[Update of the German S3 guideline on renal cell carcinoma]. / Aktualisierte S3-Leitlinie Nierenzellkarzinom.

BACKGROUND: Renal cell carcinoma is the third most common tumor among urological tumors. In Germany more than 14,000 people are affected every year. The sex ratio is 2/3 men and 1/3 women. OBJECTIVES: The S3 guideline is intended to provide all disciplines dealing with renal cell carcinoma with the current status of diagnostics, therapy and follow-up care of the patients with this tumor. MATERIALS AND METHODS: The first version of the German guideline on renal cell carcinoma was published in 2015. The development was carried out at S3 level, which means that a structured, evidence-based literature search was carried out, recommendations and statements were developed in topic-related working groups and were approved by an interdisciplinary group of officials elected by the different medical societies. The chapters were gradually revised in 2017, 2020 and 2021 to reflect new aspects. This article provides information about the most important innovations of the most recent update from 2023. RESULTS: In the epidemiology subsection, the substance trichlorethene has been added as a risk factor for the development of renal cell carcinoma. While there were no new data on neoadjuvant therapy, the checkpoint inhibitor pembrolizumab was the first substance to demonstrate improved disease-specific and overall survival in the adjuvant situation. The combination nivolumab plus cabozantinib and lenvatinib plus pembrolizumab were included in the chapter on systemic therapy for metastatic clear cell renal cell carcinoma. New are the chapters on non-clear cell renal cell carcinoma and hereditary tumors. CONCLUSIONS: The S3 guideline provides a structured, evidence-based overview of all aspects of renal cell carcinoma.

Feasibility of orbital friction stir welding on clad pipes of API X65 steel and Inconel 625.

Orbital friction stir welding (FSW) has been applied to clad pipes, which is certainly of interest to the oil and gas industry. In this context, an FSW system capable of performing sound joints in one pass with full tool penetration was developed. Orbital FSW was executed in 6 mm thick API X65 PSL2 steel clad pipes with 3 mm thick Inconel 625 using a polycrystalline cubic boron nitride (pcBN) tool. The metallurgical and mechanical properties of the joints were investigated. Sound joints with axial forces of 45-50 kN, tool rotational speeds of 400-500 rpm, and a welding speed of 2 mm/s were obtained, illustrating that the developed system can perform FSW joints without volumetric defects.

Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

Immune checkpoint inhibitor-associated myocarditis : Case reports and a review of the literature.

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

Ferumoxytol-enhanced MR imaging for differentiating intrapancreatic splenules from other tumors.

OBJECTIVES: Ferumoxytol is an ultra-small superparamagnetic iron oxide (USPIO) agent that is taken up by splenic tissue. This study describes our initial institutional experience of ferumoxytol-enhanced MRI (feMRI) for differentiating intrapancreatic splenules (IPS) from other pancreatic lesions. METHODS: In this retrospective study, patients with computed tomographic imaging that identified small enhancing lesions in the tail of the pancreas subsequently underwent feMRI for further characterization. The feMRI protocol included T2-weighted (T2w) imaging with and without fat suppression (FS), R2* mapping, diffusion-weighted imaging (DWI), and T1-weighted (T1w) imaging with FS, prior to contrast injection. Immediately after slow intravenous infusion with 3 mg/kg body weight ferumoxytol, T1w was repeated. Delayed imaging with all sequences were obtained 24-72 h after ferumoxytol administration. RESULTS: Seven patients underwent feMRI. In two patients, the pancreatic lesions were presumed as pancreatic neuroendocrine tumor (PNET) from feMRI and in the remaining 5 IPS. One of the two patients with PNET was symptomatic for NET. In another symptomatic patient with pathologically proven duodenal NET and suspected PNET, the pancreatic lesion was proven to be an IPS on feMRI. IPS demonstrated strong negative enhancement in feMRI on T2w and increased R2* values consistent with splenic tissue, while the presumed PNETs did not enhance. T2w FS was helpful on the pre-contrast images to identify IPS, while R2* did on post-contrast images. Neither DWI nor T1w contributed to differentiating PNETs from IPS. CONCLUSIONS: This study demonstrates the potential utility of feMRI as a helpful adjunct diagnostic tool for differentiating IPS from other pancreatic lesions. Further studies in larger patient cohorts are needed.

Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

Burden of non-motor symptoms in Parkinson's disease patients predicts improvement in quality of life during treatment with levodopa-carbidopa intestinal gel.

BACKGROUND AND PURPOSE: GLORIA, a registry conducted with 375 advanced Parkinson's disease patients treated with levodopa-carbidopa intestinal gel (LCIG) for 24 months in routine clinical care, demonstrated significant reductions from baseline in 'off' time and 'on' time with dyskinesia and improvements in the Non-Motor Symptom Scale (NMSS) total and individual domain scores, and in Parkinson's Disease Questionnaire 8 item (PDQ-8) total score. METHODS: Associations between baseline NMSS burden (NMSB), the multi-domain NMSS total score and the PDQ-8 total score were investigated for 233 patients. Baseline NMSB was assigned to five numerical categories defined by the NMSS total cutoff scores (0-20, 21-40, 41-60, 61-80 and >80). Pearson and Spearman correlations were calculated at month 24. RESULTS: The response of LCIG was assessed using validated criteria after 24 months. The proportion of patients decreasing ≥ 30 NMSS score points was 47% in the most affected NMSB category (NMSS total score > 80). A positive association was noted between baseline NMSB and NMSS total score (0.57, P < 0.0001), as well as between NMSS total score and PDQ-8 total score (0.46, P < 0.0001). Associations between improvements of the NMSS domain sleep/fatigue and PDQ-8 total score (0.32, P = 0.0001) as well as between the NMSS domain mood/cognition and PDQ-8 total score (0.37, P < 0.0001) were also shown. CONCLUSIONS: This analysis demonstrated positive associations between NMSS baseline burden and improvements of non-motor symptoms. Improvements of non-motor symptoms were associated with improved quality of life in advanced parkinsonian patients during a 2-year treatment with LCIG and reflect the long-term non-motor efficacy of this treatment.

Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer.

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

[Measurement of contrast vision: mesopic or photopic vision? : Comparison of different methods for measuring contrast sensitivity within the framework of driving licence regulations]. / Kontrastsehen messen: mesopisch oder photopisch? : Ein Vergleich verschiedener Verfahren zur Messung der Kontrastempfindlichkeit im Rahmen der Fahrerlaubnisverordnung.

BACKGROUND: Since 2011 the regulations for occupational driving licences make the examination of contrast vision sensitivity obligatory; however, apart from mesopic procedures no uniform regulations are available for methods and minimum requirements. OBJECTIVE: By comparing different mesopic and photopic contrast sensitivity tests this study analyzed whether these could be equivalently used and lead to the same results. MATERIAL AND METHODS: Contrast vision sensitivity was determined in 150 subjects with emmetropia using five different methods, i.e. the mesopic test device Mesotest II as the reference method, Rodatest 302 and Optovist as photopic test devices and two photopic test charts (Vistech chart and Mars charts). The results of passing the tests were compared and Cohens κ was determined to quantify the conformity between the tests. RESULTS: Poor agreement was found between Mesotest II and Optovist as well as between Mesotest II and the Vistech chart. There was no agreement between Rodatest 302 or Mars charts and Mesotest II; nevertheless, the contrast vision sensitivity measured with Optovist, Rodatest 302 and the Vistech chart showed good correlation (0.46 ≤ r ≤ 0.69). CONCLUSION: Apart from a few limitations, the reference method Mesotest II as well as Optovist and the Vistech chart are suitable for testing contrast vision sensitivity, whereas Rodatest 302 and Mars charts cannot be recommended based on the current criteria for minimum requirements. The minimum requirements must be urgently adapted and strict regulations for measurement must be formulated. In addition, due to the poor agreement between the methods an amendment of the driving licence regulations should be considered, which requires examination of both mesopic and photopic contrast vision or alternatively mesopic contrast vision alone.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

Patients with metastatic renal cell carcinoma have a life-limiting prognosis. Therefore, the aim of therapy is normally palliative care. Nevertheless, substantial achievements have been made in the past years. Cytokines as long-term standard therapy have been replaced by new targeted therapies. Sunitinib, the combination of bevacizumab+interferon-alfa, pazopanib and temsirolimus are now approved for first-line therapy. Sunitinib and pazopanib can also be administered as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Everolimus (after TKI therapy) und sorafenib (after cytokines) are other compounds now available for second-line therapy. In addition, axitinib was approved for second-line therapy after failure of sunitinib or cytokines. For questions regarding the optimal sequence, first study results are now available from the phase III trial.The purpose of an interdisciplinary expert meeting held in 2014 was to debate about which criteria should influence the therapy decision. The members discussed several aspects of treating patients with the disease. Results from the 2012 conference provided the basis for the 2014 meeting 1. As in previous years, the experts intended to provide common recommendations for clinical practice. The results of the 2012 conference are presented as short theses and a current therapy algorithm.

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

Patients with metastatic renal cell carcinoma have a life-limiting prognosis. Therefore, the aim of therapy is normally palliative care. Nevertheless, substantial achievements have been made in the past years. Cytokines as long-term standard therapy have been more and more replaced by new targeted therapies. Sunitinib, the combination of bevacizumab+interferon alfa, pazopanib and temsirolimus are now approved for first-line therapy. Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to cases of cytokine failure. Everolimus (after TKI therapy) and sorafenib (after cytokines) are other compounds available for second-line therapy. In addition, axitinib was recently approved for second-line therapy after failure of sunitinib or cytokines. For questions regarding the optimal sequence, first study results are now available from the phase III trial. The purpose of an interdisciplinary expert meeting held in 2012 was to debate upon which criteria should influence the therapy decision. The members discussed several aspects of treating patients with the disease. Results from the 2011 conference provided the basis for the 2012 meeting 1. As in previous years, the experts intended to provide common recommendations for clinical practice. The results of the 2012 conference are presented as short theses and a current therapy algorithm.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

Targeted therapies such as sunitinib, pazopanib, bevacizumab, sorafenib and everolimus have become established as new therapeutic standards in the treatment of metastatic renal cell carcinoma. New substances are going to complement these treatment options. Therefore, cytokines as long-term standard therapy are being more and more replaced. The achievements raise a lot of questions in clinical daily routine: Which criteria influence the decision for therapy? How can a remission be assessed when antiangiogenetic agents are administered? And last but not least, the optimal sequence remains a controversially discussed topic. Based on the current study situation, an interdisciplinary expert meeting was held to debate these aspects. Results from the 2010 conference provided the basis for the 2011 meeting. The results of the 2011 conference are presented as short theses.