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Somatic nonsynonymous SNV and indels identified in our corhort.

Supplementary figures and figure legends

MaxQuant output file, protein ratios, and pathway enrichment analysis (GSEA) of all up-regulated and down-regulated pathways between chRCC and kidney tissues.

Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. chRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC and papillary RCC. Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. chRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC) pathway significantly impaired the activation of endocytosis for amino acid uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca2+/PKC axis as a potential therapeutic target in patients with chRCC.Significance:This study reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner.

Captions of supplementary movie and tables

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.Significance:These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.

Supplementary file captions

Live-cell fluorescence imaging showed that the DQ-Red BSA accumulated in UOK276 cells over time, providing evidence that macropinocytosis is an established process in chRCC cells to uptake macromolecules as nutrient source.

Correlation between mtDNA content, ETC protein and transcript levels, and GSH level in 786-O and HK2 cells

Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. chRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC and papillary RCC. Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. chRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC) pathway significantly impaired the activation of endocytosis for amino acid uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca2+/PKC axis as a potential therapeutic target in patients with chRCC. Significance: This study reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner.

Compliant actuators are employed in exoskeleton robots instead of stiff actuators for safe human-robot interaction. In parallel with this idea, we previously constructed a biomimetic compliant exoskeleton robot (BioComEx). In this study, to provide more stable and safe trajectory tracking even under disturbances, magneto-rheological (MR) brakes were added to all joints of BioComEx as variable damping actuators and a PID+D controller was proposed. To evaluate the robot and controller, first, BioComEx was hung on a platform and the controller was applied without device user under external forces. This primary test results showed that the proposed design and controller can effectively minimize disturbance effects and consequently reduce trajectory tracking oscillations. In the rest of the study, the similar control experiments were repeated with a user who has unilateral lower limb movement disorders. In these experiments, the movements of the user's healthy leg were detected by force feedback impedance control algorithm and then were used as reference for the impaired leg with walking cycle delay in real time. The secondary test results showed that the variable impedance exoskeleton robot design with PID+D controller can ensure effective walking assistance for the impaired human legs.

Nowadays, the number of people with hemiplegia is constantly increasing due to the cumulative elderly population and accidents, henceforth; it is becoming difficult for therapists to meet this burden as labor, time and cost. Robotic rehabilitation provides a longer lasting and cost-effective treatment option in the comfort of home environment, and it is very easy to make repeatable, measurable and controllable limb movements with the help of these devices. In this study, two separate control modes were added to an active wrist orthosis developed for wrist rehabilitation in order to perform both passive rehabilitation and resistive exercise applications, therefore; it is ensured that all the requirements that will be needed in a wrist rehabilitation can be met with a single device., Günümüzde gittikçe artan yaşlı nüfusa ve yaşanan kazalara bağımlı olarak kısmi felçli insan sayısı sürekli artmakta olup gün geçtikçe terapistlerin emek, zaman ve maliyet olarak bu külfeti karşılamaları giderek zorlaşmaktadır. Robotik rehabilitasyon ise ev ortamı rahatlığında daha uzun süreli ve düşük maliyetli bir tedavi seçeneği sunmakta olup bu cihazlar yardımıyla tekrarlanabilir, ölçülebilir ve kontrol edilebilir uzuv hareketlerin yaptırılması oldukça kolaydır. Bu çalışmada el bileği rehabilitasyonu için geliştirilmiş olan bir aktif bilek ortezine hem pasif rehabilitasyon hem de dirençli egzersiz uygulamalarının yaptırılması amacıyla iki ayrı denetim modu daha eklenerek bir bilek rehabilitasyonunda ihtiyaç duyulacak tüm gereksinimlerin tek bir cihaz ile karşılanabilmesi sağlanmıştır.

Myeloperoxidase (MPO) is an enzyme secreted by neutrophil granulocytes as a result of phagocytosis during inflammation. In colorectal cancer, tumour infiltration by MPO expressing cells has been shown to be independently associated with a favourable prognosis. In this study, we explored the role of MPO-positive cell infiltration and its prognostic significance in invasive breast cancer. We performed immunohistochemical staining for MPO on multiple tissue microarrays comprising a total of 928 human breast cancer samples with detailed clinical-pathological annotation and outcome data. MPO-positive cell infiltration (≥ 5 cells/tissue punch) was found in 150 (16%) of the 928 evaluable breast cancer cases. In univariate survival analyses, infiltration by MPO-positive cells was associated with a significantly better overall survival (p

Objectives: Bladder cancer is a heterogeneous malignancy. Therefore, it is difficult to find single predictive markers. Moreover, most studies focus on either the immunohistochemical or molecular assessment of tumor tissues by next-generation sequencing (NGS) or PCR, while a combination of immunohistochemistry (IHC) and PCR for tumor marker assessment might have the strongest impact to predict outcome and select optimal therapies in real-world application. We investigated the role of proliferation survivin/BIRC5 and macrophage infiltration (CD68, MAC387, CLEVER-1) on the basis of molecular subtypes of bladder cancer (KRT5, KRT20, ERBB2) to predict outcomes of adjuvant treated muscle-invasive bladder cancer patients with regard to progression-free survival (PFS) and disease-specific survival (DSS). Materials and Methods: We used tissue microarrays (TMA) from n = 50 patients (38 males, 12 female) with muscle-invasive bladder cancer. All patients had been treated with radical cystectomy followed by adjuvant triple chemotherapy. Median follow-up time was 60.5 months. CD68, CLEVER-1, MAC387, and survivin protein were detected by immunostaining and subsequent visual inspection. BIRC5, KRT5, KRT20, ERBB2, and CD68 mRNAs were detected by standardized RT-qPCR after tissue dot RNA extraction using a novel stamp technology. All these markers were evaluated in three different centers of excellence. Results: Nuclear staining rather than cytoplasmic staining of survivin predicted DSS as a single marker with high levels of survivin being associated with better PFS and DSS upon adjuvant chemotherapy (p = 0.0138 and p = 0.001, respectively). These results were validated by the quantitation of BIRC5 mRNA by PCR (p = 0.0004 and p = 0.0508, respectively). Interestingly, nuclear staining of survivin protein was positively associated with BIRC5 mRNA, while cytoplasmic staining was inversely related, indicating that the translocation of survivin protein into the nucleus occurred at a discrete, higher level of its mRNA. Combining survivin/BIRC5 levels based on molecular subtype being assessed by KRT20 expression improved the predictive value, with tumors having low survivin/BIRC5 and KRT20 mRNA levels having the best survival (75% vs. 20% vs. 10% 5-year DSS, p = 0.0005), and these values were independent of grading, node status, and tumor stage in multivariate analysis (p = 0.0167). Macrophage infiltration dominated in basal tumors and was inversely related with the luminal subtype marker gene expression. The presence of macrophages in survivin-positive or ERBB2-positive tumors was associated with worse DSS. Conclusions: For muscle-invasive bladder cancer patients, the proliferative activity as determined by the nuclear staining of survivin or RT-qPCR on the basis of molecular subtype characteristics outperforms single marker detections and single technology approaches. Infiltration by macrophages detected by IHC or PCR is associated with worse outcome in defined subsets of tumors. The limitations of this study are the retrospective nature and the limited number of patients. However, the number of molecular markers has been restricted and based on predefined assumptions, which resulted in the dissection of muscle-invasive disease into tumor&ndash, biological axes of high prognostic relevance, which warrant further investigation and validation.

İnsan kas-iskelet sistemi yürüme esnasında ayak bileği ekleminde sertliği devamlı değiştirerek esnek ve kararlı bir yürüme kabiliyeti sunmaktadır. Bilek ekleminin bu hareketini taklit edebilmek için hareket esnasında bilek ekleminin sertlik kestirimi önem arz etmektedir. Bu çalışmada bilek ekleminin EMG tabanlı bir model üzerinden sertlik kestirimi ve uygulanan kuvvet geri beslemeli empedans kontrol algoritması ile VS-AnkleExo-kullanıcı arasında düşük etkileşim torkları sağlanarak gerçek zamanlı robotun kullanıcıya ait sertlik değerini taklit edebildiği gösterilmiştir. Çalışmada öncelikle bilek ekleminin davranışını tanımlamak için iki adet kas tarafından tahrik edilen bir eklemden oluşan kas-iskelet model yaklaşımı kullanılmıştır. Bileğin plantar-fleksiyon ve dorsal fleksiyon hareketlerini sağlayacak kas kuvvetlerini oluşturmak amacıyla Mykin kas modelinden faydalanılmıştır. Daha sonra sinyal işleme yönetimleri ile elde edilen veriler ve ölçülen tork verileri kullanılarak Mykin modelindeki parametreler belirlenmiştir. Bu parametrelerin kestirimi sinyal işleme yöntemlerine göre farklılık gösterdiğinden, yapılan doğrulama deneyi ile EİD sinyal işleme yönteminin en uygun yöntem olduğuna karar verilmiştir. Bu yöntem ile bulunan biyomekanik parametreler Mykin modeli yardımıyla elde edilen denklemlerde yerine konarak bilek ekleminin sertlik kestirimi gerçekleştirilmiştir. Çalışmada son olarak bilek ekleminin kestirilen sertlik değeri gerçek zamanlı VS-AnkleExo’nun sertlik ayarlama mekanizmasına gönderilmiş ve kullanıcı-VS-AnkleExo arasında minimum etkileşim torku elde etmek için cihaz üzerinde kuvvet geri beslemeli bir empedans kontrol algoritması uygulaması gerçekleştirilmiştir.

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy. Significance: These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.

560 Background: The objective of the present study was to evaluate whether preoperative standard urine parameters such as leucocyte count in urine samples dominate in particular molecular subtypes of bladder cancer and reflect the immune infiltration status in the tissue in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB within the prospective Real World Experience registry trial "BRIDGister". Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 48 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits- Relative gene expression of subtyping markers (KRT5, KRT20) by standardized RT-qPCR systems for PD-1, PD-L1, CTLA4 (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed for leucocyte and erythrocyte count. Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 48 patients (median age: 77, male 65% vs. female 35%) of diverse clinical stages (Benign lesions/no tumor 38%, pTa 23%, pT1 20%, pT2 19%) and WHO 1973 grade (G1 11%, G2 43%, G3 23%). Presence of leucocytes but not erythrocytes was negatively associated with KRT20 (r=-0.4249, p=0.0216) but positive with KRT5 (r=0.3704, p=0.0479). Moreover high levels of leucocytes in urine were positively associated with tumor expression of PD-L1 (r=0.5081, p=0.0041), PD-1 (r=0.5342, p=0.00024) and CTLA4 (r=0.4244, p=0.0194). In contrast there was no significant association of tumor PDL-1, PD-1 and CTLA4 expression with erythrocyte count in urine. Conclusions: Presence of leucotytes in urine is strongly associated with basal subtype and immune cell infiltration into early bladder cancer. As the presence of erythrcytes did not reveal these significant associations, the presence of leucocytes is not due to simple bleeding or tissue vulnerability. Moreover, the strong tumor subtype specificity further demonstrate the basal tumor specificity of urine leucocytes and therefore may be helpful for detecting and monitoring basal bladder cancer in a non invasive fashion. Given the prognostic value of tissue determination of PD-L1, PD-1 and CTLA4 quantitation on mRNA level, these results warrant further investigation to conclude on its impact on outcome prediction (BCG responsiveness, recurrence, progression, etc.), which will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.

// Andreas Maxeiner 1 , Ergin Kilic 2 , Julia Matalon 1 , Frank Friedersdorff 1 , Kurt Miller 1 , Klaus Jung 1,3 , Carsten Stephan 1,3 and Jonas Busch 1 1 Department of Urology, Charite, Universitaetsmedizin Berlin, Berlin, Germany 2 Department of Pathology, Charite, Universitaetsmedizin Berlin, Berlin, Germany 3 Berlin Institute for Urologic Research, Berlin, Germany Correspondence to: Andreas Maxeiner, email: // Keywords : prostate cancer; biomarker; prostate health index; prostate-specific antigen; biochemical recurrence Received : January 30, 2017 Accepted :April 15, 2017 Published : April 27, 2017 Abstract The purpose of this study was to investigate the Prostate-Health-Index (PHI) for pathological outcome prediction following radical prostatectomy and also for biochemical recurrence prediction in comparison to established parameters such as Gleason-score, pathological tumor stage, resection status (R0/1) and prostate-specific antigen (PSA). Out of a cohort of 460 cases with preoperative PHI-measurements (World Health Organization calibration: Beckman Coulter Access-2-Immunoassay) between 2001 and 2014, 437 patients with complete follow up data were included. From these 437 patients, 87 (19.9%) developed a biochemical recurrence. Patient characteristics were compared by using chi-square test. Predictors were analyzed by multivariate adjusted logistic and Cox regression. The median follow up for a biochemical recurrence was 65 (range 3-161) months. PHI, PSA, [-2]proPSA, PHI- and PSA-density performed as significant variables (p < 0.05) for cancer aggressiveness: Gleason-score

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7&ndash, 20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.

Introduction: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali­zation from associated prostatectomy samples. Methods: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging – reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization. Results: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions. Conclusion: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients.

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increasedde novosynthesis rate of GSH, based on glutamine consumption. Furthermore, rewiring of the main pathways involved in ATP and glucose synthesis was observed at the protein level. In contrast, transcripts encoding for the respiratory chain were not regulated, which prompts for non-genetic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.SIGNIFICANCE STATEMENTWe applied proteome- and metabolome profiling to elucidate molecular features in malign papillary renal cell carcinomas. By this characterization, a reprogramming of the main metabolic pathways, such as gluconeogenesis and fatty acid- and amino acid metabolism were identified. The proteins involved in the respiratory chain and the corresponding enzymatic activities were strongly reduced in pRCC, showing an anti-correlation compared with the transcriptome. Similar to renal oncocytomas, the ROS scavenger glutathione was identified as a hallmark in pRCC. Our results suggest that impaired metabolism and dysfunctional mitochondria determine the fate of pRCC. Furthermore, we propose that the specific regulation of the mitochondrial respiratory chain can differentiate highly similar malignant pRCCs from benign renal oncocytomas.

SummaryChromophobe renal cell carcinomas (chRCC) are derived from intercalated cells of the collecting duct system, and are thought to be the malignant counterpart of benign renal oncocytomas. Here, we report the characterization of nine chRCC with adjacent healthy kidney tissues by applying proteome-, transcriptome (TCGA)-, and metabolome profiling. Most strikingly, the reactive oxygen species scavenger glutathione was significantly elevated in chRCC, caused by down-regulated enzymes involved in glutathione degradation. Metabolic reprogramming including stalled gluconeogenesis, down-regulated fatty acid- and amino acid metabolism was identified, even though, the abundance of amino acids and “energy carrier” molecules were unchanged. A striking anti-correlation of the mitochondrial respiratory chain between the transcriptome and the proteome was discovered, the transcripts coding for the respiratory chain were up-, while corresponding proteins and enzymatic activities were down-regulated. Similar to renal oncocytomas, chRCC exhibited a significant increase in glutathione, but are distinguishable by distinct regulation of the respiratory chain.

Exoskeleton robots are generally used for rehabilitation and load-carrying applications. Stable and flexible walking with minimal energy consumption of the human body is achieved by the compliant operation of the human joints. Essentially, the stiffness of the human ankle joint varies continuously, while the stiffness of the knee and hip joints remains nearly constant during loading phases of the walking cycles. With inspiration from the human leg biomechanics, a new biomimetic compliant lower limb exoskeleton robot (BioComEx) was constructed and its preliminary experimental tests were carried out in this paper. A variable stiffness actuator was developed for the ankle joint of BioComEx, and series elastic actuator designs were employed in the knee and hip joints of the robot. The joint actuators of BioComEx were designed longitudinally in order to be embedded inside of the thigh and shank leg segments for the compactness. Separate force sensors were employed in each segment of the robot for the modularity of the control strategies. Since the exoskeletons can be used for both load-carrying and rehabilitation, the developed robot was tested in both human-in-charge and robot-in-charge modes, respectively. The robot needs to mimic movement of healthy user joints in the human-in-charge mode and maximize the compliance between the user and robot; thus, the interaction forces should be reduced as possible. Hence, a modular closed-loop impedance control algorithm was developed for this mode. On the other hand, in the robot-in-charge mode, the robot joints need to track predefined gait references to make the patient walk. PID position control algorithm was chosen for preliminary test of the robot in this mode. Experimental results show that BioComEx is sufficiently satisfactory for walking applications of healthy and paralyzed users.

Nodal metastasis is a strong prognostic parameter in prostate cancer (PCa). We analysed the detection of micrometastases (miN + ) in initially nodal-negative (pN0) radical prostatectomy specimens from pT2a-c and pT3a PCa patients by immunohistochemistry (IHC). A total of 2352 lymph nodes of 193 PCa patients were centrally re-examined for miN + or miN- status using IHC. Results were correlated with clinical and follow-up data. Recurrence-free survival (RFS) was calculated with the log-rank test using the Kaplan-Meier method. In addition, a logistic regression analysis was performed. IHC detected miN + in a total of 17 patients (8.8 %). miN + seemed to be significantly associated with a higher Gleason score and was detected in more advanced pT stages. A total of 45 patients (23.1 %) had a biochemical recurrence (BCR). BCR was associated with miN +. Patients with miN + had a significantly shorter RFS (22.9 versus 58.7 months; p 0.001). In the univariate (OR: 5.04; 95 % CI: 2.46 - 10.6; p-value: 0.0001) and multivariate (OR: 3.29; 95 % CI: 1.54 - 7.08; p-value: 0.002) regression model, the miN + status was the strongest predictor of a BCR. IHC seems to be of high diagnostic value for the detection of micrometastases in initially nodal-negative PCa patients. IHC should therefore be performed in PCa patients with nodal-negative findings. Lymphknotenmetastasen sind ein wichtiger prognostischer Parameter im Rahmen eines Prostatakarzinoms (PCa). Innerhalb einer Kohorte von Prostatektomie-Patienten mit pT2a-c- und pT3a-Tumoren und initial postoperativ nodal negativem (pN0) Status wurde die Detektion von Mikrometastasen (miN + ) mittels Immunhistochemie (IHC) ermittelt. Retrospektiv wurden 2352 Lymphknoten von 193 Patienten zentral auf das Vorliegen eines miN + Status untersucht. Die Ergebnisse wurden mit klinischen und postoperativen Verlaufsparametern korreliert. Das Rezidiv-freie-Überleben (RFS) wurde mittels Log-rank-Test und Kaplan-Meier-Methode ermittelt. Ferner wurde eine logistische Regression durchgeführt. IHC detektierte miN + in insgesamt 17 (8,8 %) Patienten. Eine signifikante Assoziation von miN + zeigte sich mit höheren Gleason-Scores als auch fortgeschrittenen Tumorstadien. Insgesamt hatten 45 (23,1 %) Patienten ein biochemisches Rezidiv (BCR). Das Vorliegen eines BCR war ebenfalls mit dem miN + assoziiert: miN + Patienten wiesen ein signifikant kürzeres RFS (22,9 versus 58,7 Monate; p 0,001) auf. In der Regressionsanalyse zeigte sich sowohl univariat (OR: 5,04; 95 % CI: 2.46 – 10,6; p-value: 0.0001) als auch multivariat der miN + Status als stärkster Prädiktor für ein BCR. IHC scheint von hohem diagnostischen Wert in der Detektion von Mikrometastasen in initial nodal negativen PCa-Patienten zu sein. Daher sollte die Option einer IHC stets in Patienten mit nodal negativem Befund evaluiert werden.

İnsan alt uzuv eklemleri biyomekaniği literatür çalışmalarına göre ayak bileği kas-iskelet sistemi yürüme esnasında sürekli olarak eklem sertliğini değiştirmektedir. İnsan bileği ekleminin bu biyomekanik davranışından esinlenilerek, VS-AnkleExo (Variable Stiffness Ankle Exoskeleton) isimli değişken sertliğe sahip bir eyleyici ile tahrik edilen ayak bileği dış iskelet robot tasarımı ortaya koyulmuştur. Sertliği değiştirilebilir bir bilek eklemi tasarımı ile esnek, güvenli ve biyomimetik bir hareket kabiliyeti sağlamasına karşın dış etkiler altında kararlı ve hassas pozisyon takibinin zorluğu bu tür yumuşak eyleyicilerin en büyük problemidir. Bu makalede, VS-AnkleExo üzerinde geleneksel Oransal İntegral Türev (Proportional Derivative Integral – PID ) kontrol yönteminin ve bulanık mantık teorisinin farklı tiplerde kombine edilmesi ile oluşturulan karma kontrolcülerin pozisyon takip performansı ve dış bozuculara karşı duyarlılıkları deneysel olarak değerlendirilmiştir. VS-AnkleExo rehabilitasyon ve yürüme yardımı gibi uygulamalar için kullanılacaktır. Bu uygulamalarda ise genellikle pozisyon takibine dayanan tekrarlı hareket egzersizleri kullanılmaktadır. Bu kapsamda, çalışmada ilk olarak bozucu etkiler olmadan farklı referanslar için geleneksel PID, Bulanık PD, Bulanık PD+I, Bulanık PD+PID ve ZTS (Z, T ve S tip üyelik fonksiyonlu) Bulanık PD kontrolcülerin pozisyon takip performansı değerlendirilmiştir. Çalışmanın devamında ise, bozucu kuvvetler karşısında önerilen kontrolcülerin duyarlılığını test etmek için bozuculu basamak ve sinüs eğrisi cevap deneyleri gerçekleştirilmiştir. Elde edilen deney sonuçları, diğer kontrolcülere göre Bulanık PD+PID kontrolcünün pozisyon izleme hatalarını daha etkili azaltabildiğini ve dışarıdan uygulanan bozuculara karşı daha sağlam olduğunu göstermiştir. Ayrıca, pozisyon takibi deneyleri kapsamında, en başarılı olan Bulanık PD+PID kontrolcü kullanılarak, gerçek insana ait bilek eklemi pozisyon verileri ile bir deney daha gerçekleştirilmiş ve VS-AnkleExo robotun Bulanık PD+PID kontrolcü ile birlikte gerçek insan verilerine dayalı hareket egzersizleri çalışmalarında kullanılabileceği gösterilmiştir.

Background The Rearranged during Transfection (RET) protein is overexpressed in a subset of Estrogen Receptor (ER) positive breast cancer, with both signalling pathways functionally interacting. This cross-talk plays a pivotal role in the resistance of breast cancer cells to anti-endocrine therapies, and RET expression is assumed to correlate with poor prognosis based on findings in small patient cohorts. The aim of our study was to investigate the impact of RET expression on patient outcome in human breast cancer. Methods We performed an immunohistochemical analysis of RET protein expression on a tissue microarray encompassing 990 breast cancer patients and correlated its expression with clinicopathological parameters and survival data. Results Expression of RET was detected in 409 out of 990 cases (41.3%). RET and ER expression significantly correlated (p

e16533 Background: The objective of the present study was to identify molecular charactersitics associated with FGFR positive tumors in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB at the pilot center of the multicentric BRIDGister Real World Experience trial that are helpful for patient management and prognosis. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 28 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). Relative gene expression of subtyping markers (KRT5, KRT0) as well as FGFR1, FGFR2, FGFR3, FGFR4, ERBB2 was centrally tested by standardized test systems (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed by commercially available urine tests (UBC Rapid, BTA stat, NMP22). Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 28 patients (median age: 73, male 71% vs female 29%) of diverse clinical stages (Benign lesions/no tumor 21%, pTa 32%, pT1 21%, pT2 21%) and WHO 1973 grade (G1 7%, G2 43%, G3 21%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 9 out of 28 patients exhibited FGFR alterations (32%). FGFR positive tumors were associated with high expression of FGFR3 mRNA (r = 5.951, p = 0.0011) but low FGFR1 mRNA as well as FGFR4 mRNA (r = -0.3882, p = 0.0412 and r = -0.6305, p = 0.0004, respectively). Interestingly, FGFR alteration was positively associated with the basal marker KRT5 (r = 0.3929, p = 0.0386), but not with luminal KRT20 mRNA expression (r = -0.0208, p = 0.9179). Moreover FGFR3 altered bladder cancer was associated with elevated NMP22 levels in pretreatment urine (r = 0.3978, p = 0.0361). Conclusions: In early bladder cancer FGFR3 alterations are tightly associated with a characteristic FGFR mRNA signature. Mutation/Fusion of FGFR3 results in high FGFR3 but low FGFR1 and FGFR4 mRNA expression, which might be i.a. relevant for the response to FGFR inhibition and important to predict outcome of FGFR inhibitors. Morever FGFR alteration was associated with elevated NMP22 urine levels, which might be helpful for detecting and monitoring FGFR altered bladder cancer in a non invasive fashion. These results warrant further investigation and its impact on outcome prediction (BCG responsiveness, recurrence, proegression, etc) will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.

Aim: To evaluate the expression and prognostic value of RARRES1 at protein level in renal cell carcinoma (RCC). Materials & methods: Expression profile of RARRES1 was analyzed in 903 documented RCC followed by clinicopathological correlations and survival analysis. Results: RARRES1 expression was seen in 72.5% of RCC. A stronger RARRES1 expression was seen in high grade compared with low grade RCC (p < 0.001). Logrank tests revealed shorter overall survival in RARRES1 positive RCC (p = 0.006) and in pT1/2 tumors with RARRES1 expression (p = 0.002). Conclusion: The variable expression profile in low and high grade RCC may reflect and confirm the differences of previous gene expression analysis. There was a significant prognostic value of RARRES1 expression in patients with RCC, especially in pT1/2 tumors.

SALL4 is a transcription factor originally identified as a homeotic gene essential for organ development. Early studies suggested that SALL4 is a useful marker to identify testicular and ovarian germ cell tumors. The aim of the study was to evaluate the diagnostic potential of SALL4 immunohistochemistry. Immunohistochemical staining was performed on a tissue microarray (TMA) with 3966 samples from 94 different tumor types and on a further TMA with 492 esophagus carcinomas. SALL4 immunostaining was by far most prevalent and most intensive in testicular tumors with a positivity rate of 93.1% in seminomas, 80% in mixed germ cell tumors (embryonic carcinomas/yolk sac tumors), and 18.5% in teratomas, respectively. However, SALL4 expression is not specific to germ cell tumors. We observed SALL4 positivity in non-germ cell tumors as carcinomas of the kidney (28.9% of chromophobe, 34.4% of clear cell carcinoma), in intestinal type adenocarcinoma of the stomach (10.9%), in adenocarcinoma (10.5%) and squamous cell carcinoma (7.2%) of the esophagus, and in malignant melanoma (8.1%) and invasive urothelial bladder carcinoma (20%). SALL4 expression was not found in lymphomas, in soft tissue tumors or breast tumors. At analysis of esophagus carcinoma TMA, no significant association was seen between SALL4 expression and overall survival in adenocarcinoma. However, SALL4 expression was strongly associated with worse overall survival in squamous cell carcinoma. SALL4 expression can be found at relevant frequencies in various tumors of different primary sites. SALL4 expression in squamous cell carcinoma of the esophagus may constitute a sign of dedifferentiation leading to poor patient prognosis.

Background There is inconsistent information about the clinical usefulness of circulating cell-free DNA (cfDNA) in plasma from clear cell renal cell cancer (RCC) patients. This is attributed to preanalytical, analytical, and clinical factors that were considered as far as possible in this study. Methods cfDNA was extracted from EDTA plasma of healthy people (n = 40), non-metastatic (n = 145) and metastatic (n = 84) RCC patients using the QIAamp Circulating Nucleic Acid Kit. Genomic and mitochondrial cfDNA concentrations were determined using qPCR of different cfDNA fragments (67–306 bp). Their diagnostic and prognostic potential was estimated using receiver operating characteristics (ROC) and Cox regression analyses. Results The 67 bp and 180 bp genomic cfDNA fragments did not differ between the three study groups while the 306 bp fragment was lower in RCC patients than in controls. The mitochondrial cfDNA was higher in metastatic than in non-metastatic patients and controls. The cfDNA integrity indices decreased from controls to metastatic patients. Models built by logistic regression and Cox regression resulted in area under the ROC curves > 0.75 and concordance indices of > 0.800 in predicting recurrence-free survival and overall survival. Conclusion The study suggests that combinations of cfDNA markers have promising diagnostic and prognostic potential in RCC patients and are worth for further validation in future prospective multicenter studies.

Son zamanlarda insan-dış iskelet robot etkileşim alanında umut verici ilerlemeler kaydedilmektedir. Tipik bir fiziksel kullanıcı-robot etkileşimi olarak, sağlıklı bir kullanıcının performansını arttırmak ya da fonksiyonları azalmış olan kullanıcılara yürüme desteği ve yürüme rehabilitasyonu sağlamak amacıyla dış iskelet robotlar geliştirilmiştir. Bu cihazlar performans arttırma çalışmalarında kullanıcılara herhangi bir engel çıkarmadan ya da onların hareketlerini sınırlamadan insan anatomisi ile uyumlu bir şekilde ve aralarında minimum etkileşim kuvveti oluşturarak şekilde hareket etmelidirler. Özellikle askeri uygulamalarda dış iskelet robotun sırtına yerleştirilmiş bir yükün robotun kendi ağırlığı ile birlikte kullanıcıya hissettirilmeden taşınması gerekmektedir. Bu bağlamda bu çalışmada daha önceden Geyer, (2010) tarafından oluşturulmuş 2 boyutlu bir insan modeli geliştirilerek insan-dış iskelet robot üzerinde etkileşim kuvvetlerini azaltma çalışması yapılmıştır. Çalışma kapsamında öncelikli 3 boyutlu bir insan modeli oluşturulmuştur. Bu insan modeli iki ayak, iki alt ekstremite ve bir gövdeden oluşan toplam beş zincirden meydana gelmektedir. Gerçek insan modeline en yakın sonuçlar elde edebilmek için kütlesi yaklaşık 66,75 kg ve boyu 190 cm olan erkek bir bireyin düz bir zeminde yürüme verileri alınmış ve 1 m/s hız ile yürütülmüştür. Geyer, (2010) tarafından oluşturulmuş 2 boyutlu insan modeli 3 boyutlu olarak geliştirildikten sonra, bir dış iskelet robot modeli elde edilmiştir. İnsan modeli üzerine bu dış iskelet model giydirilerek yeni bir insan-dış iskelet robot model yapısı oluşturulmuştur. İnsan-dış iskelet robot model üzerinde ilk önce herhangi bir kontrol olmadan yürüme çalışması gerçekleştirilmiştir. Daha sonra eklemler (aya bileği, diz ve kalça) için tanımlanan bir geri besleme kuvvet/tork kontrolü insan-dış iskelet robot model üzerine uygulanmış ve elde edilen sonuçlar kontrolsüz durum ile karşılaştırılmıştır., Recently, many promising advancements have been recorded in the field of human-exoskeleton robot interaction. As a typical physical user-robot interaction, exoskeleton robots have been developed to augment power of a healthy user or provide walking support and rehabilitation for paralyzed patient. These devices should provide flexible movement on human anatomy by using any obstacles or limiting their movement in terms of minimum interaction force law. Especially in military applications, a robotic robot placed on the back of an exoskeleton robot needs to be transported with its own weight without being felt by the user. In this study, based on a created 2D human model, which is inspired by Geyer (2010), a three dimensional (3D) human-exoskeleton robot is enhanced to drastically reduce interaction forces between them. For this purpose, the human model is created by consisting of two feet, two lower extremities and a trunk. In order to collect correct data from 3D human-exoskeleton robot model against human model, walking data of an individual male, a weight of 66.75 kg and a height of 1.90 cm, was run across a road at a speed of 1 m/s. After 2D human model created by Geyer has been developed as 3D, the exoskeleton robot model is covered on the human model and a new human-exoskeleton robot model is re-created. A walking exercise was carried out on the human-exoskeleton model without any control. Then, a defined feedback force control was applied on the human-exoskeleton model and the results are compared with uncontrolled state.

// Gerrit Kurschner 1, 2, * , Qingzhou Zhang 3, * , Rosanna Clima 4, 5 , Yi Xiao 1, 6 , Jonas Felix Busch 7 , Ergin Kilic 8 , Klaus Jung 7, 9 , Nikolaus Berndt 10 , Sascha Bulik 10 , Hermann-Georg Holzhutter 10 , Giuseppe Gasparre 5 , Marcella Attimonelli 4 , Mohan Babu 3 and David Meierhofer 1 1 Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany 2 Technical University of Berlin, Institute of Bioanalytics, Department of Biotechnology, Berlin, Germany 3 University of Regina, Department of Biochemistry, Regina, Canada 4 University of Bari, Department of Biosciences, Biotechnology and Biopharmaceutics, Bari, Italy 5 Department of Medical and Surgical Sciences-DIMEC, Medical Genetics Unit, University of Bologna, Bologna, Italy 6 Freie Universitat Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin, Germany 7 University Hospital Charite, Department of Urology, Berlin, Germany 8 University Hospital Charite, Institute of Pathology, Berlin, Germany 9 Berlin Institute for Urologic Research, Berlin, Germany 10 Charite University Medicine Berlin, Institute of Biochemistry Computational Systems Biochemistry Group, Berlin, Germany * These authors have contributed equally to this work Correspondence to: David Meierhofer, email: Meierhof@molgen.mpg.de Mohan Babu, email: mohan.babu@uregina.ca Keywords: renal oncocytoma; complex I deficiency; glutathione metabolism; mtDNA mutation Received: July 10, 2017 Accepted: September 21, 2017 Published: November 11, 2017 ABSTRACT Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD + , NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.

This study proposes an Electromyography (EMG) based neural network and admittance control strategy for an Active wrist orthosis (AWO) that is mobile, powerful and lightweight in order to avoid the occurrence and/or for the treatment of repetitive strain injuries. The device has an EMG based control strategy so that it can track the contraction of the forearm muscles of interest in real time to assist the device user during the extension and flexion wrist movements. Indeed, time-delayed artificial neural networks were trained offline to predict the forearm muscle forces based on features extracted from raw EMG signals. The predicted force values were used to calculate a reference velocity command by using an admittance model with properly adjusted parameters. A closed loop velocity control system was used to perform the desired wrist motion. Some experimental studies were performed to evaluate the assistive performance of the AWO device with the proposed control system under various disturbance loads. The experimental results show that the activation levels of the forearm muscles were considerably reduced when the AWO device was enabled.

People who perform excessive wrist movements throughout the day because of their professions have a higher risk of developing lateral and medial epicondylitis. If proper precautions are not taken against these diseases, serious consequences such as job loss and early retirement can occur. In this study, the design and control of an active wrist orthosis that is mobile, powerful and lightweight is presented as a means to avoid the occurrence and/or for the treatment of repetitive strain injuries in an effective manner. The device has an electromyography-based control strategy so that the user’s intention always comes first. In fact, the device–user interaction is mainly activated by the electromyography signals measured from the forearm muscles that are responsible for the extension and flexion wrist movements. Contractions of the muscles are detected using surface electromyography sensors, and the desired quantity of the velocity value of the wrist is extracted from a fuzzy logic controller. Then, the actuator system of the device comes into play by conveying the necessary motion support to the wrist. Experimental studies show that the presented device actually reduces the demand on the muscles involved in repetitive strain injuries while performing challenging daily life activities including extension and flexion wrist motions.

A wide range of braking forces, from near zero to high values, is required in specific applications such as forces in haptic devices or steering stability in motorcycles. Classical piston cylinder type magnetorheological (MR) brakes are not suitable for these applications due to their high off-state forces. In this paper, a new linear type MR brake employing shear mode braking principle with a multipole outer coil structure is presented for high on-state and low off-state force outputs. To implement this device, an analytical model of the brake is derived by using magnetic circuit analysis to determine braking force. Magnetic finite element models are developed and coupled with an optimization algorithm to determine the optimal set of parameters of the brake design. A prototype is manufactured and tested experimentally to characterize the device's force response, transient response, hysteresis, force tracking, and damping performance. The proposed brake achieved a maximum braking force of 480 N and a low off-state force of 6 N with infinite stroke. The results show that the ratio of maximum force to off-state force for our device is about 80, even though it is a maximum of 32 for the best linear brakes in the literature.

To improve the clinical decision‐making regarding further treatment management and follow‐up scheduling for patients with muscle‐invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR‐100‐5p, miR‐130b‐3p, miR‐141‐3p, miR‐199a‐3p, miR‐205‐5p, and miR‐214‐3p) was measured by RT‐qPCR in formalin‐fixed, paraffin‐embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow‐up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy‐three samples from adjacent normal tissue were used as controls. Kaplan–Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR‐130b‐3p and miR‐141‐3p) and reduced (miR‐100‐5p, miR‐199a‐3p, and miR‐214‐3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P

Hintergrund: Die Magnet Resonanz Tomografie (MRT)/Ultraschall (US) fusionierte Biopsie detektiert in Patienten mit Indikation zur Wiederholungsbiopsie mehr Prostatakarzinome (PCa) als die konventionelle transrektal Ultraschall (TRUS) gestutzte Biopsie. Ziel der Studie war es a) die Detektionsraten der MRT/US-Fusionsbiopsie mit der konventionell TRUS gestutzten Biopsie in einer Doppelzentrums-Kohorte gemeinsam zu evaluieren und b) die Detektionsraten in Abhangigkeit der Anzahl der Vorbiopsien zu untersuchen. Material und Methoden: Im Zeitraum von Januar 2012 bis Juli 2014 erhielten 310 Patienten mit mindestens einer PCa suspekten Lasion in einer zuvor erfolgten multiparametrischen MRT bei 3 Tesla eine MRT/US fusionierte Biopsie der Prostata. Konsekutiv wurde zum direkten Vergleich eine randomisierte 10-fach konventionelle TRUS gestutzte Biopsie durchgefuhrt. Detektionsraten wurden nach Methode, Gleason Score und in Abhangigkeit der Vorbiopsien ermittelt. Ergebnisse: In 310 biopsierten Patienten konnte eine Gesamtdetektionsrate fur ein PCa mit 51% (158 Patienten) erreicht werden. Die histologische Auswertung ergab fur die detektierten 158 PCa einen Gleason Score 6 in 60 Patienten (38%), einen Gleason Score 7 in 54 Patienten (34%) und einen Gleason Score≥8 in 44 Patienten (28%). Unter den 158 Patienten mit PCa wurden 110 (69,7%) mittels MRT/US Fusion detektiert. Unter den singular mittels TRUS detektierten PCa zeigte sich eine hohere Rate an Gleason Score 6 Karzinomen (54% vs. 38%) und eine geringere Detektion von Gleason≥8 Karzinomen (15% vs. 28%). Hingegen imponierte eine hohere Anzahl niedriger Gleason Scores in Patienten mit einer hoheren Anzahl an Vorbiopsien. Die Detektionsrate lag bei Patienten mit primarer Fusionsbiopsie bei 75% (40 Patienten). Hierbei wurden 75% PCa mit einem Gleason Score≥7 diagnostiziert. Schlussfolgerung: Die MRT/US-Fusionsbiopsie detektiert auch in dieser Doppelzentrums-Analyse mehr und auch signifikante PCa als die konventionelle TRUS. Die Anzahl an Vorbiopsien divergiert mit der Anzahl signifikanter PCa. Eingeschlossene Primarbiopsien mit 75% Detektionsrate gilt es in einer Folgestudie naher zu evaluieren.

Introduction C-kit overexpression has previously been described in chromophobe renal cell carcinoma (cpRCC) and renal oncocytoma (RO). However, so far no KIT mutations have been found. The objective of our study was to analyse c-kit in a large cohort of renal tumors and to perform KIT mutation analysis in a subset cpRCC and RO cases with overexpression of c-kit. Materials and methods We studied the immunohistochemical expression of c-kit on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 948 patients with renal tumors. CpRCC and RO cases with c-kit overexpression ( n = 23) were analyzed for KIT mutations in exons 9, 11, 13, 14, 15, and 17. Results Expression of c-kit was found in 6/642 (0.9%) clear cell RCC, 3/154 (1.9%) papillary RCC, 54/69 (78.3%) cpRCC, 37/45 (82.2%) RO and 2/30 (6.7%) of other unclassified tumor types. In none of the RO and cpRCC cases analyzed, a KIT gene mutation was found. Conclusion C-kit expression is found in the majority of cpRCC and RO, but these tumors do not harbor the usual c-kit activating mutations. This may have implications for the use of tyrosine kinase inhibitors in patients with advanced cpRCC and c-kit expression.

Hintergrund: Patienten mit steigenden PSA-Werten oder positivem Tastbefund in der digital rektalen Untersuchung (DRU) oder einer atypischen mikroazinaren Proliferation nach einer negativen Prostatabiopsie erhalten nach den Leitlinien der Europaischen Gesellschaft fur Urologie eine Wiederholungsbiopsie. Die geringen Detektionsraten bei der transrektal Ultraschall (TRUS) gestutzten Wiederholungsbiopsie zeigen das Dilemma in der Prostatakarzinom (PCa) Diagnostik. Die Kombination des dynamischen TRUS mit den hohen Spezifitaten und Sensitivitaten der Prostata Magnet Resonanz Tomografie (MRT) im Rahmen der sogenannten Echtzeit MRT/US-Fusion, wurde fur die Detektion klinisch signifikanter Karzinome evaluiert. Material und Methoden: Es wurden 128 konsekutive Patienten in der Zeit von Januar 2012 bis August 2013 in die Studie eingeschlossen. Alle Patienten hatten mindestens eine vorausgegangene negative Prostatabiopsie und es bestand weiterhin der klinische Verdacht auf ein PCa. Alle Patienten erhielten zuvor eine multiparametrische 3 Tesla MRT ohne Endorektalspule. Es folgte die Datenfusion der MR-Sequenzen mit folgenden US-Techniken: B-Bild, Farbdoppler, Elastografie, CEUS zur Charakterisierung der MR-suspekten Herde. Diese Herde wurden mittels der genannten US-Techniken mit einem US-Summen-Score bewertet und anschliesend gezielt biopsiert. Unmittelbar im Anschluss daran folgte eine systematische 10-fach Biopsie. Ergebnisse: Unter 128 Patienten konnte in 51 Fallen ein PCa diagnostiziert werden; dies entspricht einer Rate von 39,8%. Von den 51 PCa Patienten konnten klinisch signifikante PCa haufiger durch die MRT/US-Fusion nachgewiesen werden: Gleason Score >7 in 9 von 10 Fallen; Gleason Score=7 in 14 von 20 Fallen und Gleason Score Schlussfolgerung: Die MRT/US-Fusion erhoht die Detektionsrate in zuvor negativ biopsierter Patienten. Insbesondere Tumoren mit einem Gleason Score ≥ 7 sind nahezu ausschlieslich durch die MRT/US-Fusionsbiopsie detektiert und biopsiert worden.