Publications by authors named "Peter Horak"

84 Publications

PD-1 and PD-L1 expression on TILs in peritoneal metastases compared to ovarian tumor tissues and its associations with clinical outcome.

Sci Rep 2021 Mar 18;11(1):6400. Epub 2021 Mar 18.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.

The therapeutic potential of immune checkpoint inhibitors is currently being investigated in epithelial ovarian cancer (EOC), but immunological effects of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis in EOC still remain poorly understood. The aim of this study was thus to compare infiltration rates of PD-1 and PD-L1 expressing tumor infiltrating leucocytes (TILs) in primary ovarian tumor tissue and metastatic intraperitoneal implants and to investigate its impact on overall survival (OS). Tumor specimens (ovarian tumor tissues and intraperitoneal metastases) of 111 patients were used to investigate the PD-1, PD-L1 and CD8 expression rates on TILs and PD-L1 expression rate of tumor cells. The percentages of CD8, PD-1, and PD-L1 expressing subpopulations of TILs differ in primary ovarian tumor tissues and metastatic intraperitoneal implants. High PD-1 among TILs in peritoneal metastases were associated with favorable OS. High PD-L1 expression in TILs was associated with poor OS. Combining both factors in peritoneal metastases revealed an unfavorable prognosis. Primary ovarian tumor tissue and intraperitoneal metastatic tissues in EOC might have different strategies to evade immune control. Those findings are of importance for the process of biomarker assessment to predict patients' response to immunotherapy.
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http://dx.doi.org/10.1038/s41598-021-85966-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973418PMC
March 2021

Targeting rare and non-canonical driver variants in NSCLC - An uncharted clinical field.

Lung Cancer 2021 04 19;154:131-141. Epub 2021 Feb 19.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany; German Cancer Consortium (DKTK), Berlin, Munich and Heidelberg Partner Sites, Germany. Electronic address:

Objectives: Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments.

Material And Methods: Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively.

Results And Conclusion: Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18-21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.022DOI Listing
April 2021

Sarcoma classification by DNA methylation profiling.

Authors:
Christian Koelsche Daniel Schrimpf Damian Stichel Martin Sill Felix Sahm David E Reuss Mirjam Blattner Barbara Worst Christoph E Heilig Katja Beck Peter Horak Simon Kreutzfeldt Elke Paff Sebastian Stark Pascal Johann Florian Selt Jonas Ecker Dominik Sturm Kristian W Pajtler Annekathrin Reinhardt Annika K Wefers Philipp Sievers Azadeh Ebrahimi Abigail Suwala Francisco Fernández-Klett Belén Casalini Andrey Korshunov Volker Hovestadt Felix K F Kommoss Mark Kriegsmann Matthias Schick Melanie Bewerunge-Hudler Till Milde Olaf Witt Andreas E Kulozik Marcel Kool Laura Romero-Pérez Thomas G P Grünewald Thomas Kirchner Wolfgang Wick Michael Platten Andreas Unterberg Matthias Uhl Amir Abdollahi Jürgen Debus Burkhard Lehner Christian Thomas Martin Hasselblatt Werner Paulus Christian Hartmann Ori Staszewski Marco Prinz Jürgen Hench Stephan Frank Yvonne M H Versleijen-Jonkers Marije E Weidema Thomas Mentzel Klaus Griewank Enrique de Álava Juan Díaz Martín Miguel A Idoate Gastearena Kenneth Tou-En Chang Sharon Yin Yee Low Adrian Cuevas-Bourdier Michel Mittelbronn Martin Mynarek Stefan Rutkowski Ulrich Schüller Viktor F Mautner Jens Schittenhelm Jonathan Serrano Matija Snuderl Reinhard Büttner Thomas Klingebiel Rolf Buslei Manfred Gessler Pieter Wesseling Winand N M Dinjens Sebastian Brandner Zane Jaunmuktane Iben Lyskjær Peter Schirmacher Albrecht Stenzinger Benedikt Brors Hanno Glimm Christoph Heining Oscar M Tirado Miguel Sáinz-Jaspeado Jaume Mora Javier Alonso Xavier Garcia Del Muro Sebastian Moran Manel Esteller Jamal K Benhamida Marc Ladanyi Eva Wardelmann Cristina Antonescu Adrienne Flanagan Uta Dirksen Peter Hohenberger Daniel Baumhoer Wolfgang Hartmann Christian Vokuhl Uta Flucke Iver Petersen Gunhild Mechtersheimer David Capper David T W Jones Stefan Fröhling Stefan M Pfister Andreas von Deimling

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Supercontinuum generation in tantalum pentoxide waveguides for pump wavelengths in the 900 nm to 1500 nm spectral region.

Opt Express 2020 Oct;28(21):32173-32184

We characterize the spectral broadening performance in silica clad and unclad Tantalum pentoxide (TaO) waveguides as a function of the input pulse central wavelength and polarization, sweeping over a wavelength range from 900 nm to 1500 nm, with an average incident power of 110 mW. The waveguides are 0.7 µm high and between 2.2 and 3.2 µm wide, and the SiO top cladding layer is 2 µm thick. We model the dispersion of the higher order spatial modes, and use numerical simulations based on the generalized nonlinear Schrödinger equation to analyze the nonlinear behaviour of the spatial modes within the waveguides as well as the dispersive effects observed in the experiments. We achieve octave spanning supercontinuum with an average power of 175 mW incident on the waveguide at 1000 nm pump wavelength.
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http://dx.doi.org/10.1364/OE.403089DOI Listing
October 2020

Integrating proteomics into precision oncology.

Int J Cancer 2021 Mar 25;148(6):1438-1451. Epub 2020 Sep 25.

Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

DNA sequencing and RNA sequencing are increasingly applied in precision oncology, where molecular tumor boards evaluate the actionability of genetic events in individual tumors to guide targeted treatment. To work toward an additional level of patient characterization, we assessed the abundance and activity of 27 proteins in 134 patients whose tumors had previously undergone whole-exome and RNA sequencing within the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program of National Center for Tumor Diseases, Heidelberg. Proteomic and phosphoproteomic targets were selected to reflect the most relevant therapeutic baskets in MASTER. Among six different therapeutic baskets, the proteomic data supported treatment recommendations that were based on DNA and RNA analyses in 10% to 57% and frequently suggested alternative treatment options. In several cases, protein activities explained the patients' clinical course and provided potential explanations for treatment failure. Our study indicates that the integrative analysis of DNA, RNA and protein data may refine therapeutic stratification of individual patients and, thus, holds potential to increase the success rate of precision cancer therapy. Prospective validation studies are needed to advance the integration of proteomic analysis into precision oncology.
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http://dx.doi.org/10.1002/ijc.33301DOI Listing
March 2021

Successful BRAF/MEK inhibition in a patient with -mutated extrapancreatic acinar cell carcinoma.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany.

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic mutation and a germline stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
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http://dx.doi.org/10.1101/mcs.a005553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476408PMC
August 2020

Patient expectations are better for immunotherapy than traditional chemotherapy for cancer.

J Cancer Res Clin Oncol 2020 Dec 19;146(12):3189-3198. Epub 2020 Aug 19.

Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: The main aim of the study was to explore the expectations and knowledge of advanced-stage cancer patients about immunotherapy.

Methods: This mixed methods study included 53 cancer patients on immune checkpoint inhibitors (ICIs), 55 cancer patients undergoing chemotherapy (CT), and 53 non-cancer patients. Participants' expectations about ICIs and CT were compared. Additional qualitative data were derived from semi-structured interviews.

Results: Among patients who did not receive ICIs, 63 (58%) had never heard of ICIs and 94 (87%) had large gaps in their knowledge of ICIs. Among ICI patients, 33 (62%) simply described ICIs without errors. ICI perception was positive, regardless of whether respondents received or had heard of ICIs, which became particularly evident when compared to CT. ICIs were rated as more promising, and all adverse effects were expected to be significantly lower than those of CT. Knowledge about ICIs was also limited in the interviewed ICI patients. Some patients reported adverse effects of ICIs that were mostly mild and well-tolerated or easily treated.

Conclusions: The lack of understanding of ICIs should be improved by activities to increase the knowledge of ICI patients and the general population. In contrast to CT, ICIs invoked fewer negative associations with efficacy and toxicity. Therefore, attention should be paid to risk awareness when educating patients. (Clinical trial registration number: DRKS00011868) Trial Registration: German clinical trials register, www.germanctr.de , number DRKS00011868.
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http://dx.doi.org/10.1007/s00432-020-03336-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679331PMC
December 2020

Germline SDHB-inactivating mutation in gastric spindle cell sarcoma.

Genes Chromosomes Cancer 2020 10 26;59(10):601-608. Epub 2020 Jun 26.

Department of Translational Medical Oncology, National Center for Tumor Diseases Heidelberg and German Cancer Research Center, Heidelberg, Germany.

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Inactivating mutations or epigenetic deregulation of succinate dehydrogenase complex (SDH) genes are considered defining features of a subset of GIST occurring in the stomach. Based on comprehensive molecular profiling and biochemical analysis within a precision oncology program, we identified hallmarks of SDH deficiency (germline SDHB-inactivating mutation accompanied by somatic loss of heterozygosity, lack of SDHB expression, global DNA hypermethylation, and elevated succinate/fumarate ratio) in a 40-year-old woman with undifferentiated gastric spindle cell sarcoma that did not meet the diagnostic criteria for other mesenchymal tumors of the stomach, including GIST. These data reveal that the loss of SDH function can be involved in the pathogenesis of non-GIST sarcoma of the gastrointestinal tract.
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http://dx.doi.org/10.1002/gcc.22876DOI Listing
October 2020

The landscape of chromothripsis across adult cancer types.

Nat Commun 2020 05 8;11(1):2320. Epub 2020 May 8.

Group Genome Instability in Tumors, DKFZ, Heidelberg, Germany.

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.
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http://dx.doi.org/10.1038/s41467-020-16134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210959PMC
May 2020

Metastatic adult pancreatoblastoma: Multimodal treatment and molecular characterization of a very rare disease.

Pancreatology 2020 Apr 29;20(3):425-432. Epub 2020 Feb 29.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and DKFZ Dresden, Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address:

Background: Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance.

Methods: Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER).

Results: We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion.

Conclusion: Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.
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http://dx.doi.org/10.1016/j.pan.2020.02.017DOI Listing
April 2020

Monolithically-integrated cytometer for measuring particle diameter in the extracellular vesicle size range using multi-angle scattering.

Lab Chip 2020 04 9;20(7):1267-1280. Epub 2020 Mar 9.

Optoelectronics Research Centre, University of Southampton, UK.

Size measurement of extracellular vesicles is hampered by the high cost and measurement uncertainty of conventional flow cytometers which is mainly due to the use of non-specialised free space optics. Integrated cytometry, where the optics and fluidics are embedded in a monolithic chip shows promise for the production of low cost, micro-flow cytometers dedicated for extracellular vesicle (EV) analysis with improved size measurement accuracy and precision. This research demonstrates a unique integrated cytometer for sub-micron particle size measurement using multi-angle scattering analysis. A combination of three technologies is used: (i) Dean-based hydrodynamic focussing to deliver a tight sample core stream to the analysis region, (ii) integrated waveguides with multimode interference devices to focus a narrow excitation beam onto the sample stream, and (iii) an angular array of collection waveguides to measure particle scattering distribution and calculate diameter. Low index 200 nm liposomes could be detected and polystyrene size standards as small as 400 nm diameter could be measured with an uncertainty of ±21 nm (1/2 IQR) demonstrating a first step on the path to high performance integrated cytometry of EVs.
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http://dx.doi.org/10.1039/c9lc01182jDOI Listing
April 2020

Community-driven development of a modified progression-free survival ratio for precision oncology.

ESMO Open 2019 13;4(6):e000583. Epub 2019 Nov 13.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objective: Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5.

Methods: To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times.

Results: A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies.

Conclusions: The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.
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http://dx.doi.org/10.1136/esmoopen-2019-000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863673PMC
June 2020

Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.

Oncogene 2020 01 26;39(4):814-832. Epub 2019 Sep 26.

Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearrangement between TTYH3, encoding a membrane-resident, calcium-activated chloride channel, and BRAF intron 1, resulting in a TTYH3-BRAF fusion protein that retained all features essential for BRAF autoinhibition. Accordingly, the BRAF moiety of the fusion protein alone, which represents full-length BRAF without the amino acids encoded by exon 1 (BRAF), did not induce MEK/ERK phosphorylation or transformation. Likewise, neither the TTYH3 moiety of the fusion protein nor full-length TTYH3 provoked ERK pathway activity or transformation. In contrast, TTYH3-BRAF displayed increased MEK phosphorylation potential and transforming activity, which were caused by TTYH3-mediated tethering of near-full-length BRAF to the (endo)membrane system. Consistent with this mechanism, a synthetic approach, in which BRAF was tethered to the membrane by fusing it to the cytoplasmic tail of CD8 also induced transformation. Furthermore, we demonstrate that TTYH3-BRAF signals largely independent of a functional RAS binding domain, but requires an intact BRAF dimer interface and activation loop phosphorylation sites. Cells expressing TTYH3-BRAF exhibited increased MEK/ERK signaling, which was blocked by clinically achievable concentrations of sorafenib, trametinib, and the paradox breaker PLX8394. These data provide the first example of a fully autoinhibited BRAF protein whose oncogenic potential is dictated by a distinct fusion partner and not by a structural change in BRAF itself.
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http://dx.doi.org/10.1038/s41388-019-1021-1DOI Listing
January 2020

Selective wavelength conversion in a few-mode fiber.

Opt Express 2019 Aug;27(17):24072-24081

We experimentally demonstrate a means to selectively enhance wavelength conversion of WDM channels on a 100 GHz grid exploiting nonlinear effects between the spatial modes of a few mode fiber. The selectivity of parametric gain is obtained by dispersion design of the fiber such that the inverse group velocity curves of the participating modes are parallel and their dispersion is suitably large. We describe both theoretically and experimentally the observed dependence of the idler gain profile on pump mode (quasi) degeneracy.
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http://dx.doi.org/10.1364/OE.27.024072DOI Listing
August 2019

Finding Options Beyond Standard of Care in Oncology: A Proposal for Workflows Utilizing Knowledge Databases.

Stud Health Technol Inform 2019 Aug;264:950-953

Division of Medical Informatics for Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Baden Württemberg, Germany.

With the novel approach of molecularly stratified therapies based on genetic characteristics of individual tumors, the need for databases providing information on molecular alterations and targeted treatment options is increasing rapidly. In Molecular Tumor Boards (MTB) professionals discuss molecular alterations and provide biological context for therapeutic options using external knowledge databases. The identification of informative databases and the information on their specific contents can greatly facilitate and standardize the functioning of a MTB. In this work we present a list of databases which have been deemed useful and relevant for MTB in a clinical setting. We describe workflows to recommend the use of specific databases at different steps in the clinical curation process. Information obtained from these databases is a necessary prerequisite to evaluate molecular alterations and devise rational targeted therapies in MTB.
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http://dx.doi.org/10.3233/SHTI190364DOI Listing
August 2019

KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors - TORC1/2 Inhibition as Salvage Strategy.

Mol Cancer Ther 2019 11 15;18(11):1985-1996. Epub 2019 Jul 15.

Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of or , favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients-adding further complexity to the scope of resistance. We collected genotyping data for from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary mutations ( = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates () potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in , and We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT-related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1224DOI Listing
November 2019

FCM Software Aids Extracellular Vesicle Light Scatter Standardization.

Cytometry A 2020 06 28;97(6):569-581. Epub 2019 Jun 28.

Faculty of Medicine, University of Southampton, Southampton, UK.

The study of extracellular vesicles (EVs) is a rapidly growing field due to their great potential in many areas of clinical medicine including diagnostics, prognostics, theranostics, and therapeutics. Flow cytometry is currently one of the most popular methods of analyzing EVs due to it being a high-throughput, multiparametric technique, that is readily available in the majority of research labs. Despite its wide use, few commercial flow cytometers are designed specifically for the detection of EVs. Many flow cytometers used for EV analysis are working at their detection limits and are unable to detect the majority of EVs. Currently, very little standardization exists for EV flow cytometry, which is an issue because flow cytometers vary considerably in the way they collect scattered or fluorescent light from particles being interrogated. This makes published research hard to interpret, compare, and in some cases, impossible to reproduce. Here we demonstrate a method of flow cytometer light scatter standardization, utilizing flow cytometer postacquisition analysis software (FCM ). FCM is built upon Mie theory and enables the approximation of flow cytometer geometric parameters either by analyzing beads of known diameter and refractive index or by inputting the collection angle if known. The software is then able to create a scatter-diameter curve and scatter-refractive index curve that enables researchers to convert scattering data and instrument sensitivity into standardized units. Furthermore, with the correct controls, light scatter data can be converted to diameter distributions or refractive index distributions. FCM therefore offers a freely available and ergonomic method of standardizing and further extending EV characterization using flow cytometry.
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http://dx.doi.org/10.1002/cyto.a.23782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061335PMC
June 2020

Integrated polarizer based on 45° tilted gratings.

Opt Express 2019 Apr;27(8):11174-11181

We report the first integrated implementation of a polarizer based on the use of 45° tilted gratings in planar waveguides. The waveguides and gratings are fabricated by direct UV writing in a hydrogenated germanium-doped silica-on-silicon chip. We experimentally demonstrate a polarization extinction ratio per unit length of 0.25 dB mm  with a modelled wavelength dependence smaller than 0.3 dB for a 20 mm device over the C band from 1530-1570 nm. We also present a novel numerical study and analytical description of the architecture that are in good agreement with each other and the experimental data.
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http://dx.doi.org/10.1364/OE.27.011174DOI Listing
April 2019

Variant classification in precision oncology.

Int J Cancer 2019 12 21;145(11):2996-3010. Epub 2019 May 21.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.
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http://dx.doi.org/10.1002/ijc.32358DOI Listing
December 2019

Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.

Nat Commun 2019 04 9;10(1):1635. Epub 2019 Apr 9.

German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
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http://dx.doi.org/10.1038/s41467-019-09633-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456501PMC
April 2019

Response to olaparib in a germline mutated prostate cancer and genetic events associated with resistance.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.
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http://dx.doi.org/10.1101/mcs.a003657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549578PMC
April 2019

Synthetic lethal combinations of low-toxicity drugs for breast cancer identified by genetic screens in yeast.

Oncotarget 2018 Nov 20;9(91):36379-36391. Epub 2018 Nov 20.

Department for Internal Medicine I-Oncology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

In recent years, the concept of synthetic lethality, describing a cellular state where loss of two genes leads to a non-viable phenotype while loss of one gene can be compensated, has emerged as a novel strategy for cancer therapy. Various compounds targeting synthetic lethal pathways are either under clinical investigation or are already routinely used in multiple cancer entities such as breast cancer. Most of them target the well-described synthetic lethal interplay between PARP1 and BRCA1/2. In our study, we investigated, using an methodological approach, clinically utilized drug combinations for breast cancer treatment, by correlating their known molecular targets with known homologous interaction partners that cause synthetic lethality in yeast. Further, by creating a machine-learning algorithm, we were able to suggest novel synthetic lethal drug combinations of low-toxicity drugs in breast cancer and showed their negative effects on cancer cell viability . Our findings foster the understanding of evolutionarily conserved synthetic lethality in breast cancer cells and might lead to new drug combinations with favorable toxicity profile in this entity.
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http://dx.doi.org/10.18632/oncotarget.26372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284748PMC
November 2018

Frequency-banded nonlinear Schrödinger equation with inclusion of Raman nonlinearity.

Opt Express 2018 Aug;26(17):21527-21536

The well-established generalized nonlinear Schrödinger equation (GNLSE) to simulate nonlinear pulse propagation in optical fibers and waveguides becomes inefficient if only narrow spectral bands are occupied that are widely separated in frequency/wavelength, for example in parametric amplifiers. Here we present a solution to this in the form of a coupled frequency-banded nonlinear Schrödinger equation (BNLSE) that only simulates selected narrow frequency bands while still including all dispersive and nonlinear effects, in particular the inter-band Raman and Kerr nonlinearities. This allows for high accuracy spectral resolution in regions of interest while omitting spectral ranges between the selected frequency bands, thus providing an efficient and accurate way for simulating the nonlinear interaction of pulses at widely different carrier frequencies. We derive and test our BNLSE by comparison with the GNLSE. We finally demonstrate the accuracy of the BNLSE and compare the computational execution times for the different models.
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http://dx.doi.org/10.1364/OE.26.021527DOI Listing
August 2018

Prospective Use of High-Refractive Index Materials for Single Molecule Detection in Flow Cytometry.

Sensors (Basel) 2018 Aug 1;18(8). Epub 2018 Aug 1.

Vaccine Branch, Centre for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.

Phenotyping extracellular vesicles (EVs), where surface receptor expression is often as low as one molecule per EV, remains problematic due to the inability of commercial flow cytometers to provide single-fluorescent molecule sensitivity. While EVs are widely considered to be of great potential as diagnostic, prognostic and theranostic biomarkers, their use is currently hindered by the lack of tools available to accurately and reproducibly enumerate and phenotype them. Herein, we propose a new class of labels that leverage the biophysical properties of materials with unique complex refractive indices and demonstrate that this class of labels has the possibility of allowing single-epitope detection using conventional flow cytometry.
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http://dx.doi.org/10.3390/s18082461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111846PMC
August 2018

Fusions in Wild-Type Pancreatic Cancer.

Cancer Discov 2018 09 25;8(9):1087-1095. Epub 2018 May 25.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with wild-type () tumors (4 of 17). These alterations included recurrent rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with -rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as fusions as disease-driving events in tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0036DOI Listing
September 2018

Enabling Stroke Rehabilitation in Home and Community Settings: A Wearable Sensor-Based Approach for Upper-Limb Motor Training.

IEEE J Transl Eng Health Med 2018 2;6:2100411. Epub 2018 May 2.

BioSensicsLLCWatertownMA02472USA.

High-dosage motor practice can significantly contribute to achieving functional recovery after a stroke. Performing rehabilitation exercises at home and using, or attempting to use, the stroke-affected upper limb during Activities of Daily Living (ADL) are effective ways to achieve high-dosage motor practice in stroke survivors. This paper presents a novel technological approach that enables 1) detecting goal-directed upper limb movements during the performance of ADL, so that timely feedback can be provided to encourage the use of the affected limb, and 2) assessing the quality of motor performance during in-home rehabilitation exercises so that appropriate feedback can be generated to promote high-quality exercise. The results herein presented show that it is possible to detect 1) goal-directed movements during the performance of ADL with a [Formula: see text]-statistic of 87.0% and 2) poorly performed movements in selected rehabilitation exercises with an [Formula: see text]-score of 84.3%, thus enabling the generation of appropriate feedback. In a survey to gather preliminary data concerning the clinical adequacy of the proposed approach, 91.7% of occupational therapists demonstrated willingness to use it in their practice, and 88.2% of stroke survivors indicated that they would use it if recommended by their therapist.
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http://dx.doi.org/10.1109/JTEHM.2018.2829208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951609PMC
May 2018

Nonlinear dynamic of picosecond pulse propagation in atmospheric air-filled hollow core fibers.

Opt Express 2018 Apr;26(7):8866-8882

Atmospheric air-filled hollow core (HC) fibers, representing the simplest yet reliable form of gas-filled hollow core fiber, show remarkable nonlinear properties and have several interesting applications such as pulse compression, frequency conversion and supercontinuum generation. Although the propagation of sub-picosecond and few hundred picosecond pulses are well-studied in air-filled fibers, the nonlinear response of air to pulses with a duration of a few picoseconds has interesting features that have not yet been explored fully. Here, we experimentally and theoretically study the nonlinear propagation of ~6 ps pulses in three different types of atmospheric air-filled HC fiber. With this pulse length, we were able to explore different nonlinear characteristics of air at different power levels. Using in-house-fabricated, state-of-the-art HC photonic bandgap, HC tubular and HC Kagomé fibers, we were able to associate the origin of the initial pulse broadening process in these fibers to rotational Raman scattering (RRS) at low power levels. Due to the broadband and low loss transmission window of the HC Kagomé fiber we used, we observed the transition from initial pulse broadening (by RRS) at lower powers, through long-range frequency conversion (2330 cm) with the help of vibrational Raman scattering, to broadband (~700 nm) supercontinuum generation at high power levels. To model such a wide range of nonlinear processes in a unified approach, we have implemented a semi-quantum model for air into the generalized nonlinear Schrodinger equation, which surpasses the limits of the common single damping oscillator model in this pulse length regime. The model has been validated by comparison with experimental results and provides a powerful tool for the design, modeling and optimization of nonlinear processes in air-filled HC fibers.
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http://dx.doi.org/10.1364/OE.26.008866DOI Listing
April 2018

TUSC3: functional duality of a cancer gene.

Cell Mol Life Sci 2018 03 19;75(5):849-857. Epub 2017 Sep 19.

Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 126/3, 625 00, Brno, Czech Republic.

Two decades ago, following a systematic screening of LOH regions on chromosome 8p22, TUSC3 has been identified as a candidate tumor suppressor gene in ovarian, prostate and pancreatic cancers. Since then, a growing body of evidence documented its clinical importance in various other types of cancers, and first initial insights into its molecular function and phenotypic effects have been gained, though the precise role of TUSC3 in different cancers remains unclear. As a part of the oligosaccharyltransferase complex, TUSC3 localizes to the endoplasmic reticulum and functions in final steps of N-glycosylation of proteins, while its loss evokes the unfolded protein response. We are still trying to figure out how this mechanistic function is reconcilable with its varied effects on cancer promotion. In this review, we focus on cancer-related effects of TUSC3 and envisage a possible role of TUSC3 beyond endoplasmic reticulum.
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http://dx.doi.org/10.1007/s00018-017-2660-4DOI Listing
March 2018