Prognostic Value of Molecular Breast Cancer Subtypes based on Her2, ESR1, PGR and Ki67 mRNA-Expression in Muscle Invasive Bladder Cancer.

INTRODUCTION: Gene expression analyses have identified similarities between bladder and breast cancer, where clinical risk stratification is based on Her2, ESR1, PGR and Ki67 expression. The aim of the study was to assess the respective marker gene expression in patients treated with radical cystectomy for muscle-invasive bladder cancer (MIBC) and to evaluate the applicability of breast cancer subtypes for MIBC risk stratification. MATERIALS & METHODS: 102 patients treated with radical cystectomy for MIBC were assessed. Using routine FFPE tissue and an IVD validated kit, mRNA expression was measured by single step RT-qPCR. Partition test were employed to define cut-off values for high or low marker gene expression. Association of expression with outcome was assessed using Kaplan-Meier analysis and multivariate cox regression analysis. Finally, we performed validation of our results in the MD-Anderson cohort (n=57). RESULTS: Cancer specific survival (CSS) was impaired in patients with high gene expression of Her2 (P=0.0009) and ESR1 (P=0.04). In the multivariate regression model Her2 expression remained significant for the prediction of CSS (HR=2.11, CI 1.11-4.21, P=0.024). Furthermore, molecular stratification by breast cancer subgroups was significant (P=0.023) for CSS prediction. Especially the differentiation between Her2-positive and Luminal A (HR=4.41, CI 1.53-18.71, P=0.004) and Luminal B (HR=1.96, CI 0.99-4.08, P=0.053) respectively was an independent prognostic parameter for CSS. External validation resulted in comparable risk stratification with differences in fractional subgroups distribution. CONCLUSION: Gene expression of Her2, ESR1, PGR, Ki67 and corresponding breast cancer subtypes allow a risk-stratification in MIBC, whereby Her2 overexpressing tumors reveal a particularly poor prognosis.

Increasing use of radical prostatectomy for locally advanced prostate cancer in the USA and Germany: a comparative population-based study.

BACKGROUND: Current guidelines do not recommend a preferred treatment modality for locally advanced prostate cancer. The aim of the study was to compare treatment patterns found in the USA and Germany and to analyze possible trends over time. METHODS: We compared 'Surveillance Epidemiology and End Results' (SEER) data (USA) with reports from four German federal epidemiological cancer registries (Eastern Germany, Bavaria, Rhineland-Palatinate, Schleswig-Holstein), both from 2004 to 2012. We defined locally advanced prostate cancer as clinical stage T3 or T4. Exclusion criteria were metastatic disease and age over 79 years. RESULTS: We identified 9127 (USA) and 11 051 (Germany) patients with locally advanced prostate cancer. The share was 2.1% in the USA compared with 6.0% in Germany (P<0.001). In the United States, the utilization of radiotherapy (RT) and radical prostatectomy (RP) was comparably high with 42.0% (RT) and 42.8% (RP). In Germany, the major treatment option was RP with 36.7% followed by RT with 22.1%. During the study period, the use of RP increased in both countries (USA P=0.001 and Germany P=0.003), whereas RT numbers declined (USA P=0.003 and Germany P=0.002). The share of adjuvant RT (aRT) was similar in both countries (USA 21.7% vs Germany 20.7%). CONCLUSION: We found distinctive differences in treating locally advanced prostate cancer between USA and Germany, but similar trends over time. In the last decade, a growing number of patients underwent RP as a possible first step within a multimodal concept.

Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC.

[Side effect management of tyrosine kinase inhibitors in urology : Hypertension]. / Nebenwirkungsmanagement von Tyrosinkinaseinhibitoren in der Urologie : Arterielle Hypertonie.

Tyrosine kinase inhibitors like sunitinib, sorafenib, pazopanib or axintinib are regarded the standard of care in the systemic therapy of metastatic renal cell carcinoma. However, the many side effects associated with this therapy pose challenges for the treating physician and the patient. This review offers an overview of the classification and the treatment of hypertension, which is one of the major side effects induced by all tyrosine kinase inhibitors, in order to improve treatment efficacy and patient compliance.

[Side effect management of tyrosine kinase inhibitors in urology : Gastrointestinal side effects]. / Nebenwirkungsmanagement von Tyrosinkinaseinhibitoren in der Urologie : Gastrointestinale Nebenwirkungen.

For approximately one decade, tyrosinkinase inhibitors (TKIs, smart drugs) have dramatically changed and improved the treatment of patients suffering from metastasized renal cell carcinoma. However, the different drugs have substantial side effects. Especially gastrointestinal symptoms may be problematic for patients. These side effects represent a challenge for the physician. On the one hand, dosage modifications and treatment interruption should be avoided to minimize the risk for progression. On the other hand, only mild side effects are tolerable for the patient. Based on a literature review, a clear overview of the incidence of possible side effects for the drugs axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib is provided. Furthermore, we give a practical guide on how to prevent and treat the different gastrointestinal side effects. Finally, it is pointed out when dosage modifications or interruption of treatment are necessary and how to expeditiously re-escalate the treatment after mitigation of side effects.

[Side effect management of tyrosine kinase inhibitors in urology : Fatigue and hypothyroidism]. / Nebenwirkungsmanagement von Tyrosinkinaseinhibitoren in der Urologie : Fatigue und Hypothyreose.

Not only has the use of tyrosine kinase inhibitors (TKI) for the treatment of metastatic renal cell carcinomas (mRCC) changed the therapeutic options for this disease significantly, but with the occurrence of typical side effects this therapy also poses a challenge for the treating physician. Fatigue und hypothyroidism are two common side effects of TKI therapy that can often appear simultaneously. By reducing the patients' quality of life these side effects often lead to a discontinuation of therapy. With this review we want to give the treating physician an overview of the classification and the specific treatment of TKI-induced fatigue and hypothyroidism in order to maximize patients' compliance and the therapeutic efficacy of TKI therapy.

[Vertebral metastases of urogenital carcinomas: Diagnosis and conservative therapy]. / Wirbelsäulenmetastasen urologischer Tumoren : Diagnostik und konservative Therapie.

The high incidence of bone metastases of urologic neoplasms and their morbidity, especially of vertebral metastases, requires exact diagnosis and consequent therapy. Conventional radiography plays an important role in the diagnosis of symptomatic bone lesions. Computed tomography can evaluate the stability of metastatic lesions and is indispensable for therapy planning. MRI and PET-CT have the highest diagnostic accuracy for the detection of bone metastases and MRI can evaluate their intra- and extraosseus components. PET-CT, PET-MRI, or SPECT-CT in combination with specific tracers - due to their high specificity and sensitivity - have the potential to replace conventional methods in the future. Conservative treatment basically consists of analgesic therapy, the administration of calcium and vitamin D3 and bisphosphonates or inhibitors of RANKL (denosumab). Moreover radium-223-dichloride can improve overall survival and the time to the first symptomatic skeletal event in castration-resistant prostate cancer patients with bone metastases.

Long-Term Respiratory Support for Children and Adolescents in Austria: A National Survey.

BACKGROUND: Population-based data on pediatric patients on long-term respiratory support (LTRS) in Austria are lacking. This study aimed to record the pediatric departments active in this field, as well as number and characteristics of patients on LTRS. METHODS: A national cross-sectional study was carried out by means of questionnaires sent to all pediatric departments in Austria. RESULTS: All departments answered to the questionnaires. On June 1st, 2013, the reference day for this study, 12 of the 41 pediatric departments in Austria were active in the field. At this time, these centers were caring for 143 patients, 111 (77.6%) of them under 18 years, which corresponds to a prevalence of 7.4 per 100 000. The patients suffered from neuromuscular disorders (44%), other neurological disorders (18.9%), disorders of respiratory drive (9.1%), obstructive sleep apnea (8.4%), thoracal and spinal diseases (8.4%), pulmonary disorders (4.9%) and other diseases (6.3%). Continuous positive airway pressure was used in 6.3%, non-invasive ventilation in 60.1% and invasive ventilation in 33.6% of the patients, respectively. LTRS was performed at home in 92.3%. CONCLUSION: LTRS represents a common management strategy in children and adolescents with a variety of disorders. Census reports such as this one provide the basis for appropriate planning of resource allocation. The age distribution of our patients shows the need for structured transition into adult care.

[Operative therapy of spinal metastases from urological tumors]. / Operative Therapie von Wirbelsäulenmetastasen urologischer Tumoren.

The treatment of bone metastases from urological tumors represents a palliative form of therapy, apart from the resection of solitary metastases from renal cell carcinomas. Due to the high incidence of spinal metastases this can result in clinically significant symptoms and possible complications for patients, such as pain, spinal instability and compression of the spinal canal with corresponding neurological deficits. By the use of targeted diagnostics and induction of radiotherapeutic and/or surgical treatment, for the majority of patients an immediate reduction in pain as well as early mobilization and sometimes even regression of existing neurological deficits and therefore an improved quality of life can be achieved.

Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients.

The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p = 0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p = 0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.

[Treatment of nonmetastatic prostate cancer: a systematic review of interactive, personalized patient decision aids]. / Therapie des nichtmetastasierten Prostatakarzinoms : Eine systematische Übersicht interaktiv personalisierter patientenorientierter Entscheidungshilfen.

BACKGROUND: Patients with nonmetastatic prostate cancer face a complex treatment decision. To support them with personalized information, a variety of interactive computerized decision aids have been developed in Anglo-Saxon countries. Our goal was to identify relevant decision aids and investigate their didactic strengths and limitations. MATERIALS AND METHODS: We included decision aids that derived individualized content from personal and clinical data provided by the patient. By conducting a systematic literature and internet research through November 2013 supplemented by expert interviews, we identified 10 decision aids of which 6 had been investigated scientifically. We compared their individual characteristics as well as the design and results of the evaluation studies. RESULTS: The decision aids present two to seven therapy choices, whereby radical prostatectomy and percutaneous radiotherapy are always included. Number and type of parameters provided by the patient also vary considerably. Two decision aids derive a therapeutic recommendation from the patient's input. Evaluation studies showed higher disease-related knowledge and greater confidence in the treatment decision after using one of six decision aids. Satisfaction with the decision aid was predominantly high. CONCLUSIONS: Currently personalized patient decision aids for treatment of nonmetastatic prostate cancer are only available in English. These tools can facilitate the shared decision making process for patients and physicians. Therefore, comparable decision aids should be developed in German.

[Austrian interdisciplinary recommendations on pediatric perioperative pain management: background, aims, methods and key messages]. / Österreichische interdisziplinäre Handlungsempfehlungen zum perioperativen Schmerzmanagement bei Kindern : Hintergrund, Ziel, Methodik und Kernaussagen.

These recommendations were originally commissioned by the"Österreichische Gesellschaft für Anästhesiologie, Reanimation und Intensivmedizin" (ÖGARI, Austrian Society for Anesthesiology, Resuscitation and Intensive Care Medicine). Against this background, Austrian experts from the disciplines anesthesiology, pain management, pediatrics and the "Berufsverband Kinderkrankenpflege" (Professional Association of Pediatric Nursing) have with legal support developed evidence-based and consensus recommendations for the clinical practice. The recommendations include key messages which cover the most important recommendations for the individual topics. The complete recommendations on pediatric perioperative pain management consist of seven separate articles which each deal with special sub-topics with comments on and explanations of the key messages. The target groups of the recommendations are all medical personnel of the individual disciplines involved in the treatment of perioperative and posttraumatic pain for neonates, infants and children up to 18 years old.

[Pharmacodynamic and pharmacokinetic characteristics of pain therapy in neonates: Austrian interdisciplinary recommendations on pediatric perioperative pain management]. / Pharmakodynamische und pharmakokinetische Besonderheiten der Schmerztherapie bei Neugeborenen : Österreichische interdisziplinäre Handlungsempfehlungen zum perioperativen Schmerzmanagement bei Kindern.

The false assumption that neonates are less sensitive to pain than adults led to a long delay in the introduction of a reasonable pain therapy for children. Even if the basic principles of the development, transmission and perception of pain in premature infants and neonates are not completely understood, the results of studies have clearly shown that pain can be perceived from 22 weeks of gestation onwards. This knowledge results in the necessity to also administer an adequate pain therapy to premature and newly born infants. However, for the use of pharmaceuticals in neonates and infants the pharmacodynamic and pharmacokinetic characteristics must also be considered. The immaturity of the organs liver and kidneys limits the metabolism and also excretion processes. The different physical proportions also modify the dosing of pharmaceuticals. Children in the first year of life differ substantially from adults in physiology, pharmacodynamics and pharmacokinetics. The care of neonates and infants requires specialist knowledge which is described in this article.

MicroRNA profiles classify papillary renal cell carcinoma subtypes.

BACKGROUND: Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes. METHODS: We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes. RESULTS: Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes. CONCLUSION: MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling.

[Bladder cancer in focus: update 2012 of the German Bladder Cancer Association]. / Das Harnblasenkarzinom im Fokus : Update 2012 des Deutschen Forschungsverbundes Blasenkarzinom e. V.

The German Bladder Cancer Association (DFBK) invited its members to the 3rd annual meeting 2012 in Hannover 4 years after the official founding. The meeting was directed to discuss the progress of ongoing and newly initiated projects and collaborations. In this article we will introduce current research activities and collaborations of the DFBK and would like to invite interested researchers to join this national interdisciplinary research association. The aim of the DFBK is to initiate interdisciplinary collaboration and to support scientific discussions among its members. For further information please visit our website at www.forschungsverbund-blasenkarzinom.de.

[Plasmacytoid and micropapillary urothelial carcinoma: rare forms of urothelial carcinoma]. / Das plasmazytoide und mikropapilläre Urothelkarzinom : Seltene Varianten eines Urothelkarzinoms.

Plasmacytoid urothelial carcinomas (PUC) along with micropapillary urothelial carcinoma (MPC), small cell cancer, and nested-typed tumors are among the rare variations of urothelial carcinomas. The molecular characterization of PUC and MPC is currently the focus of our research on bladder cancer which we are conducting in cooperation with the Institute of Pathology in Erlangen. PUCs account for approximately 0.9% of all urothelial carcinomas. The diagnosis of these rare variants has acquired increasing importance since this may have prognostic and possibly therapeutic consequences for the patients. By analysis of 32 PUCs we were able to demonstrate the most comprehensive results available to date on the underlying molecular and clinical characteristics of these variants. Micropapillary cancers have already been described in multiple organs. Micropapillary breast cancer represent an individual entity with characteristic genomic aberrations and corresponding clinical and pathological features.

[Value of biomarkers in urology]. / Stellenwert von Biomarkern in der Urologie.

As part of the diagnosis and treatment of cancer objective biological measures are becoming increasingly important and may help to elicit the individual patient's risk of future outcome. Among theses measures are markers as determinants for the biological potential of the malignant disease, the prediction of recurrence after systemic treatment or the response to a specific therapy. In counselling patients with uro-oncologic diseases, the emerging role of evidence-based treatment choices reveals with cumulative certainty that the available information on markers is inconclusive.The aim of this review is to provide a summary of the current evidence of the evaluation of markers, which may be supportive for a treatment decision and/or provide additional valuable information as part of the treatment option. In addition, this may provide access to some of the most promising investigations, which may yield perspectives for future relevant clinical questions.

Technical note: RabbitCT--an open platform for benchmarking 3D cone-beam reconstruction algorithms.

PURPOSE: Fast 3D cone beam reconstruction is mandatory for many clinical workflows. For that reason, researchers and industry work hard on hardware-optimized 3D reconstruction. Backprojection is a major component of many reconstruction algorithms that require a projection of each voxel onto the projection data, including data interpolation, before updating the voxel value. This step is the bottleneck of most reconstruction algorithms and the focus of optimization in recent publications. A crucial limitation, however, of these publications is that the presented results are not comparable to each other. This is mainly due to variations in data acquisitions, preprocessing, and chosen geometries and the lack of a common publicly available test dataset. The authors provide such a standardized dataset that allows for substantial comparison of hardware accelerated backprojection methods. METHODS: They developed an open platform RabbitCT (www.rabbitCT.com) for worldwide comparison in backprojection performance and ranking on different architectures using a specific high resolution C-arm CT dataset of a rabbit. This includes a sophisticated benchmark interface, a prototype implementation in C++, and image quality measures. RESULTS: At the time of writing, six backprojection implementations are already listed on the website. Optimizations include multithreading using Intel threading building blocks and OpenMP, vectorization using SSE, and computation on the GPU using CUDA 2.0. CONCLUSIONS: There is a need for objectively comparing backprojection implementations for reconstruction algorithms. RabbitCT aims to provide a solution to this problem by offering an open platform with fair chances for all participants. The authors are looking forward to a growing community and await feedback regarding future evaluations of novel software- and hardware-based acceleration schemes.

[Plasmacytoid carcinoma. Five case reports of a rare variant of urothelial carcinoma]. / Das plasmazytoide Urothelkarzinom. 5 Fallberichte einer seltenen Variante des konventionellen Urothelkarzinoms.

Plasmacytoid carcinoma is a rare variant of urothelial carcinoma and is characterised by distinct histopathological and clinical characteristics. The incidence varies between 2.7% and 3.1% of all muscle-invasive urothelial carcinoma. It is an aggressive, high-grade tumor with poor prognosis. Negative E-cadherin expression seems to be important for exact diagnosis. Systemic chemotherapy of plasmacytoid carcinoma could lead to prolonged patient survival.