensity (PE), time to peak (TTP) and wash-in rate (Wi) were quantified. In case of a cystic lesion classified as ≤ Bosniak 2F, follow-up imaging was performed. RESULTS: 77 out of 123 patients underwent surgical resection of a lesion due to suspect imaging findings, whereas 46 patients underwent FU, which did not show upgrading in Bosniak category. Histopathology revealed 58 renal cell carcinomas [five chromophobe (chRCC), 18 papillary (pRCC) and 35 clear cell (ccRCC)], ten oncocytomas and nine non-malignant renal lesions (one minimal fat AML, three focal nephritis and five infected cysts). SWV and SWR differed significantly between ccRCC, pRCC, chRCC (p = 0.0024, F = 13.94) and in SWR also for oncocytoma (p < 0.0001, F = 14.35). In CEUS, oncocytoma and ccRCC showed significant higher PE values (p < 0.0001, F = 77.31) as well as higher Wi and lower TTP compared to all other solid lesions. CONCLUSIONS: Quantitative CEUS and ARFI imaging can provide relevant information to further characterize CT-indeterminate renal masses to guide urological decision making and offer the possibility of differentiation between ccRCC from less malignant RCC subtypes and from oncocytoma.

Safety and effectiveness of a novel generator algorithm for bipolar vessel sealing: a randomised controlled chronic animal study.

BACKGROUND: Electrosurgical vessel sealers are gradually replacing conventional techniques such as ligation and clipping. Algorithms that control electrosurgical units (ESU), known as modes, are important for applications in different surgical disciplines. This chronic porcine animal study aimed to evaluate the safety and effectiveness of the novel thermoSEAL electrosurgical vessel sealing mode (TSM). The BiClamp® mode (BCM) of the renowned VIO® 300 D ESU served as control. BCM has been widely available since 2002 and has since been successfully used in many surgical disciplines. The TSM, for the novel VIO® 3 ESU, was developed to reduce sealing time and/or thermal lateral spread adjacent to the seal while maintaining clinical success rates. The primary aim of this study was to investigate the long-term and intraoperative seal quality of TSM. METHODS: The BiCision® device was used for vessel sealing with TSM and BCM in ten German Landrace pigs which underwent splenectomy and unilateral nephrectomy during the first intervention of the study. The seals were cut with the BiCision® knife. Ninety-nine arteries, veins and vascular bundles were chronically sealed for 5 or 21 days. Thereafter, during the second and terminal intervention of the study, 97 additional arteries and veins were sealed. The carotid arteries were used for histological evaluation of thermal spread. RESULTS: After each survival period, no long-term complications occurred with either mode. The intraoperative seal failure rates, i.e. vessel leaking or residual blood flow after the first sealing activation, were 2% with TSM versus 6% with BCM (p = 0.28). The sealing time was significantly shorter with TSM (3.5 ± 0.69 s vs. 7.3 ± 1.3 s, p < 0.0001). The thermal spread and burst pressure of arteries sealed with both modes were similar (p = 0.18 and p = 0.61) and corresponded to the histological evaluation. The measured tissue sticking parameter was rare with both modes (p = 0.33). Tissue charring did not occur. Regarding the cut quality, 97% of the seals were severed in the first and 3% in the second attempt (both with TSM and BCM). CONCLUSIONS: The novel TSM seals blood vessels twice as fast as the BCM while maintaining excellent tissue effect and clinical success rates. TRIAL REGISTRATION: Not applicable.

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma.

The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.

Clinical utility of the S3-score for molecular prediction of outcome in non-metastatic and metastatic clear cell renal cell carcinoma.

BACKGROUND: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR. METHODS: A 97 gene-based S3-score (S397) was evaluated in a set of 52 primary non-metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S315). This S315-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints. RESULTS: The S397-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, PLog-rank = 3.3 × 10-2) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, PLog-rank = 2.2 × 10-2). The qRT-PCR based S315-score performed similarly to the S397-score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, PLog-rank = 5.1 × 10-5) including metastatic (9.3, 1.8-50.0, PLog-rank = 2.3 × 10-3) and non-metastatic patients (4.4, 1.2-16.3, PLog-rank = 1.6 × 10-2), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, PWald = 3.3 × 10-4). Matched primary tumors and metastases revealed similar S315-scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S315-score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 × 10-3). CONCLUSION: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting.

Targeted vs systematic robot-assisted transperineal magnetic resonance imaging-transrectal ultrasonography fusion prostate biopsy.

OBJECTIVE: To evaluate the performance of transperineal robot-assisted (RA) targeted (TB) and systematic (SB) prostate biopsy in primary and repeat biopsy settings. PATIENTS AND METHODS: Patients underwent RA biopsy between 2014 and 2016. Before RA-TB, multiparametric magnetic resonance imaging (mpMRI) was performed. Prostate lesions were scored (Prostate Imaging, Reporting and Data System, version 2) and used for RA-TB planning. In addition, RA-SB was performed. Available, whole-gland pathology was analysed. RESULTS: In all, 130 patients were biopsy naive and 72 had had a previous negative transrectal ultrasonography-guided biopsy. In total, 202 patients had suspicious mpMRI lesions. Clinically significant prostate cancer was found in 85% of all prostate cancer cases (n = 123). Total and clinically significant prostate cancer detection rates for RA-TB vs RA-SB were not significantly different at 77% vs 84% and 80% vs 82%, respectively. RA-TB demonstrated a better sampling performance compared to RA-SB (26.4% vs 13.9%; P < 0.001). CONCLUSION: Transperineal RA-TB and -SB showed similar clinically significant prostate cancer detection rates in primary and repeat biopsy settings. However, RA-TB offered a 50% reduction in biopsy cores. Omitting RA-SB is associated with a significant risk of missing clinically significant prostate cancer.

Prostate cancer detection in patients with prior negative biopsy undergoing cognitive-, robotic- or in-bore MRI target biopsy.

PURPOSE: To evaluate the detection rate among three different targeted biopsy approaches of robot-assisted MRI/TRUS fusion (RA-TB), mpMRI in-bore (MRGB), cognitive fusion guidance biopsy (COG-TB) for the detection of prostate cancer (PC) and clinically significant PC (csPC). METHODS: Between 2014 and 2016, 156 patients with a lesion on mpMRI, performed in accordance with ESUR guidelines, due to cancer suspicion or on-going cancer suspicion after prior negative prostate biopsy, underwent targeted biopsy with RA-TB, MRGB or COG-TB. All lesions were rated according to PI-RADS v2. We compared detection rates between techniques. Models were constructed to predict the detection of overall PC and csPC and using a 1000 boot-strap sample. RESULTS: In the all cohort, 73, 45 and 38 patients underwent RA-TB, MRGB or COG-TB, respectively. Overall PC was found in 39 (52.42%), 23 (51.11%) and 11 (28.95%) (p = 0.04) patients of RA-TB, MRGB and COG-TB arm, respectively. As concerning the detection of csPC, it was found in 26 (35.62%),18 (40.0%) and 9 (23.68%) patients of RA-TB, MRGB and COG-TB arm (p = 0.27). Model 1 showed that RA-TB [OR: 10.08 (95% CI 1.95-51.97); p < 0.01] and MRGB [OR: 12.88 (95% CI 2.36-70.25); p < 0.01] were associated with overall PC detection in TB, while only MRGB was associated with csPC at TB (model 2) [OR: 5.72; (95% CI 1.40-23.35); p < 0.01]. The c-index for model 1 and model 2 was 0.86 and 0.85, respectively. We did not report significant complications between groups. CONCLUSION: In-bore biopsy and MRI/TRUS fusion-guided biopsy showed greater accuracy in detecting PC compared to cognitive fusion as modeled in a newly established normogram.

Single-use versus reusable ureterorenoscopes for retrograde intrarenal surgery (RIRS): systematic comparative analysis of physical and optical properties in three different devices.

INTRODUCTION: Retrograde intrarenal surgery (RIRS) represents a standard option for kidney stone removal. However, RIRS is considered a cost-intensive procedure. Single-use flexible ureterorenoscopes have been introduced to improve budget predictability in RIRS. We assessed differences in physical and optical properties of single-use devices compared to standard reusable endoscopes. METHODS: In two single-use (LithoVue™, Boston Scientific; Pusen Uscope UE3011™), and one reusable ureterorenoscope (Flex-Xc™, Karl Storz), we investigated flow rates, deflection, illuminance, and intrapelvic pressure in a porcine kidney model. Subjective image quality was assessed using a standardized questionnaire. Common insertable devices were applied to investigate additional influence on physical properties. RESULTS: Significant variability in maximum flow rates was observed (Flex-Xc™: 25.8 ml/min, LithoVue™: 30.3 ml/min, Pusen™: 33.4 ml/min, p < 0.05). Insertion of a guide wire resulted in the highest reduction of flow rates in all endoscopes. Flection led to a reduction of absolute flow rates up to 9.4% (Flex-Xc™). Light intensity at 20/50 mm distance was 9090 lx/1857 lx (Flex-Xc™) and 5733 lx/1032 lx (LithoVue™) and 2160 lx/428 lx (Pusen™), respectively (p < 0.05). Subjective image quality score was highest using the Flex-Xc™ endoscope. During manipulation, maximum intrarenal pressure up to 66 mmHg (Pusen™) was measured. CONCLUSIONS: Significant differences in physical and optical properties of single-use or reusable flexible ureterorenoscopes are present, with putative influence on surgical efficacy and complications. Further comparative evaluation of single-use and reusable endoscopes in a clinical scenario is useful. Moreover, utilization of ureteral access sheaths may be considered to avoid renal damage.

Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT.

PURPOSE: Prostate-specific membrane antigen (PSMA) is expressed ubiquitously on the membrane of most prostate tumors and its metastasis. While PET/CT using 11C-choline was considered as the gold standard in the staging of prostate cancer, PET with radiolabelled PSMA ligands was introduced into the clinic in recent years. Our aim was to compare the PSMA ligand 68Ga-PSMA-11 with 11C-choline in patients with primary and recurrent prostate cancer. METHODS: 123 patients underwent a whole-body PET/CT examination using 68Ga-PSMA-11 and 11C-choline. Suspicious lesions were evaluated visually and semiquantitatively (SUVavg). Out of these, 103 suffered from a confirmed biochemical relapse after prostatectomy and/or radiotherapy (mean PSA level of 4.5 ng/ml), while 20 patients underwent primary staging. RESULTS: In 67 patients with biochemical relapse, we detected 458 lymph nodes suspicious for metastasis. PET using 68Ga-PSMA-11 showed a significantly higher uptake and detection rate than 11C-choline PET. Also 68Ga-PSMA-11 PET identified significantly more patients with suspicious lymph nodes as well as affected lymph nodes regions especially at low PSA levels. Bone lesions suspicious for prostate cancer metastasis were revealed in 36 patients' biochemical relapse. Significantly more bone lesions were detected by 68Ga-PSMA-11, but only 3 patients had only PSMA-positive bone lesions. Nevertheless, we detected also 29 suspicious lymph nodes and 8 bone lesions, which were only positive as per 11C-choline PET. These findings led to crucial differences in the TNM classification and the identification of oligometastatic patients. In the patients who underwent initial staging, all primary tumors showed uptake of both tracers. Although significantly more suspicious lymph nodes and bone lesions were identified, only 2 patients presented with bone lesions only detected by 68Ga-PSMA-11 PET. CONCLUSION: Thus, PET using 68Ga-PSMA-11 showed a higher detection rate than 11C-choline PET for lymph nodes as well as bone lesions. However, we found lymph nodes and bone lesions which were not concordant applying both tracers.

Differential expression and clinical relevance of MUC1 in renal cell carcinoma metastasis.

PURPOSE: To determine the differential expression patterns and prognostic relevance of Mucin-1 (MUC1) expression in clear cell renal cell carcinoma (RCC) metastasis. METHODS: Tissue microarrays (TMA) from samples of 151 RCC metastases, 61 primary RCCs and corresponding benign renal tissues were immunohistochemically stained for MUC1 and semi-quantitatively evaluated by immunoreactivity scores (IRS). MUC1 differential expression in metastasis, primary RCC and normal tissue were comparatively analyzed. Patient characteristics and clinical follow-up for patients with metastatic RCC (mRCC) were recorded. Correlations of MUC1 expression with mRCC survival were determined. RESULTS: Median cytoplasmic expression was highest in benign tissue (IRS = 1.04). Primary RCC (0.50) and metastasis (0.12) showed significantly lower cytoplasmic staining intensity. Membranous expression in benign tissue was, however, significantly lower (0.21) compared with primary RCC (0.59) and metastasis (0.57). Notable differences of MUC1 cytoplasmic and membranous expression were observed between different metastasis sites. Significantly higher (P = 0.014) membranous expression was observed in pulmonary versus non-pulmonary lesions, while no significant differences of cytoplasmic MUC1 expression were observed. The prognostic relevance of MUC1 expression in metastatic RCC was limited. CONCLUSIONS: MUC1 is differentially expressed in benign renal tissue, primary RCC and RCC metastasis. Membranous MUC1 expression was significantly elevated in pulmonary metastases compared to non-pulmonary lesions, which may reflect individual biology and putative response to MUC1-based anti-cancer therapy.

Evaluation of the 'Prostate Interdisciplinary Communication and Mapping Algorithm for Biopsy and Pathology' (PIC-MABP).

INTRODUCTION: Experience from interdisciplinary cooperation revealed the need for a prostate mapping scheme to communicate multiparametric MRI (mpMRI) findings between radiologists, urologists, and pathologists, which should be detailed, yet easy to memorize. For this purpose, the 'Prostate interdisciplinary communication and mapping algorithm for biopsy and pathology' (PIC-MABP) was developed. This study evaluated the accuracy of the PIC-MABP system. METHODS: PIC-MABP was tested and validated in findings of 10 randomly selected patients from routine clinical practise with 18 histologically proven cancer lesions. Patients received an mpMRI of the prostate prior to prostatectomy. After surgery the prostates were prepared as whole-mount step sections. Cancer lesions, which were found suspicious on mpMRI, were assigned to the according PIC-MABP sectors by a radiologist. MpMRI slides were masked and sent to seven urologists from different centres, providing only the PIC-MABP location of each lesion. Urologists marked the accordant regions. Then mpMRI slides were unmasked, and the correctness of each mark was evaluated. RESULTS: One hundred and seventeen of the 126 marks (93%) were correctly assigned. Detection rates differed for lesions >0.5 cc compared with lesions <0.5 cc (p < 0.005): 3/7 (43%) marks were correctly assigned in lesions <0.3 cc, 16/21 (76%) in lesions with 0.3-0.5 cc, and 98/98 (100%) in lesions >0.5 cc. Interobserver agreement was good for lesions >0.5 cc and poor for lesions <0.3 cc (Fleiss Kappa 1 vs. 0.0175). CONCLUSION: PIC-MABP seems to be a reliable system to communicate the location of mpMRI findings >0.5 cc between different disciplines and can be a useful guidance for cognitive mpMRI/TRUS fusion biopsy.

Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine.

Multidrug and toxin extrusion (MATE; SLC47A) proteins are membrane transporters mediating the excretion of organic cations and zwitterions into bile and urine and thereby contributing to the hepatic and renal elimination of many xenobiotics. Transported substrates include creatinine as endogenous substrate, the vitamin thiamine and a number of drug agents with in part chemically different structures such as the antidiabetic metformin, the antiviral agents acyclovir and ganciclovir as well as the antibiotics cephalexin and cephradine. This review summarizes current knowledge on the structural and molecular features of human MATE transporters including data on expression and localization in different tissues, important aspects on regulation and their functional role in drug transport. The role of genetic variation of MATE proteins for drug pharmacokinetics and drug response will be discussed with consequences for personalized medicine.

Metastasectomy for metastatic renal cell carcinoma in the era of modern systemic treatment: C-reactive protein is an independent predictor of overall survival.

OBJECTIVE: To define the predictive capability of serum C-reactive protein for a contemporary patient collective undergoing metastasectomy for metastatic renal cell carcinoma with access to modern targeted therapies. METHODS: A total of 88 patients treated with metastasectomy for metastatic renal cell carcinoma from 2003 to 2014 were evaluated for putative clinicopathological risk factors and survival. Kaplan-Meier analyses, univariate and multivariate testing were carried out. Receiver operating characteristic curve analysis was applied to evaluate available risk stratification instruments for patients undergoing metastasectomy. RESULTS: Median overall survival for the collective was 66.31 months (95% confidence interval 50.67-135.47; 5-year overall survival 55%). The median preoperative C-reactive protein level was 6.7 mg/L (range 0.1-161.7). A C-reactive protein cut-off value of 5 mg/dL was significantly discriminative of survival (P = 0.029). Median survival in dependence of C-reactive protein accounted for 50.67 months (range 33.86-63.05 months) in the C-reactive protein >5 mg/L group, and 135.47 months in the C-reactive protein ≤5 mg/L group (range 66.31-135.47 months). C-reactive protein elevation >5 mg/L, anemia and surgical margin status were identified as significant predictors of overall survival in univariate analysis. In a multivariate model, resection margin status (P = 0.015) and C-reactive protein elevation (P = 0.038) were confirmed as independent predictive variables. CONCLUSIONS: Elevated C-reactive protein >5 mg/L was identified as an independent predictor of survival in a contemporary patient collective undergoing metastasectomy for metastatic renal cell carcinoma. Future analyses and risk stratification tools for patients undergoing metastasectomy for metastatic renal cell carcinoma should aim to evaluate and include C-reactive protein. To overcome low patient numbers, multi-institutional studies should be carried out.

Combined unsupervised-supervised classification of multiparametric PET/MRI data: application to prostate cancer.

Multiparametric medical imaging data can be large and are often complex. Machine learning algorithms can assist in image interpretation when reliable training data exist. In most cases, however, knowledge about ground truth (e.g. histology) and thus training data is limited, which makes application of machine learning algorithms difficult. The purpose of this study was to design and implement a learning algorithm for classification of multidimensional medical imaging data that is robust and accurate even with limited prior knowledge and that allows for generalization and application to unseen data. Local prostate cancer was chosen as a model for application and validation. 16 patients underwent combined simultaneous [(11) C]-choline positron emission tomography (PET)/MRI. The following imaging parameters were acquired: T2 signal intensities, apparent diffusion coefficients, parameters Ktrans and Kep from dynamic contrast-enhanced MRI, and PET standardized uptake values (SUVs). A spatially constrained fuzzy c-means algorithm (sFCM) was applied to the single datasets and the resulting labeled data were used for training of a support vector machine (SVM) classifier. Accuracy and false positive and false negative rates of the proposed algorithm were determined in comparison with manual tumor delineation. For five of the 16 patients rates were also determined in comparison with the histopathological standard of reference. The combined sFCM/SVM algorithm proposed in this study revealed reliable classification results consistent with the histopathological reference standard and comparable to those of manual tumor delineation. sFCM/SVM generally performed better than unsupervised sFCM alone. We observed an improvement in accuracy with increasing number of imaging parameters used for clustering and SVM training. In particular, including PET SUVs as an additional parameter markedly improved classification results. A variety of applications are conceivable, especially for imaging of tissues without easily available histopathological correlation.