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Pdf) The Fabrication Of The Philosophe: Catholicisms, Court Culture And The Origins Of The Enlightenment Moralism
By Rouven Hoefflin 1, 2 , Adriana Lazarou 1, 2, † , Maria Elena Hess 2, 3, † , Meike Reiser 2, 4 , Julius Wehrle 1, 2, 5 , Patrick Metzger 3 , Anna Verena Frey 2, 4 , Heiko Becker 1, 2 , Konrad Aumann 2, 4 , Kai Berner 2, 6 , Martin Boeker 2, 7 , Nico Buettner 2, 8 , Christine Dierks 1, 2 , Jesus Duque-Afonso 1, 2 , Michel Eisenblaetter 2, 9 , Thalia Erbes 2, 6 , Ralph Fritsch 1, 2, 5 , Isabell Xiang Ge 2, 6 , Anna-Lena Geißler 2, 4 , Markus Grabbert 2, 10 , Steffen Heeg 2, 8 , Dieter Henrik Heiland 2, 11 , Simone Hettmer 2, 12 , Gian Kayser 2, 4 , Alexander Keller 1, 2 , Anita Kleiber 1, 2 , Alexandra Kutilina 1, 2 , Leman Mehmed 2, 13 , Frank Meiss 2, 14 , Philipp Poxleitner 2, 15 , Justyna Rawluk 1, 2 , Juri Ruf 2, 16 , Henning Schäfer 2, 11, 17 , Florian Scherer 1, 2 , Khalid Shoumariyeh 1, 2, 5 , Andreas Tzschach 2, 18 , Christoph Peters 2, 5, 19, 20 , Tilman Brummer 2, 5, 19, 20 , Martin Werner 2, 4, 5 , Justus Duyster 1, 2, 5 , Silke Lassmann 2, 4, 5, 20, ‡ , Cornelius Miething 1, 2, 5, ‡ , Melanie Boerries 2, 3, 5, ‡ , Anna L. Illert 1, 2, 5, *, ‡ and Nikolas von Bubnoff 1, 2, 5, ‡ add Show full author list remove Hide full author list
Access to molecular cancer treatments outside of clinical trials is limited and the benefit of molecular-guided, individualized patient care in patients with cancer progression after standard treatment is unclear. We here present the four-year experience of one of Europe’s first Molecular Tumor Boards and show that precision oncology in the era of affordable, extended genetic and phenotypic tumor profiling is feasible and effective for a small but relevant proportion of advanced cancer patients. We performed a comprehensive analysis of clinical follow-up data and report our workflow optimizations and upscaling processes. These could help other centers to establish similar structures to support molecular-guided treatment for patients with limited therapy options.
Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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Personalized cancer medicine; precision oncology; molecular profiling; molecular tumor board; targeted therapies; combination therapies; cancer progression; cancer genetics; cancer molecular biology; cancer immunotherapy
Oncology evolves as the most innovative field in medicine; it was responsible for 28 FDA drug approvals from 2018 to 2019, a rapid expansion of the anti-cancer drug repertoire comprising numerous targeted and immunotherapies [1, 2]. For the first time, approvals have been granted to tumor-agnostic drugs including pembrolizumab for microsatellite instability-high (MSI-H), mismatch repair deficient (MMRd), or tumor mutational burden-high (TMB-H) metastatic tumors [3, 4, 5] and larotrectinib for malignancies harboring neurotrophic receptor tyrosine kinase (NTRK) gene fusions [6]. These approvals highlight the increasing therapeutic significance of molecular and genetic testing in oncology. After initial trials failed to demonstrate a clear benefit [7, 8, 9, 10], numerous studies and reports now support the feasibility and the effectiveness of molecular precision oncology [11, 12, 13, 14, 15, 16, 17]. Despite these advances in tailored diagnostic and therapy, cancer remains the second leading cause of death globally, accounting for over 9 million deaths world-wide in 2018 [18].
The large number of available cancer treatments and clinical trials in combination with increasing accessibility of affordable extended molecular tumor profiling offer numerous new therapy options, especially for patients who have failed standard-of-care treatment. Furthermore, the growing knowledge of predictive biomarkers and the understanding of treatment resistance mechanisms rapidly change treatment paradigms. To keep pace with the dynamic field of personalized precision oncology and to provide cancer patients state-of-the-art molecular diagnostics and treatment recommendations, we established a Molecular Tumor Board (MTB) at the University Medical Center Freiburg Comprehensive Cancer Center in March 2015. Here, we report a broad four-year analysis showing patient characteristics, diagnostics and therapy recommendations, adherence, and clinical outcome measurements. Following and extending the report of our proof-of-concept study in 2018 [19], our most recent analyses focus on structural and organizational improvements that enabled us to triple the annual cases while confirming that clinical actionability of molecular targets translates into improved patient outcomes.
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The MTB was founded in March 2015 and comprises a multidisciplinary team of physicians with molecular cancer expertise from more than 16 departments and experts from molecular pathology, molecular biology, and medical bioinformatics. There are no formal inclusion or exclusion criteria for the presentation of patients to the MTB. Thus, it is open for all cancer patients with the intention to focus on those who lack standard treatment options or suffer from rare tumors. All patients discussed from March 2015 to December 2018 and treated on site (n = 488) were included in this retrospective, single-center analysis. Patients are registered via an online system by the treating physician, who is responsible for the initial clinical case presentation (Supplementary Figure S1). Recommendations for molecular analyses are given after the first case presentation according to entity-specific and entity-independent diagnostic standard operation procedures (SOP, Supplementary Procedures), that are regularly updated. Treatment recommendations are given upon interdisciplinary discussion according to results of molecular analyses, which are presented by the pathology- and bioinformatics-team at the second case presentation and include levels of molecular evidence (Supplementary Table S1). This trial was approved by the local institutional review board of the Medical Center—University of Freiburg (protocol code 369/19). All patients gave written informed consent.
The MTB determines patient tissue sampling for molecular pathology analyses or recommends re-biopsies if necessary. All routine molecular analyses (RMA) are performed using nationally certified tests in the accredited laboratories of the Institute for Surgical Pathology. These include immunohistochemistry (IHC) (comprising an immuno-oncology (IO)-panel, mismatch repair deficiency (MMRd)-testing, NTRK-testing, and individual biomarkers), in situ hybridization, microsatellite instability (MSI)-testing, and targeted next generation sequencing (tNGS; Supplementary Procedures). The IO-panel includes IHC against CD3, CD4, CD8, PD1, and PD-L1. Scoring was performed by evaluating the combined positivity score (CPS), tumor proportion score (TPS), and the immune cell (IC) score [20]. MSI-testing is performed by microsatellite analysis using either the standard panel of two mononucleotide (BAT-25, BAT-26) and three dinucleotide (D2S123, D5S346, and D17S250) [21, 22] or using a commercial test (Promega, Walldorf, Germany) of five monomorphic mononucleotide (BAT-25, BAT-26, MONO-27, NR-21, and NR-24) repeat markers and two polymorphic pentanucleotide (Penta C and Penta D) for additional quality control [23]. NTRK-testing is performed with IHC (NTRK-A, B, and C)
The MTB was founded in March 2015 and comprises a multidisciplinary team of physicians with molecular cancer expertise from more than 16 departments and experts from molecular pathology, molecular biology, and medical bioinformatics. There are no formal inclusion or exclusion criteria for the presentation of patients to the MTB. Thus, it is open for all cancer patients with the intention to focus on those who lack standard treatment options or suffer from rare tumors. All patients discussed from March 2015 to December 2018 and treated on site (n = 488) were included in this retrospective, single-center analysis. Patients are registered via an online system by the treating physician, who is responsible for the initial clinical case presentation (Supplementary Figure S1). Recommendations for molecular analyses are given after the first case presentation according to entity-specific and entity-independent diagnostic standard operation procedures (SOP, Supplementary Procedures), that are regularly updated. Treatment recommendations are given upon interdisciplinary discussion according to results of molecular analyses, which are presented by the pathology- and bioinformatics-team at the second case presentation and include levels of molecular evidence (Supplementary Table S1). This trial was approved by the local institutional review board of the Medical Center—University of Freiburg (protocol code 369/19). All patients gave written informed consent.
The MTB determines patient tissue sampling for molecular pathology analyses or recommends re-biopsies if necessary. All routine molecular analyses (RMA) are performed using nationally certified tests in the accredited laboratories of the Institute for Surgical Pathology. These include immunohistochemistry (IHC) (comprising an immuno-oncology (IO)-panel, mismatch repair deficiency (MMRd)-testing, NTRK-testing, and individual biomarkers), in situ hybridization, microsatellite instability (MSI)-testing, and targeted next generation sequencing (tNGS; Supplementary Procedures). The IO-panel includes IHC against CD3, CD4, CD8, PD1, and PD-L1. Scoring was performed by evaluating the combined positivity score (CPS), tumor proportion score (TPS), and the immune cell (IC) score [20]. MSI-testing is performed by microsatellite analysis using either the standard panel of two mononucleotide (BAT-25, BAT-26) and three dinucleotide (D2S123, D5S346, and D17S250) [21, 22] or using a commercial test (Promega, Walldorf, Germany) of five monomorphic mononucleotide (BAT-25, BAT-26, MONO-27, NR-21, and NR-24) repeat markers and two polymorphic pentanucleotide (Penta C and Penta D) for additional quality control [23]. NTRK-testing is performed with IHC (NTRK-A, B, and C)
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