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PubMed | University Paris - Sud, Ludwig Maximilians University of Munich, REK Consulting, TU Munich and 2 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

This study investigated the cost effectiveness of guideline-recommended (American Society of Clinical Oncology, European Society of Medical Oncology) urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) biomarkers to guide adjuvant chemotherapy decisions for hormone receptor-positive, node-negative early breast cancer patients at intermediate risk of relapse, in France, Germany, and The Netherlands.uPA/PAI-1 testing was compared to chemotherapy for all patients and to no chemotherapy in two age-related subgroups (35-49 and 50-75 years). A partitioned survival analysis was performed using patient-level data for survival outcomes and secondary sources. Mean quality-adjusted life years (QALYs) and costs were estimated over a lifetime horizon to calculate the incremental net monetary benefit (INMB) at a willingness-to-pay of 50,000/QALY. Uncertainty was explored through bootstrap and probabilistic sensitivity analysis using 5000 replicates.In the 35-49 year age group, INMBs were negative when uPA/PAI-1 testing was compared to chemotherapy for all patients but positive when it was compared to no chemotherapy for the three countries. In the 50-75 year age group, INMBs of uPA/PAI-1 testing compared to both reference strategies were positive in the three countries, with cost-effectiveness probabilities for the uPA/PAI-1 strategy of 65%, 70%, and 59% for France, Germany, and the Netherlands, respectively, compared with chemotherapy for all patients, and 64%, 58%, and 65%, respectively, compared with no chemotherapy.uPA/PAI-1 testing could allow the selection of patients older than 50 years requiring chemotherapy in this population, but the cost effectiveness of this strategy is uncertain. Chemotherapy for all patients is the most cost-effective strategy for patients younger than 50 years.


Kruger A.,TU Munich | Kates R.E.,REK Consulting | Edwards D.R.,University of East Anglia
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2010

Phase III clinical trials with cancer patients with the first generation of synthetic MMP inhibitors (MMPIs) failed due to inefficacy and adverse side effects. These results were unexpected, given the wealth of pre-clinical data implicating MMPs as cancer targets, but are attributable to the broad-spectrum activity of these early MMPIs and the limited knowledge of the variety of biological functions of MMPs at the time they were deployed. These experiences stimulated the development of a variety of highly specific synthetic MMPIs. However, the bottle-neck is the identification of true target-MMPs. Functional genetic approaches are being complicated by the existence of the protease web, i.e., the dynamic interconnectivity of MMPs and other proteases, their inhibitors, and substrates that collectively establish homeostasis in signaling in healthy and disease-afflicted tissue. Therefore, even specific MMP inhibition can result in seemingly unpredictable induction of systemic protease web-associated modulations (spam), which can comprise metastasis-promoting molecules such as other proteases and cytokines. Such undesired information in local proteolytic networks or relayed systemically in the organism via the proteolytic internet needs to be understood and defined in order to design specific metastasis therapies employing highly specific MMPIs in combination with spam-filtering agents. © 2009 Elsevier B.V.


Warm M.,University of Cologne | Kates R.,REK Consulting | Overkamp F.,Day Clinic for Hematology and Oncology | Thomas A.,Charité - Medical University of Berlin | Harbeck N.,University of Cologne
Breast Cancer Research and Treatment | Year: 2011

Response to fulvestrant and survival in postmenopausal hormone-sensitive advanced breast cancer was investigated within a non-randomized, In-Practice Evaluation Program, with the aim of optimizing treatment decisions. 848 patients (median age 64 years; 52% co-morbidity; 78% prior palliative therapy; median 4 prior regimens) received monthly fulvestrant injections (250 mg/month) and were followed-up three-monthly for 9 months. Clinical benefit (PFS ≥ 24 weeks) occurred in 532/848 (62.7%); stable disease (SD) in 627/848 patients (74%), including 62 complete and 177 partial responses. Best response was delayed in 115 patients. Estimated 9-month overall survival (OS) was 89%; 9-month event-free survival (EFS) was 71%. Indicators of disease aggressiveness affected response and survival, but number of fulvestrant cycles was the key OS and EFS determinant. The patients with SD at 3 months benefitted from continued fulvestrant. Excluding deaths, 7 serious adverse events occurred (none attributable to fulvestrant). No new or unexpected safety issues arose; 90% of the patients and physicians rated fulvestrant tolerability as "very good" or "good". In the largest prospective, fulvestrant-treated cohort to date, advanced breast cancer patients achieving SD or better after 3 months of treatment gained survival benefit by prolonging fulvestrant therapy-independent of disease and treatment history. © 2010 Springer Science+Business Media, LLC.


Kolben T.,Ludwig Maximilians University of Munich | Augustin D.,Hospital Deggendorf | Armbrust R.,Charité - Medical University of Berlin | Kolben T.M.,Ludwig Maximilians University of Munich | And 7 more authors.
Breast Cancer Research and Treatment | Year: 2016

The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003–2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical–pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan–Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5 % of patients with low uPA/PAI-1, i.e., 38.8 % of the total patient collective. Median follow-up was 52.5 months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99 %. Five-year overall survival including all causes of death was 95 %. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5 years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center. © 2015, Springer Science+Business Media New York.


PubMed | Ludwig Maximilians University of Munich, Hospital Deggendorf, Charité - Medical University of Berlin and REK Consulting
Type: Journal Article | Journal: Breast cancer research and treatment | Year: 2016

The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5% of patients with low uPA/PAI-1, i.e., 38.8% of the total patient collective. Median follow-up was 52.5months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99%. Five-year overall survival including all causes of death was 95%. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center.


Helmer T.,BMW AG | Kates R.,REK Consulting
19th Intelligent Transport Systems World Congress, ITS 2012 | Year: 2012

This paper presents a detailed statistical analysis of a large, representative accident dataset with the aim of obtaining characteristics of vehicle accidents involving cyclists. To this end, using the German In-Depth Accident Study (GIDAS) and national databases, current national trends in accident scenarios, statistics, and characteristics are evaluated and analyzed in terms of frequency, impact, and contributing factors. The scenarios of cyclist accidents are qualitatively similar to those of pedestrian collisions; in particular, crossing conflict scenarios are the most important both in terms of prevalence and severity-weighting. The scenario analysis also implies that vehicle-based measures focusing on the vehicle front-both by means of active and passive safety-could have a large impact on cyclist as well as pedestrian accidents and their consequences. The typically higher cyclist speeds in all scenarios pose important challenges for potential engineering approaches to vehicle-cyclist accident reduction.


Warm M.,University of Cologne | Kates R.,REK Consulting | Grosse-Onnebrink E.M.,University of Cologne | Stoff-Khalili M.,University of Cologne | And 4 more authors.
Anticancer Research | Year: 2010

Background: The central objective of this study was to determine the predictive impact of several established tumor biological factors (PgR, ER, HER2 and Ki-67) on response to pre-operative chemotherapy in primary breast cancer. Patients and Methods: 59 primary M0 breast cancer patients received pre-operative sequential dose-dense epirubicin and cyclophosphamide followed by docetaxel (19 patients at dosage 100 mg/m2, 40 patients at 75 mg/m2). Results: Pathological complete remission (pCR) occurred in 17 patients (29%) and at least partial remission in 42 (71%). Higher proliferation (Ki-67) and lack of hormone receptors (either or both) were significant predictive factors for pCR; moreover, 8/11 (73%) patients with triple-negative tumors (HER2-/ER-/PgR-) had pCR (p=0.001). Breast conserving surgery was achieved in 46/59 patients (78%). Hand-foot syndrome occurred in 12/19 patients treated at the higher docetaxel dosage but only 1/40 of the remaining patients. Higher docetaxel dosage was associated with improved pCR in the non-triple-negative subgroup. Conclusion: The tumor biology of hormone receptor-negative, especially triple-negative, and highly proliferating breast cancer is associated with strongly positive response to dose-dense, pre-operative epirubicin/cyclophosphamide/docetaxel chemotherapy.


Helmer T.,BMW AG | Radwan samaha R.,George Washington University | Scullion P.,George Washington University | Ebner A.,BMW AG | Kates R.,REK Consulting
International Research Council on the Biomechanics of Injury - 2010 International IRCOBI Conference on the Biomechanics of Injury, Proceedings | Year: 2010

Evaluation of safety benefits is an essential part during design and development of pedestrian protection systems. Translating physics into human benefits for large-scale simulations of the benefit requires reliable and validated injury and fatality models. To this end, multivariate predictive models for pedestrian fatalities and different injury severities by means of the ISS as well as the MAIS scale are developed using the US Pedestrian Crash Data Study (PCDS). In addition to impact speed, significant multivariate predictors include physiological and vehicle characteristics. The in-sample as well as out-of-sample predictive quality is remarkably high. An approach to define a metric suitable for comparing active and passive safety is presented. As active safety is capable of influencing impact speed directly, the benefits of a reduction of impact speed regarding injury probability / mortality while controlling other influencing factors is computed. The relative reduction of injury probability / mortality with respect to exposure seems to be an appropriate metric to evaluate and compare safety benefits of measures considering both active and passive safety.


Helmer T.,BMW AG | Kuhbeck T.,BMW AG | Gruber C.,BMW AG | Kates R.,REK Consulting
Lecture Notes in Electrical Engineering | Year: 2013

This paper describes recent progress toward achieving representative and reliable active safety performance assessment of advanced driver assistance systems (ADAS). Because ADAS act within a complex, dynamic traffic environment, reliable evaluation of their safety benefits poses methodological challenges. For a proposed ADAS, its expected contribution to reduction of mortality and injuries as well as false positives should be predicted. To meet these challenges, our approach incorporates identification of target scenarios; calibration and validation of stochastic behavior and accident injury models; stochastic (Monte-Carlo) simulation of target scenarios in varied traffic contexts with/without ADAS; and integration of supporting and corroborating field and laboratory analyses. These include a new controlled, high-throughput approach to sensor testing and algorithm validation in camera-based ADAS using a virtual graphical test bed, which supports systematic identification of critical external conditions that could modify performance or lead to a failure mode. The methodologies introduced here are designed to ensure validity of all key links in the assessment chain, not limited to those aspects that can be assessed in a single test. © Springer-Verlag 2013.


Helmer T.,BMW AG | Wang L.,BMW AG | Kompass K.,BMW AG | Kates R.,REK Consulting
IEEE Conference on Intelligent Transportation Systems, Proceedings, ITSC | Year: 2015

Advanced driver assistance and automated driving can influence traffic safety in a variety of ways. Development and implementation of safety-relevant functions require prospective, quantitative assessment of their traffic safety impacts. Both benefits and risks can be quantified using simulation-based virtual experimental techniques. To this end, traffic phenomena are modeled taking into account key safety-relevant processes and 'stochastic' simulation is performed on large, representative virtual samples. The virtual representations of traffic phenomena are based on detailed, stochastic models of drivers, vehicles, traffic flow, and the road environment, together with their interactions. The models incorporate knowledge from FOT, NDS, laboratory and driving simulator experiments, and other sources. Large-scale, comprehensive simulations could help in identifying and evaluating the relevant situations in which automated driving impacts traffic safety. The goal is a standardized harmonized methodology, agreed upon by all stakeholders, for holistic assessment of the impact of new driver assistance or automatic driving functions on traffic safety. © 2015 IEEE.

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