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We combine long-term hydro-meteorological data from the small research catchment Wernersbach (WB, 4.6 km², dominated by Norway spruce) in operation since 1967 and from two eddy-covariance (EC) flux towers, all located in the Tharandt Forest, Germany. This combination forms an observatory, addressing actual evapotranspiration ET from a water budget perspective (catchment) and from an energy perspective (EC flux towers). However, obvious differences exist in time resolution. The spruce dominated tower DE-Tha is located a few kilometres east of the catchment. After a windbreak of another spruce stand (situated inside the catchment) and planting of deciduous oaks, the tower DE-Hzd was set up in 2009. We recently reported systematically about the observatory and the long-term water budgets in Pluntke & Bernhofer et al. (https://doi.org/10.1016/j.jhydrol.2022.128873).The catchment and both towers did not show any systematic differences in meteorological data (especially wind-loss corrected precipitation totals are almost identical), allowing us to address observed differences in ET as (i) due to different soil and hydrogeological characteristics as well as (ii) due to methodological aspects. The catchment term ET plus storage, derived from precipitation P minus runoff R, showed the expected high variability with a significant increase over the more than 50 years of operation. The older, spruce-dominated flux-tower DE-Tha showed much lower inter-annual variability in ET with an average annual total of 486 mm (1997 to 2019), but no significant trend. For the same period, average catchment ET was 734 mm/year. The younger flux-tower DE-Hzd showed ET values closer to catchment ET at the very dry end of the ten-year record (2010 to 2019).For the 23 years of parallel measurements, annual ET from EC was about 250 mm lower than catchment ET, despite the careful correction of tower ET for energy balance closure. Catchment ET = P – R might have a small bias towards larger ET, as the subsurface catchment size of WB could be up to 0.4 km² smaller. In addition, precipitation and runoff may contribute to higher catchment ET. However, the difference is too large to be explained by measurement bias alone. Flux tower ET is compared to (i) independent measurements of ET components, and (ii) model output of BR90. There is evidence from interception and transpiration measurements at the flux tower that more than 100 mm of intercepted water could be missing in the annual ET from EC. Model results show a large additional contribution of interception due to negative sensible fluxes in fall and winter. The difference in ET between tower and catchment of 250 mm is probably due to a variety of reasons: overestimation of catchment ET (up to 50 mm), soil characteristics (50-100 mm), and underestimation of tower ET (100-150 mm).We conclude that the EC closure correction during interception events needs to be revisited. Generally, results of ET monitoring of similar evergreen forests in a humid climate should be checked for missing contribution of interception, as EC records might be generally too low. This illustrates the necessity of redundant and complementary measurements when dealing with large system complexity.

Interception of a Norway spruce stand was analysed based on canopy water balance measurements Emass and for Eddy Covariance (EC) related measurements. The study site is located in the Tharandt Forest (Germany) and the analysis covers a long period from 2008 to 2018. Emass was calculated as residual between gross rainfall above and net rainfall below the canopy. EC related observations are based on the water equivalent either directly measured (uncorrected) by Eddy Covariance (ETEC) or as residual in the Energy Balance equation (ETEB). Additionally, evaporation of intercepted water was modelled with the Penman-Monteith equation, which was adapted for a gradually wetted canopy (ERutter) by the use of the Rutter model. The latter approach was used to integrate the time series of all methods over the duration of modelled interception events leading to different estimates of wet canopy evaporation.The canopy water balance from 2008 to 2018 shows a mean annual gross precipitation of 936±173mm and a mean annual interception evaporation of 376±56mm (Emass). The majority of rainfall events (81%) is characterized by a depth less than 5mm, which leads to a high fraction of annual precipitation being captured by the canopy surface (0.41). The application of the Rutter model yielded good results with a mean modelled annual interception ERutter of 361±47mm being very close to Emass. Thus, the model served as a good standard to define interception events. The water equivalent of wet canopy evaporation as the residual of the energy balance ETEB and from gas analyser measurements ETEC are both systematically underestimating Emass, to a higher extent for the winter than summer half-year. On a mean annual basis, ETEB and ETEC underestimate Emass by 145mm and 288mm, respectively. Comparing the totals over the majority of interception events, ETEB corresponds to only 72% and ETEC to only 33% of canopy water balance based measurements.One reason for this underestimation might be a scaling problem between the interception measurement site and the flux tower footprint, which could not be resolved by the application of a simple scaling factor. A more likely explanation is the underestimation of turbulent fluxes by the EC method. The data is most affected during raining conditions with the highest gap in winter. An annual analysis of the linear relation between the sum of turbulent fluxes and available energy shows the lowest slope (0.57±0.15) for measurements during rain, while the highest slopes occur under completely dry conditions (0.76±0.03). Wet canopy conditions without rainfall seem not to be as crucial for energy imbalance as rain, but affect the closure gap for the winter half-year.Records of EC measurements are generally too low and the magnitude of supplied sensible heat and sustained latent heat flux rates during interception events remains unclear. We conclude that gap filling and correction of both turbulent fluxes should be done separately for rain (interception) and dry (transpiration) conditions in order to determine proper amounts of evapotranspiration with the eddy-covariance method.

Context: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). Objective: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. Evidence acquisition: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. Evidence synthesis: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. Conclusions: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. Patient summary: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.

There exists a long-standing debate in higher education on which academic calendar is optimal. Using panel data on the near universe of four-year nonprofit institutions and leveraging quasi-experimental variation in calendars across institutions and years, we show that switching from quarters to semesters negatively impacts on-time graduation rates. Event study analyses show that the negative effects persist beyond the transition. Using transcript data, we replicate this analysis at the student level and investigate possible mechanisms. Shifting to a semester: (i) lowers first-year grades, (ii) decreases the probability of enrolling in a full course load, and (iii) delays the timing of major choice. (JEL I23, I28)

Purpose To report on the clinical characteristics, outcome, and frequency of peritoneal carcinosis (PC) in patients with advanced germ cell tumors (GCT), a multicenter registry analysis was carried out. Methods A multicenter registry analysis was conducted by the German Testicular Cancer Study Group (GTCSG) with international collaborators. Data was collected and analyzed retrospectively. Patients were eligible for inclusion if PC was diagnosed either by radiologic or histopathologic finding during the course of disease. Descriptive and explorative statistical analysis was carried out with cancer-specific survival (CSS) as primary study endpoint. Results Collaborators from ten GCT expert centers identified 28 GCT (0.77%) patients with PC after screening approximately 3767 GCT patient files and one case was contributed from a cancer registry request. Patients were diagnosed from 1997 to 2019 at a median age of 37 years (interquartile range, 13). Two patients (7%) presented with stage I and 27 patients (93%) with synchronous metastatic disease at first diagnosis. The primary histology was seminoma in seven (27%) and non-seminoma in 21 patients (72%). PC was detected after a median of 15.3 months from primary diagnosis (range 0–177) and two consecutive treatment lines (range 0–5), respectively. The median CSS from the time of detection of PC was 10.5 months (95%Confidence Interval 0.47–1.30) associated with an overall 2-year CSS rate of 30%. Conclusion PC represents a rare tumor manifestation in GCT patients and was primarily associated with the occurrence of advanced cisplatin-refractory disease conferring to a dismal prognosis.

To check the influence of substituents on the bonding of the 12π-perimeter of s-indacene, a tetraalkyl derivative, the title compound 1, was synthesized. 1, red needles, is weakly paratropic. Crystal structure analysis and NMR investigations indicate a delocalized or a localized π-electron system with only a small energy barrier between the π-bond isomers.

Archives of gynecology and obstetrics 307(3), 699-708 (2023). doi:10.1007/s00404-022-06857-x, Published by Springer, Heidelberg

Um den Substituenteneinfluß auf den Bindungszustand des 12π-Perimeters von s-Indacen zu prüfen, wurde ein Tetraalkylderivat, die Titelverbindung 1, synthetisiert. 1, rote Nadeln, ist schwach paratrop. Kristallstrukturanalyse und NMR-Untersuchungen weisen auf ein delokalisiertes oder ein lokalisiertes π-Elektronensystem mit nur kleiner Energiebarriere zwischen den π-Bindungsisomeren hin.

The human epidermal growth factor receptor 2 (HER2, ERBB2) is amplified or overexpressed in approximately 20% of breast cancers. HER2 amplification results in increased homodimerization and HER3 heterodimerization, with HER2/HER3 heterodimers promoting cell proliferation via the mitogen-activated protein kinase/AKT pathway and also evasion of apoptosis via the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Oncogenic mutations in PI3KCA render tumor cells resistant to drugs that block HER2 dimerization, thereby promoting cell survival. Although several approved HER2-directed agents have shown significant survival improvements for HER2-positive patients, in the metastatic setting, nearly all of these patients will ultimately progress and die of their disease.

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. ----- Methods and materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. ----- Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. ----- Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

Integrated healthcare models (IC) have the objective of reducing the costs of an increased use of health service as well as the strong sectoral fragmentation of the German health care system. However, no national approach has been implemented in primary care to date.Ten GPs from the Cologne/Bonn district (60% male; Ø age = 52 years [35-65]) were invited to a focus group in 2016. The interview was part of the Horizon 2020 funded POLYCARE study. A semi-structured guideline was used to assess feasibility of the POLYCARE study protocol. GPs also provided information about previous experience with and attitudes toward IC models and the relevant information and communication technologies (ICT), such as home-monitoring or communication software. This information was analyzed using a transcending secondary analysis to evaluate conditions for their successful implementation.Participants reported little experience with IC and ICT. However, they reported being open to both and seeing potential for time savings, better networking opportunities, and increased quality of care for their patients. The integration of social services was considered as a chance of alleviating the burden of socio-medical tasks. Barriers to the introduction of IC and ICT were seen in the initial time investment, the lack of legal structures, the concern about overabundant data, and the susceptibility to failure.The nationwide expansion of social services as well as ICT that is easy to use, less susceptible to failure, and compatible with existing structures show great potential for relieving GPs. Future research should address the concerns - such as financial and time expenses of introducing IC and ICT - of GPs by systematic investigation in long-term studies. The provision of an additional legal basis that is regulating the respective remuneration models as well as the rights and obligations of all parties, IC and ICT can play a greater role in future patient care.Hintergrund: Modelle der integrierten Versorgung (IV) sollen die Kosten einer gestiegenen Leistungsinanspruchnahme sowie starker sektoraler Fragmentierung des deutschen Gesundheitssystems reduzieren. Bislang konnte jedoch noch kein nationaler Ansatz implementiert werden.Zehn Hausärztinnen und Hausärzte aus dem Landkreis Köln/Bonn (60% männlich; Ø-Alter = 52 Jahre [35-65]) wurden 2016 im Rahmen der durch das EU-Programm Horizont 2020 geförderten Studie POLYCARE in einer Fokusgruppe mit semistrukturiertem Leitfaden zu deren Machbarkeit befragt. Die darin enthaltenen relevanten Aussagen zu Vorerfahrungen mit und Einstellungen zu IV-Modellen sowie dafür dienlicher IKT wurden einer transzendierenden Sekundäranalyse unterzogen, um Voraussetzungen für deren erfolgreiche Implementierung zu evaluieren.Ergebnisse: Die Teilnehmenden berichteten, kaum Erfahrung mit IV und IKT zu haben. Dennoch sind sie beidem gegenüber aufgeschlossen und sehen darin Potenzial für Zeitersparnisse, bessere Vernetzungsmöglichkeiten sowie eine erhöhte Versorgungsqualität ihrer Patientinnen und Patienten. Die Integration von Sozialdiensten wurde als Entlastungsmöglichkeit genannt. Barrieren für die Einführungen von IV und IKT wurden im anfänglichen Zeitaufwand, fehlenden rechtlichen Strukturen sowie in einer befürchteten Datenflut und Störanfälligkeit gesehen.Schlussfolgerung: Der flächendeckende Ausbau von Sozialdiensten sowie einfach bedienbare, wenig störanfällige und mit bestehenden Strukturen kompatible IKT weisen großes Potenzial zur Entlastung der Ärzteschaft auf. Zukünftige Forschung sollte Bedenken von Hausärztinnen und -ärzten zum bspw. finanziellen und zeitlichen Aufwand bei der Einführung von IV und IKT durch gezielte Untersuchungen im Rahmen von Langzeitstudien adressieren. Werden auf politischer Ebene die Rechtsgrundlagen geschaffen, welche entsprechende Vergütungsmodelle sowie Rechte und Pflichten aller Beteiligten regeln, kann der IV mitsamt IKT in Zukunft größere Bedeutung in der Patientenversorgung zukommen.Schlüsselwörter: besondere Versorgungsmodelle, Barrieren der Implementierung, Pflegedienste und Sozialdienste, Technologieakzeptanz in der Hausarztpraxis, WearablesEingereicht am 7.1.2022 - Revision akzeptiert am 7.2.2022.

Gastric cancer (GC) is the 3rd leading cause of cancer mortality worldwide, therefore providing novel diagnostic and treatment options is crucial for at risk groups. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is a proposed driver of GC with frequent amplification and somatic missense mutations yet the molecular mechanism how DCLK1 mediates tumorigenesis is poorly understood. We report how DCLK1 expression orchestrates complementary cancer cell intrinsic and extrinsic processes leading to a comprehensive pro-invasive and pro-metastatic reprogramming of cancer cells and tumor stroma in a DCLK1 kinase-dependent manner. Mechanistically, we identify the chemokine CXCL12 as a key promoter of the pro-tumorigenic properties downstream of DCLK1. Importantly, inhibition of the DCLK1 kinase domain reverses the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a promising, targetable master regulator of GC.TeaserDCLK1 is a druggable cancer driver of GC

Respiratory dysfunction is a common cause of morbidity and mortality in motor neuron disease (MND). However, classical volitional measures of respiratory function in these patients are impeded by, e.g., bulbar paralysis or progressive disability. Diaphragm ultrasound imaging might be a valuable tool for assessing respiratory impairment, albeit different ultrasound measures have not been systematically investigated in adult MND patients and, in particular, have not yet been comparatively applied in adult patients with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). We hypothesized that in contrast to ALS patients, adult SMA patients show a relative sparing of diaphragm function. We retrospectively analyzed diaphragm ultrasound imaging data of 40 patients with ALS and 23 patients with SMA in comparison to a multitude of established parameters of respiratory function. Indeed, ALS patients showed more severe diaphragm dysfunction than adult SMA patients, however, diaphragm dysfunction was also common in adult SMA patients. Notably, dynamic measures of diaphragm function rather than thickness measures were impaired in ALS compared to SMA. Thus, diaphragm ultrasound imaging might be a useful tool to evaluate respiratory dysfunction in adult MND patients. Future larger and prospective studies are needed to validate our initial findings.

Approximately 420 men are diagnosed with germ-cell cancer (GCC) in Switzerland each year. Recent international guidelines outline management issues, but many aspects remain controversial in an area of highly individualised treatments. Even more than in other tumour types, in GCC the challenge is to choose exactly the correct treatment for an individual patient. Overtreatment in patients likely to be cured must be avoided to reduce long-term toxicities. On the other hand, treatment intensification is required in patients presenting with adverse prognostic factors. Therefore, referral to expert centres or consultations with an expert for a second opinion is strongly recommended. In 2020, Swiss experts discussed their strategies in a consensus meeting during the virtual Swiss Oncology and Haematology Congress (SOHC) in order to harmonise their concepts and to suggest optimal strategies for the management of GCC patients in Switzerland. Votes on controversial issues were obtained and are presented in this review wherever applicable.

Background: Metastatic prostate cancer (PCa) is associated with considerable diminished overall survival (OS). Standard treatment for metastatic PCa has long been androgen deprivation therapy alone, with patients initially responding to this treatment and then progressing to a castration-resistant phase. Summary: The advent of novel therapeutic agents has changed this paradigm, with high-level evidence that upfront combination therapy with either docetaxel or new hormonal agents results in improved OS for patients with metastatic hormone-sensitive PCa. In the absence of a comprehensive clinical trial investigating the comparative efficacy and safety of all agents, clinicians are responsible for choosing the most appropriate therapy in close coordination with patients. Furthermore, the same therapeutic agents are also efficient in the castration-resistant phase, leading to the issue of the best therapeutic sequence. Finally, along with systemic therapy and molecular imaging advancements, radiotherapy was investigated in the oligometastatic setting, whether it is to treat the primary tumour or metastases. Key Messages: In this complex landscape, where providers have multiple effective therapeutic options to treat metastatic PCa patients, priority must be given to determine which treatment combination and sequence is best suited to a particular patient, given his comorbidities and preferences.

Zusammenfassung Ziel der Studie Die medizinische Versorgung der Bundesrepublik Deutschland ist von Verteilungsproblemen geprägt. Vor allem in ländlichen Regionen droht Unterversorgung. In dieser Studie wurde untersucht, wie ältere Bewohner des Landkreises Oberspreewald-Lausitz (OSL) des Bundeslandes Brandenburg ihre derzeitige medizinische Versorgungssituation einschätzen und welche Wünsche und Bedenken sie hinsichtlich deren zukünftigen Entwicklung im Jahr 2030 haben. Methodik In der vorliegenden Querschnitterhebung wurden 3006 Einwohner im Alter von 50–56 Jahren und von 65–71 Jahren des Landkreises OSL befragt. Ein Fragebogen mit geschlossenem und offenem Antwortformat wurde zur Erfassung der Zielstellung eingesetzt. Ergebnisse In der vorliegenden Untersuchung äußerten sich die Einwohner des Landkreises OSL aktuell zufrieden oder sehr zufrieden mit der hausärztlichen (93,1%) und der fachärztlichen Versorgung (83,3%). Innerhalb des Landkreises zeigen sich in einigen Regionen Defizite. Im Gebiet Lauchhammer/Schwarzheide äußerten sich insbesondere zur fachärztlichen Versorgung 27,1% der Befragten unzufrieden oder sehr unzufrieden. Alternative und ergänzende Versorgungsangebote wie die Community Nurse sind akzeptierte, jedoch derzeit unterrepräsentierte Maßnahmen zur Sicherstellung der zukünftigen medizinischen Versorgung. Schlussfolgerung Derzeit zeigen sich Bewohner des ländlichen, metropolenfernen Landkreises OSL zufrieden mit der ambulanten medizinischen Versorgung, jedoch stellen sich in einigen Regionen Defizite, insbesondere bei der zukünftigen Facharztversorgung dar. Alternative Versorgungsangebote wie Telemedizin sind seitens der Bewohner gewünschte Maßnahmen zur Ergänzung und Sicherstellung der zukünftigen medizinischen Versorgung im ländlichen Raum.

Die radikale Zystektomie ist Goldstandard in der Behandlung des muskelinvasiven Harnblasen-karzinoms, jedoch erleiden 50 % der Patienten ein Rezidiv. Eine neoadjuvante Cisplatin-basierte Chemotherapie verbessert das Uberleben signifikant, bleibt jedoch weiterhin vielen Patienten vorenthalten. Die Evidenz fur die haufiger eingesetzte adjuvante Chemotherapie ist schwacher, aber auch hier scheint ein Uberlebensvorteil gegeben. Fur Cisplatin-ungeeignete Patienten gab es bislang keine Empfehlung zur perioperativen Systemtherapie. Neue Substanzen, inbesondere Checkpointinhibitoren, eroffnen zukunftig auch in dieser Situation perioperative Therapie-optionen.

We examine the effect of relative evaluation on test performance by implementing a classroom-level experiment in which students are financially incentivized either individually or in a tournament. Linking the experimental data with student-level administrative data allows us to study two aspects of competitive environments: tournament structure and one’s perceived position in the ability distribution. At least in our setting, we find only limited evidence that effort responses to competition are sensitive to tournament size or prize structure. However, in contrast to previous studies that examine effort responses to exogenously assigned competition, we find a large negative competition effect for students who believe they are relatively low in the ability distribution, and no competition effect for those who believe they are relatively high ability. Using additional treatments, we further show that the divergence between our results and past results is likely driven by task type and not by differences in selection into participation between lab and classroom environments.

Evapotranspiration changes with landuse, soil conditions and meteorological conditions. Landscapes in middle Europe are typically of mosaic pattern at micro to local scale with different landuses adjacent to one another and we therefore have areas of different ET. This work shall address how ET changes with landuse based on 10 years of Eddy-Covariance data for different landuses. In a first step, it will be focussed on two landuses (coniferous forest and grassland). ET obtained via measurements will be compared to ET obtained via modelling by a using a one dimensional soil-vegetation transfer scheme and a machine learning approach using gradient boosting. Results will be analysed whether typical characteristic properties of the respective landscape are preserved (e.g. Bowen ratio) as well as differences between land uses (e.g. differences in yearly ET estimates).

Recent randomized controlled trials have assessed the risksand benefits of thromboprophylaxis in ambulatory cancerpatients receiving chemotherapy and reported a relativerisk reduction of 30–60% in venous thromboembolic events(VTEs) but a doubling of bleeding risk [1–4]. Based on theseresults, the most recent American Society of ClinicalOncology clinical practice guideline update recommendsthromboprophylaxis with apixaban, rivaroxaban, or low-molecular–weight heparin (LMWH) for cancer patientswith a high risk of VTE and low risk of bleeding [5]. Patientswith metastatic germ-cell tumor (mGCT) were under-represented in all trials and thus it is not clear whether thisrecommendation applies to this group, although retrospec-tive data suggests similar efficacy of VTE prophylaxis.

PURPOSE A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.

Structured abstract: Introduction: Loss of skeletal muscle (SM) and gain of subcutaneous fat (SCF) are known side-effects of androgen-deprivation in treatment of prostate cancer. Scarce data is available concerning the effects of abiraterone/pred (ABI) on body composition and no published data regarding enzalutamide (ENZA). Our objective was to analyse the effects of ENZA on SM/SCF and to compare the results with ABI in patients with metastatic castration-resistant prostate-cancer (mCRPC). Patients and Methods: 54 patients starting ABI (n = 17) or ENZA (n = 37) at a single-centre between 2012 and 2018 were retrospectively identified. SM and SCF were assessed using CT-scans at baseline and after a median of 10.8 months on treatment. A deep learning image-segmentation software was used to quantify SM and SCF. In a subgroup of patients receiving ENZA within a trial, we investigated change of SM using serial timepoints. Results: Median time of treatment with ABI/ENZA was 14.6 months. A significant loss of SM compared to baseline was observed for ENZA (mean loss 5.2%, p