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With the numerous advances and broad applications of mobile health (mHealth), establishing concrete data sharing, privacy, and governance strategies at national (or regional) levels is essential to protect individual privacy and data usage. This article applies the recent Health Data Governance Principles to provide a guiding framework for low- and middle-income countries (LMICs) to create a comprehensive mHealth data governance strategy. We provide three objectives: (1) establish data rights and ownership to promote equitable benefits from health data, (2) protect people through building trust and addressing patients’ concerns, and (3) promote health value by enhancing health systems and services. We also recommend actions for realizing each objective to guide LMICs based on their unique mHealth data ecosystems. These objectives require adopting a regulatory framework for data rights and protection, building trust for data sharing, and enhancing interoperability to use new datasets in advancing healthcare services and innovation.

Computational fluid dynamics (CFD) has enormous potential for the development of novel cardiovascular implants. In particular, the evaluation of the thrombogenic potential of implants is gaining importance. For this purpose, the numerical model must represent the essential properties of the real system, i.e., an implant in the human blood circulation, in a suitable form. Due to its complexity, the model building process is crucial for the successful application of the model. Currently, there is no structured guideline for the application of numerical flow simulation to which model developers can refer. Based on NASA and ASTM, we present key aspects of the model building process using CFD for stent flow as an example.

New technologies such as devices, apps, smartphones, and sensors not only enable people to self-monitor their health but also share their health data with healthcare professionals. Data collection and dissemination occur across a wide variety of environments and settings, tracking everything from biometric data to mood and behavior, which has been termed Patient Contributed Data (PCD). In this work, we created a patient journey, enabled by PCD, to shape a connected health model for Cardiac Rehabilitation (CR) in Austria. Consequently, we highlighted the potential PCD benefit, which is a postulated increasing uptake of CR and improved patient outcomes through apps in a home-based setting. Finally, we addressed the related challenges and policy barriers that hinder the implementation of CR-connected health in Austria and identified actions to be taken.

Zusammenfassung Die minimalinvasive Implantation einer Transkatheter-Aortenklappenprothese (TAVR) hat sich zur Standardtherapie für Patienten mit schwerer Aortenklappenstenose und erhöhtem Operationsrisiko etabliert. Postoperative Komplikationen, wie die subklinische Klappenthrombose, rufen langfristig eine Funktionsstörung der TAVR hervor, die ohne Revisionstherapie zum Tod des Patienten führen kann. Mit der Abschätzung des Thromboserisikos von TAVR werden strömungsmechanische Mechanismen assoziiert. Die Particle Image Velocimetry (PIV) bietet ein etabliertes Messverfahren zur Bestimmung des Geschwindigkeitsfeldes einer TAVR, aus dem beispielsweise die Verweilzeit von Blut im Umfeld einer TAVR abgeleitet werden kann. Ein traversierbarer stereo-PIV Aufbau, bei dem zwei CMOS-Kameras im 45 ° Winkel zur Lichtschnittebene positioniert wurden, ermöglichte die Detektion von Tracerpartikeln in den relevanten Bereichen im Umfeld des TAVR. Mit einer geeigneten Messkammer, die in die hydraulische Nachbildung eines kardiovaskulären Kreislaufs implementiert wurde, konnte eine quasi-volumetrische Messung des physiologischen Geschwindigkeitsfeldes durchgeführt werden. Dafür wurde anhand radiologischer Daten eine realistische Implantationsumgebung rekonstruiert. Mit einem Blutersatzfluid (NaCl-Glycerin-Gemisch) wurde die normativ (ISO 5840:2021) geforderte kinematische Viskosität von ν = 3,5 cSt realisiert. Phasengetriggerte Aufnahmen ermöglichten die Messung zu definierten Zeitpunkten im kardiologischen Zyklus. Insgesamt ist es gelungen die komplexe Strömungstopologie mit dem dargestellten Messaufbau in allen relevanten Bereichen zu erfassen und damit zukünftig das Thromboserisiko abschätzen zu können.

It is commonly accepted that hemodynamic situation is related with cardiovascular diseases as well as clinical post-procedural outcome. In particular, aortic valve stenosis and insufficiency are associated with high shear flow and increased pressure loss. Furthermore, regurgitation, high shear stress and regions of stagnant blood flow are presumed to have an impact on clinical result. Therefore, flow field assessment to characterize the hemodynamic situation is necessary for device evaluation and further design optimization. In-vitro as well as in-silico fluid mechanics methods can be used to investigate the flow through prostheses. In-silico solutions are based on mathematical equitation’s which need to be solved numerically (Computational Fluid Dynamics - CFD). Fundamentally, the flow is physically described by Navier-Stokes. CFD often requires high computational cost resulting in long computation time. Techniques based on deep-learning are under research to overcome this problem. In this study, we applied a deep-learning strategy to estimate fluid flows during peak systolic steady-state blood flows through mechanical aortic valves with varying opening angles in randomly generated aortic root geometries. We used a data driven approach by running 3,500 two dimensional simulations (CFD). The simulation data serves as training data in a supervised deep learning framework based on convolutional neural networks analogous to the U-net architecture. We were able to successfully train the neural network using the supervised data driven approach. The results showing that it is feasible to use a neural network to estimate physiological flow fields in the vicinity of prosthetic heart valves (Validation error below 0.06), by only giving geometry data (Image) into the Network. The neural network generates flow field prediction in real time, which is more than 2500 times faster compared to CFD simulation. Accordingly, there is tremendous potential in the use of AIbased approaches predicting blood flows through heart valves on the basis of geometry data, especially in applications where fast fluid mechanic predictions are desired.

Patients undergoing transcatheter aortic valve replacement (TAVR) may suffer severe clinical complications, caused by paravalvular leakage (PVL) which is defined as leakage between TAVR and aortic annulus. PVL is often facilitated by a severely calcified annulus. This limits the expansion of a self-expandable TAVR stent. To assess TAVR performance in terms of leakage, measurement of regurgitation fraction in a pathophysiological annulus is recommended according to ISO 5840. For this purpose, a configuration of a circular annulus with a calcification nodule has been proposed in the recently published ISO 5840. The impact of the proposed pathophysiological annulus model on the expansion of self-expandable TAVR stents and on the regurgitation fraction was investigated in this study. For this purpose, two commercially available selfexpandable TAVRs (Evolut R and Portico) were implanted in a calcified annulus model. Circular expansion of the TAVR stents was investigated based on μCT scans of the implanted TAVR. The calcification-induced area in which retrograde flow can occur during diastole was detected. These results were then compared with the experimentally determined regurgitation fraction obtained from pulse duplicator tests. The results of the μCT scans showed a continuous leakage area in the region of the annulus for the Evolut R compared to a locally larger leakage area of the Portico, which, however, reattaches to the annulus in the distal inflow region. The hydrodynamic measurements confirmed a smaller leakage in the pathological annulus for the Portico. In summary, it can be assumed that a continuous leakage area in the TAVR stent inflow region encourages the PVL of TAVR.

To assess the hydrodynamic performance of transcatheter aortic valve prostheses (TAVP), in vitro test using pulse duplicators is required. Test conditions as well as minimum performance criteria are specified in ISO 5840- 3:2013 and ISO 5840-3:2019-draft. In the 2019 published draft, modifications regarding hydrodynamic testing are proposed. Among others, the geometrical configuration of the fixation has changed, with the intention to improve the anatomical representation as well as the comparability of results from different test laboratories. We analyzed the consequences of altered annulus fixations regarding native leaflets as well as a step in the proximal area of the protheses to prevent their migration. The analyses were conducted with regard to the degree of calcification of the annulus ring on hydrodynamic parameters. By using 3D stereolithography printing technology, molds for casting of silicone elastomer of annulus models with and without native leaflets were manufactured. A modular system enabled us to use the same annulus ring to model the degree of calcification as well as different step sizes. We performed in vitro hydrodynamic testing according to ISO 5840-3:2019-draft of a selfexpandable valve prototype with porcine pericardial leaflets by using a commercially available pulse duplicator system. As expected, regurgitation increases with increasing degree of calcification, whereby the use of a step has no influence on the backflow of fluid during diastole. The effective orifice area (EOA) of the valve showed a clear tendency with respect to radial protrusion of the step. The EOA decreased as the radial protrusion increased. We also present a suggestion to prevent migration without affecting the general test results, by using a novel step design. We also found that the novel annulus model with native leaflet drastically reduced the regurgitation.

Nanofiber nonwoven membranes produced by electrospinning provide the possibility to adjust mechanical material parameters as well as simultaneously the biologically relevant properties - a fundamental aspect in developing new implants and medical devices. Wettability and permeability are also of great importance, as they have a decisive influence on the release of drugs, cell attachment, degradability and finally the nutrient supply of the surrounding tissue. Within this work the wettability and permeability of several electrospun poly-L-lactide nonwovens, including different additives, were investigated and a correlation to membrane morphology was found. A potential modification of the permeability by the fluid viscosity was also investigated. The results form a fundamental building block in the development of permeable biodegradable implants and medical devices.

Due to the raising number of TAVR implantations (transcatheter aortic valve replacement), tests for durability and prevention of associated diseases are becoming increasingly important. Not only the anatomy but also the positioning of the TAVR is decisive for its clinical performance. A misalignment in the circumferential direction can influence the flow in the sinus and thus inhibit the blood supply of the coronary arteries and influence the thrombosis potential. Therefore, the modification of the flow field is investigated in this study. For the characterization of the flow fields the measuring method of digital particle image velocimetry is used. A hydraulic circulation model is used to generate physiological flow and pressure conditions. Additionally, an aortic root model with Sinus Valsalvae, which represents the implantation environment, was developed. A prototype of a TAVR was implanted aligned to the commissure lines of the native valve leaflets on the one hand, and misaligned by 60 degree to the commissure of the native valves on the other hand. By determining the velocity vector fields, it could be shown that implantation of the TAVR with a commissureal misalignment influences the flow around the leaflets. A comparison of the flow fields shows that different recirculation areas occur. This is also indicated by a comparison of the mean velocities in the sinus and the observed shear rates. The influence of the altered flow field on the thrombosis and hemolysis potential should be investigated in future studies.

Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

The formation of a thrombus is associated with dramatic consequences for the patient, such as increased risks of neurologic events and myocardial infarction or even death. A pathologically altered blood flow is associated with these complications. Consequently, a consistent fluid-mechanical analysis of implants, such as coronary stents, must be carried out. Computational fluid dynamics (CFD) is an important in silico tool for the analysis of different stent designs. Using three different generic stent designs (closed-cell, open-cell and helical), CFD could be performed with the OpenFOAM software package. The stents were implemented in a vascular model having a fully developed Hagen-Poiseuille velocity profile (umean = 0.6 m/s) as inlet condition. In combination with the dynamic viscosity of the Newtonian test fluid of 6.04·10-5m2/s, Reynolds numbers up to 460 were achieved. Spatially high-resolved velocity fields from measurements in the magnetic resonance tomograph (magnetic resonance velocimetry, MRV) were available for validation. The velocity field was compared in selected cross sections and longitudinal sections. The difference of the main flow proximal and distal to the stent models were below 6 %. In addition, a similar flow topology could be quantified using the Q-criterion. Due to the very good agreement of the numerical results with the MRV-measurements, the numerical method has been applied to further analysis of stent designs regarding to time average wall shear stress (TAWSS) distribution on the luminal vessel surface (surface area with TAWSS < 0.4 Pa was related to overall vessel surface) under pulsatile conditions. Although all stent designs have the same square cross-section, a large influence of the stent design on WSS distribution could be observed (closedcell vs. helical = -50.2 %; open-cell vs. helical = -38.5 %). By using validated CFD it was possible to quantify the hemodynamic benefit of helical stent design in terms of thrombosis potential.

Background The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. Materials and methods We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. Results Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. Conclusion A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice., Highlights • Treatment options for metastatic clear cell renal cell carcinoma have become diverse. • We performed a decision-making analysis among 11 international kidney cancer experts. • Significant inter-expert variations for systemic first line treatments were observed. • Influencing factors were performance status, IMDC risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. • The treatments selected were: sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib.

BackgroundEndothelial healing after deployment of cardiovascular devices is particularly important in the context of clinical outcome. It is therefore of great interest to develop tools for a precise prediction of endothelial growth after injury in the process of implant deployment. For experimental investigation of re-endothelialization in vitro cell migration assays are routinely used. However, automatic analyses of live cell images are often based on gray value distributions and are as such limited by image quality and user dependence. The rise of deep learning algorithms offers promising opportunities for application in medical image analysis. Here, we present an intelligent cell detection (iCD) approach for comprehensive assay analysis to obtain essential characteristics on cell and population scale.ResultsIn an in vitro wound healing assay, we compared conventional analysis methods with our iCD approach. Therefore we determined cell density and cell velocity on cell scale and the movement of the cell layer as well as the gap closure between two cell monolayers on population scale. Our data demonstrate that cell density analysis based on deep learning algorithms is superior to an adaptive threshold method regarding robustness against image distortion. In addition, results on cell scale obtained with iCD are in agreement with manually velocity detection, while conventional methods, such as Cell Image Velocimetry (CIV), underestimate cell velocity by a factor of 0.5. Further, we found that iCD analysis of the monolayer movement gave results just as well as manual freehand detection, while conventional methods again shows more frayed leading edge detection compared to manual detection. Analysis of monolayer edge protrusion by ICD also produced results, which are close to manual estimation with an relative error of 13.2 %. In comparison, the conventional Canny method gave a relative error of 61 %. ConclusionThe results of our experiments indicate that deep learning algorithms such as our iCD have the ability to outperform conventional methods in the field of wound healing analysis. The combined analysis on cell and population scale using iCD is very well suited for timesaving and high quality wound healing analysis enabling the research community to gain detailed understanding of endothelial movement.

Background The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic. Methods We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19. Findings For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%). In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both. Conclusion mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy. CA extern

Background Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. Methods The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. Discussion Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. Conclusions The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. Trial registration ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

Objectives Cisplatin-related hearing loss (HL) is claimed to progress after treatment. This controlled longitudinal study with extended follow-up investigates HL in testicular cancer survivors (TCSs) after cisplatin-based chemotherapy (CBCT). Study design Controlled longitudinal study. Methods Eighty-two TCSs treated with CBCT between 1980 and 1994 in Norway participated in two surveys (S1/S3), including pure-tone audiograms (0.125-8 kHz) and self-reported HL, 12 and 31 years after treatment, respectively. Hearing thresholds were age-adjusted based on age-matched hearing thresholds from the general population (controls). Hearing loss was defined as thresholds >20 dB at any frequency. Results Between the two surveys, the prevalence of high-frequency HL (4, 6, and 8 kHz) increased from 73% to 94% but approached those of the aging general population after age adjustment. In TCSs aged >40 years at first survey, HL at the subsequent survey equaled that of controls. Self-reported HL increased from seven (9%) at S1 to 20 (26%) at S3. At S1, age-adjusted HL was identified in all (seven) TCSs reporting decreased hearing whereas at S3, hearing thresholds did not differ from controls in seven out of 20 patients reporting HL. Conclusion CBCT-related ototoxicity causes high-frequency HL, but in contrast to reports from follow-up studies from the first post-treatment decade, no major progression was found beyond the first post-treatment decade for frequencies 0.125-8 kHz. Importantly, with extended follow-up, hearing thresholds of patients approach those of the general population, possibly due to a less-than-additive effect with age-related hearing loss (ARHL) in CBCT-treated patients. Age-and sex-matching is strongly advised in long-term follow-up of CBCT-related ototoxicity. Specificity for detecting ototoxicity with self-reported questionnaires decreases with extended follow-up. Level of evidence 3 Laryngoscope, 130:E515-E523, 2020.

The authors regret that a co-author was mistakenly missed from the authorship. The following co-author should have been included in the authorship: Peter-Paul M. Willemse Department of Oncological Urology, University Medical Center, Utrecht Cancer Center, Utrecht, The Netherlands

The long-term toxicities after cisplatin-based chemotherapy (CBCT) reveal a remarkable inter-individual variation among testicular cancer survivors (TCSs). Therefore, we assessed long-term platinum (Pt) changes and their associations with CBCT-related late effects in TCSs.In 77 TCSs treated with CBCT from 1984 to 1990, blood samples for analyses of Pt and a questionnaire including self-reported neuro- and ototoxicity (NTX) symptoms were collected during two follow-up surveys at median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. Information about second cancers after SII was retrieved from the Norwegian Cancer Registry.A larger Pt decline from SI to SII was associated with a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62-0.99 per 10 ng/L/year), and worsening of paresthesias in hands (OR 1.98, 95% CI 1.09-3.59 per 10 ng/L/year) and tinnitus (OR 1.51, 95% CI 1.01-2.27 per 10 ng/L/year).In summary, we found a significant association between a larger Pt decline and a reduced risk of second cancers and deterioration of paresthesias in hands and tinnitus.

Background: Tyrosine kinase inhibitors (TKIs) constitute the backbone of treatment of metastatic (m) RCC. TKIs show great inter-individual variability of both efficacy and toxicity. The aim of this study was to compare the tyrosine kinase activity in normal and malignant kidney tissue and explore TKI effect on tumor tissue ex vivo. Materials and methods: Human nephrectomy samples (n = 295) consecutively collected at Akershus University Hospital from 2013 to 2019 were available. For this study, 22 samples of patients with mRCC (twenty-one clear cell and one chromophobe histology) and 3 with non-metastatic disease (two clear cell and one papillary histology) were selected. Tumor and normal tissue from each patient were prepared and assessed by an experienced pathologist, and 5µg of protein lysates was extracted. Kinase activity profiling of 144 tyrosine kinase peptides was performed using PamChip Arrays for PAMSTATION12. Protein lysates from tumors were in addition treated with four different TKIs ex vivo, based on IC50; sunitinib (2.5 µM), cabozantinib (2.5 µM), pazopanib (10 µM) and tivozanib (2 µM). All data was processed and analyzed in Bionavigator V.6 (PamGene). Results: The overall tyrosine kinase activity was increased in tumor tissue compared to normal tissue in all samples. The activity of 36 tyrosine kinases differed significantly (FDR < 0.05), with 20 kinases showing higher and 16 showing lower phosphorylation in tumor compared to normal tissue. Furthermore, adding TKIs to tumor samples ex vivo revealed different potencies of the TKIs. Tivozanib and cabozantinib showed higher inhibition potency compared to sunitinib and pazopanib. Two well-defined peptide clusters were especially affected by tivozanib and cabozantinib exposure. Compared to untreated tumor tissue, the activity of 29 kinases including common TKI targets MET, EGFR, PDGFR and FGFR was significantly reduced in cluster 1. However, we also identified reduced activity of several other kinases i.e. RB, CDK2, CLB, CAM, ZAP70 and PDK1 involved in RAS, RAP1, PI3K-AKT and prostate cancer signaling pathways. In cluster 2, 21 kinases showed increased activity upon TKI exposure, amongst them JNK, ERK, erbB1/erbB2, Shp2 and PLCγ involved in MAPK, ERBB and proteoglycans signaling pathways, and possibly accounting for subsequent TKI resistance. Conclusion: Kinase activity differs significantly between malignant and normal kidney tissue. Furthermore, we have demonstrated different inhibitory effects of TKIs ex-vivo and identified two peptide clusters significantly affected by TKI. Further analysis of affected kinases and signaling pathways as well as correlations with clinical data for the same group of patients will be performed. To our knowledge, similar systematic comprehensive analysis of tyrosine kinase activity and correlation to clinical data has not been reported previously. Citation Format: Katarina Puco, Andliena Tahiri, Faris Naji, Daniel Heinrich, Vessela N. Kristenssen, Glenny C. Alfsen, Lorant Farkas, Frode S. Nilsen, Stig Müller, Jan Oldenburg, Jürgen Geisler. Tyrosine kinome profiling of renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2292.

Background Treatment options in patients with advanced urothelial carcinoma (aUC) have improved significantly in the last decade, highlighting the need for adequate biomarkers. High tumor CGB5 mRNA, encoding Human Chorionic Gonadotrophin β (hCGβ) and elevated serum free hCGβ are related to poorly differentiated UC and correlated to poor prognosis. Hypothetically, hCG could be used as serum tumor marker in aUC patients. Patients and methods From December 2018 to November 2020, serum hCG levels were measured in 62 aUC patients referred to the oncology department, Akershus University Hospital. Median age 68 years, 42 male and 21 female. Total serum hCG (intact hCG + free hCGβ) was measured by electrochemiluminescence immunoassay “ECLIA”. In order to compensate for hypogonadism-related increases, hCG ≥ 50% above upper normal limit was considered as being elevated (hCG+), otherwise it was considered negative (hCG-). Further, hCG levels were defined as increasing (↑) or declining (↓) at treatment evaluation and follow up. Radiologically, patients had newly diagnosed disease (ND), progressive disease (PD) or non-PD (stable disease, partial or complete response) according to RECIST 1.1 at evaluation and follow up. hCG values were correlated with radiological findings at diagnosis, during and after treatment. Statistics by 2 x 2 contingency table and Chi Square (χ2) test. Results At least one hCG+ value was measured in 38 of 62 patients (61%), range 0.8 - 62,700 IU/L, and hCG was elevated in 22 of 43 patients (51%) with available hCG value at diagnosis, mean 15 IU/L (range 0.8 - 58). In total 213 hCG measurements could be correlated with concomitant CT or MR scans. At radiologic evaluation of ND & PD, hCG+/↑ and hCG -/↓ was found in 62 and 50 measurements, respectively. At non-PD, hCG -/↓ and hCG+/↑ was found in 94 and 7 measurements, respectively. For ND & PD versus non-PD, hCG showed a sensitivity and specificity of 55% and 93% respectively (95% CI 46-65% and 86-97%), positive and negative predictive value of 90% and 65% (95% CI 81-95% and 60-70%) and accuracy of 73% (95% CI 66-79%), χ2: p Conclusions Ectopic hCG production was observed in 61% of aUC patients with a strong and meaningful correlation between hCG changes and radiologic evaluation of treatment response. Intriguingly, hCG increase sometimes preceded radiologic PD, thus categorized as “false positive” until subsequent radiologic PD. hCG appears to be a promising tumor marker for biochemical treatment response evaluation in aUC patients. Citation Format: Katarina Puco, Johan Bjerner, Stig Müller, Gunder M. Lilleaasen, Haldor Husby, Mattias Røed-Undlien, Daniel Heinrich, Fredrik A. Dahl, Oluf D. Røe, Jan Oldenburg. Utility of hCG as a biomarker of treatment response in advanced urothelial cancer: A population based series at Akershus University Hospital, Norway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 481.

Venous ulcers of the lower limbs are one clinical manifestation of chronic venous insufficiency. Currently, there is no venous valve prosthesis available. This study presents novel venous valve prostheses made of threedimensional electrospun fibrous nonwoven leaflets. The aim of this study was to prove the feasibility of the manufacturing process as well as to investigate design features of the venous valve prostheses from a hemodynamic point of view. An adapted pulse duplicator system (ViVitrolabs, Victoria, BC, CA) was used for characterization of the hydrodynamic performance. For eight different venous valve prototypes flow rate, effective orifice area and regurgitation fraction was investigated in vitro. In particular, tricusp valve designs showed an up to 40% higher effective orifice area as well as 15% higher maximum flowrate compared to bicusp valve designs. However, the regurgitation fraction of the bicusp valve designs is up to 86% lower compared to tricusp valve. Additionally, the hemodynamic performance of the tricuspid valves showed a high sensitivity regarding the leaflet length. Bicuspid valves are less sensitive to changes of design parameters, more sufficient and therefore highly reliable.

BackgroundAlthough guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.ObjectiveTo bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DesignA steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SettingOnline Delphi survey and consensus conference.ParticipantsThe European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysisStatements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).Results and limitationsOverall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.ConclusionsThese consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.Patient summaryThis report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

Objective In this study, we evaluated the toxicity and clinical efficacy of nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, on patients with platinum resistant ovarian cancer. Methods Every second week, 18 patients with platinum resistance ovarian cancer received nivolumab until disease progression occurred. We assessed toxicity, disease control rate, progression free survival (PFS) and overall survival (OS). Radiological response evaluation according to irRECIST was performed every 12th week, while clinical evaluation was done every second week. Results The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123). The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab. Conclusion This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is similar to 99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Context: This is an update of the previous European Association of Urology testis cancer guidelines published in 2011, which included major changes in the diagnosis and treatment of germ cell tumours. Objective: To summarise latest developments in the treatment of this rare disease. Recommendations have been agreed within a multidisciplinary working group consisting of urologists, medical oncologists, and radiation oncologists. Evidence acquisition: A semi-structured literature search up to February 2015 was performed to update the recommendations. In addition, this document was subjected to double-blind peer review before publication. Evidence synthesis: This publication focuses on the most important changes in treatment recommendations for clinical stage I disease and the updated recommendations for follow-up. Conclusions: Most changes in the recommendations will lead to an overall reduction in treatment burden for patients with germ cell tumours. In advanced stages, treatment intensification is clearly defined to further improve overall survival rates. Patient summary: This is an update of a previously published version of the European Association of Urology guidelines for testis cancer, and includes new recommendations for clinical stage I disease and revision of the follow-up recommendations. Patients should be fully informed of all the treatment options available to them. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Christian Beisland,1,2 Tom B Johannesen,3 Olbjorn Klepp,4 Ulrika Axcrona,5 Knut Martin Torgersen,6 Jan Kowalski,7 Oddvar Solli,6 Rickard Sandin,8 Jan Oldenburg9,10 1Department of Urology, Haukeland University Hospital, 2Department of Clinical Medicine, University of Bergen, Bergen, 3Department of Registration, Cancer Registry of Norway, Oslo, 4Department of Oncology, Ålesund Hospital, Ålesund, 5Department of Pathology, Oslo University Hospital, the Norwegian Radium Hospital, Oslo, 6Pfizer AS, Oslo, Norway; 7JK Biostatistics AB, Stockholm, 8Pfizer AB, Sollentuna, Sweden; 9Department of Oncology, Akershus University Hospital, Lørenskog, 10Medical Faculty, University of Oslo, Oslo, Norway Background: This population-wide retrospective, non-interventional registry study assessed changes in overall survival (OS) and factors influencing OS in Norwegian patients with renal cell carcinoma (RCC). Methods: Two population-wide health registries were used to identify all RCC patients with (mRCC) or without metastases diagnosed before (2002–2005) and after (2006–2008 and 2009–2011) introduction of targeted therapies. Median OS was estimated using Kaplan–Meier method. Cox proportional hazards regression modeling was used to identify prognostic factors. Results: Overall, 5,463 patients were diagnosed with RCC during 2002–2005 (n=1,898), 2006–2008 (n=1,631), and 2009–2011 (n=1,934); of these, 1,678 (31%) had mRCC. Patients diagnosed in 2009–2011 and 2006–2008 had significant (P

Do genetic variations in the testosterone pathway genes modify the effect of treatment on the levels of testosterone and LH in long-term testicular cancer (TC) survivors (TCSs)?Variations in LH receptor (LHR) and in 5α-reductase II (SRD5A2) genes may modify the effect of TC treatment on testosterone levels, whereas genetic variations in the androgen receptor (AR) may modify the effect on LH levels.TCSs experience variable degrees of long-term reduction in gonadal function after treatment. This variability can in part be explained by treatment intensity, but may also be due to individual variations in genes involved in the function and metabolism of reproductive hormones.Cross-sectional study on testosterone and LH levels in 637 Norwegian TCSs in relation to genetic variants and TC treatment.The single nucleotide polymorphisms LHR Asn291Ser (rs12470652) and Ser312Asn (rs2293275), as well as SRD5A2 Ala49Thr (rs9282858) and Val89Leu (rs523349) were analyzed by allele-specific PCR. The insertion polymorphism LHR InsLQ (rs4539842) was analyzed by sequencing. The numbers of AR CAG and GGN repeats were determined by capillary electrophoresis. Blood samples were collected 5-21 years after diagnosis (median 11 years) and serum total testosterone and LH were analyzed by commercial immunoassays. The TCSs were divided into four groups according to their treatment; surgery only, radiotherapy and chemotherapy with ≤850 or850 mg of cisplatin. Polymorphisms presenting P0.1 for the interaction term with treatment in an initial two-way analysis of covariance (ANCOVA) were investigated further in two consecutive one-way ANCOVA analyses to elucidate the interaction between treatment and genotype.For the whole group of TCSs, there were no significant differences between the hormone levels in homozygotes for the wild type and carriers of at least one polymorphic allele for the investigated polymorphisms. Three of the polymorphisms showed signs of interaction with treatment, i.e. LHR InsLQ, SRD5A2 A49T and the AR CAG repeat. Follow-up analyses revealed three situations where only one of the genotypes of the polymorphism where associated with significantly different hormone levels after surgery compared with after additional cytotoxic treatment: For LHR InsLQ, only the wild-type allele was associated with lower testosterone levels after cisplatin850 mg compared with after surgery (24% lower, P0.001). For SRD5A2 A49T, testosterone levels were lower after radiotherapy compared with after surgery, but only for the heterozygotes for the polymorphism (39% lower, P = 0.001). In comparison, the testosterone levels were just slightly lower after radiotherapy (6% lower, P = 0.039) or cisplatin ≤ 850 mg (7% lower, P = 0.041), compared with surgery, independent of genotypes. For AR CAG, only the reference length of CAG = 21-22 had significantly higher LH levels after cisplatin ≤ 850 mg compared with after surgery (70% higher, P0.001). Independent of genotypes, however, LH levels after cisplatin ≤ 850 mg were only 26% higher than after surgery (P = 0.005).Unadjusted P-values are presented. For analysis involving genotypes, the level of statistical significance was adjusted for the total number of polymorphisms tested, n = 7, i.e. to P0.007 (0.5/7). The rather weak associations indicate that additional polymorphisms are involved in the modulation.To our knowledge, this is the first study supporting the notion that polymorphisms may explain at least some of the inter-individual differences in endocrine response to TC treatment. Our findings suggest that individuals with certain genotypes may be more vulnerable to certain treatments. Knowledge on genetic predisposition concerning treatment-related endocrine gonadotoxicity to different treatment regimens may help tailoring TC therapy when possible.This study was supported by the Research Council of Norway (Grant No. 160619). There were no competing interests.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, similar to 50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

In the article that accompanies this editorial, Frisina et al report on ototoxicity after cisplatin-based chemotherapy in the Platinum Study. This study comprehensively assesses hearing impairment, both as audiometric and as patient-reported outcome, as well as tinnitus in 488 cisplatin-treated testicular cancer (TC) survivors. One out of five survivors was found to have such severe hearing loss that a hearing aid was recommended. However, only 1.2% of the participants reported actually using such a device. Cisplatin-based chemotherapy was introduced in the late 1970s by Larry Einhorn and cures most patients with metastatic TC. However, long-term complications and late effects after cancer treatment are increasingly recognized as a major contributor to morbidity of survivors, influencing quality of life (QoL) and representing a burden for the growing community of cancer survivors. Similar to the unique position of TC as a model for a curable neoplasm, TC survivors represent a prime cohort for long-term survivorship studies because of their good life expectancy as a result of high cure rates and young age at diagnosis. Although the report by Frisina et al is a valuable contribution to the literature, it would have benefitted from inclusion of additional information, such as pretreatment assessments, the impact of ototoxicity on health-related QoL, details about and adjustment for other ototoxic agents (eg, aminoglycosides), and occupational hearing loss after completion of cisplatin-based chemotherapy. The cohort represents TC survivors receiving standard cisplatin-based chemotherapy for metastatic disease for which we do have some long-term ototoxicity outcomes, whereas high-quality data on ototoxicity after adjuvant chemotherapy with either one or two cycles of bleomycin, etoposide, and cisplatin (BEP) or carboplatin as well as after high-dose chemotherapy are still lacking. In general, long observation periods—a prerequisite for survivorship research—make translation of the impact of former to contemporary treatment challenging. Testicular cancer is an exception. For the last four decades, no alternative regimen was superior to BEP. In accordance with current guidelines, roughly nine out of 10 participants received three or four cycles of BEP or four cycles of etoposide and cisplatin (EP). Normative data from healthy individuals comprising median quartile threshold values for different age groups were applied to categorize decibel thresholds of individual TC survivors in an ordinal fashion up to 8 kHz as adjustment for physiologic age-related hearing decline—an approach similar to the percentiles of pediatric growth curves. Retesting this survivor cohort in some years would yield longitudinal data allowing testing of whether this group is vulnerable to subsequent age-related declines. A hypothesized reduced functional reserve leading to accelerated hormonal ageing could recently be demonstrated in TC survivors with a similar percentile categorization. Except for patients with TC who depend strongly on unimpaired hearing capability (eg, musicians, composers, or ornithologists), the risk of high-frequency hearing impairment should generally play no role in treatment planning of advanced testicular cancer in view of the high curative potential of platinum-based chemotherapy in this setting. In this study, hearing loss according the American SpeechLanguage-Hearing Association criteria was found in 80% of TC survivors, including 18% with a severe (71 to 90 dB) or profound (. 90 dB) hearing loss. On the other hand, one cycle of cisplatin increased the hearing threshold only by 2.5 dB. Thus, cisplatinbased chemotherapy for metastases should not cause more than 10 dB of hearing loss. Age-related hearing decline probably represented much of the observed hearing loss as defined by the American Speech-Language-Hearing Association, which might not be optimal for cross-sectional studies without preceding measurements. Calculation of hearing decline over various frequencies is complex: “For each patient i, the geometric mean Yi was calculated using standard methods by taking the arithmetic mean of the natural log-transformed hearing threshold, di, from n frequencies and then using exponentiation to return the computation to the original decibel scale (ie, log-average).” Understanding this end point, which scores high on specificity and poor on patient relevance (Fig 1), is difficult formost readers who are not familiar with this field. High specificity is needed for disentangling the impact of a single component on a given end point. Chemotherapy-related development of cardiovascular disease (CVD), for example, is complex to assess both due to interaction of different chemotherapy components and further dilution of the cause-effect relationship by multiple genetic and environmental risk factors. Chemotherapyinduced ototoxicity, on the other hand, is almost exclusively linked to cisplatin. Hypertension and hearing loss might be associated independent of cisplatin treatment. However, both symptoms might represent different cisplatin-related long-term toxicities despite adjustment for the cumulative cisplatin dose. Residual serum platinum increases the risk of paresthesia and Raynaud phenomenon more strongly than the applied cumulative cisplatin dose. Residual platinum, however, was not associated with tinnitus or hearing impairment assessed by the Scale for

Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10-30 % of patients develop resistance to cisplatin, requiring salvage therapy. We investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines.In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array.Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT.Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.

Purpose Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. Patients and Methods In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. Results At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Conclusion Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Background 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. Patients and methods FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. Results One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032). Conclusions Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

Background Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received. Methods A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980 – 1994 were invited to participate in a national multicenter follow-up survey conducted during 1998 – 2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with 2 or Kruskal – Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided. Results The median follow-up for the 1409 assessable men was 10.7 years (range = 4 – 21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapytreated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04). Conclusion Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy. J Natl Cancer Inst 2009;101:1682–1695

In this contribution, a novel approach for the modeling and numerical optimal control of hybrid (discrete–continuous dynamic) systems based on a disjunctive problem formulation is proposed. It is shown that a disjunctive model representation, which constitutes an alternative to mixed-integer model formulations, provides a very flexible, intuitive and effective way to formulate hybrid (discrete–continuous dynamic) optimization problems. The structure and properties of the disjunctive process models can be exploited for an efficient and robust numerical solution by applying generalized disjunctive programming techniques. The proposed modeling and optimization approach will be illustrated by means of optimal control of hybrid systems embedding linear discrete–continuous dynamic models.

This paper presents a modeling and numerical solution method for an integrated grade transition and production scheduling problem for a continuous polymerization reactor. The optimal sequence of production stages and the transitions between them is supposed to be determined for producing a given number of polymer grades at certain amounts and quality specifications in the most economical way. The production schedule has to satisfy due dates for specific orders. This operational problem is cast into a mixed-integer dynamic optimization problem. Disjunctions and logical constraints are combined with a validated differential–algebraic model describing the polymer process during the production of a specific grade as well as along a transition between two different grades. The modeling and solution approach proposed by Oldenburg et al. [Oldenburg, J., Marquardt, W., Heinz D., & Leineweber, D. B. (2003)] is tailored to this problem class to provide an efficient solution technique. An industrial example process serves as an example to illustrate the modeling and solution techniques suggested.

BACKGROUND: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected. RESULTS: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection

Industrial processes are usually operated in a highly dynamic environment, e.g. with time-varying market prizes, customer demand, technological development or up- and downstream processes. Due to these disturbances, the operational strategies comprising objectives and constraints are regularly adjusted to reflect a change in the environment in order to achieve or maintain optimal process performance. The related operational objectives need not only be of an economical nature, but can also include flexibility, risk or ecological objectives. In this paper, a novel methodology is presented for the modeling and dynamic predictive scheduling of operational strategies for continuous processes. Optimal control actions are computed on a moving horizon employing discrete-continuous modeling and mixed-logic dynamic optimization as introduced by Oldenburg et al. (2003). The approach is successfully demonstrated considering the operation of a wastewater treatment plant.