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1. Multi-omics analysis of overexpressed tumor-associated proteins: gene expression, immunopeptide presentation, and antibody response in oropharyngeal squamous cell carcinoma, with a focus on cancer-testis antigens

Author: Tsima Abou Kors, Matthias Meier, Lena Mühlenbruch, Annika C. Betzler, Franziska Oliveri, Martin Bens, Jaya Thomas, Johann M. Kraus, Johannes Doescher, Adrian von Witzleben, Linda Hofmann, Jasmin Ezic, Diana Huber, Julian Benckendorff, Thomas F. E. Barth, Jens Greve, Patrick J. Schuler, Cornelia Brunner, Jonathan M. Blackburn, Thomas K. Hoffmann, Christian Ottensmeier, Hans A. Kestler, Hans-Georg Rammensee, Juliane S. Walz, and Simon Laban
Subjects: oropharyngeal squamous cell carcinoma (OPSCC), HLA, cancer testis antigens (CTA), tumor-associated peptide (TAP), antibody response (AR), Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionThe human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets.Materials and methodsSnap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins).Results183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR
Published: 2024
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2. Quantification of human papillomavirus cell-free DNA from low-volume blood plasma samples by digital PCR

Author: Fabian Rosing, Matthias Meier, Lea Schroeder, Simon Laban, Thomas Hoffmann, Andreas Kaufmann, Oliver Siefer, Nora Wuerdemann, Jens Peter Klußmann, Thorsten Rieckmann, Yvonne Alt, Daniel L. Faden, Tim Waterboer, and Daniela Höfler
Subjects: HPV, liquid biopsy, digital PCR, OPC, cfDNA, early detection, Microbiology, QR1-502
Abstract: ABSTRACT The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in countries with high human development index. HPV cell-free DNA (cfDNA) isolated from 3 to 4 mL blood plasma has been successfully used for therapy surveillance. A highly discussed application of HPV-cfDNA is early detection of HPV-OPC. This requires sensitive and specific cfDNA detection as cfDNA levels can be very low. To study the predictive power of pre-diagnostic HPV-cfDNA, archived samples from epidemiological cohorts with limited plasma volume are an important source. To establish a cfDNA detection workflow for low plasma volumes, we compared cfDNA purification methods [MagNA Pure 96 (MP96) and QIAamp ccfDNA/RNA] and digital PCR systems (Biorad QX200 and QIAGEN QIAcuity One). Final assay validation included 65 low-volume plasma samples from oropharyngeal cancer (OPC) patients with defined HPV status stored for 2–9 years. MP96 yielded a 28% higher cfDNA isolation efficiency in comparison to QIAamp. Both digital PCR systems showed comparable analytical sensitivity (6–17 copies for HPV16 and HPV33), but QIAcuity detected both types in the same assay. In the validation set, the assay had 80% sensitivity (n = 28/35) for HPV16 and HPV33 and a specificity of 97% (n = 29/30). In samples with ≥750 µL plasma, the sensitivity was 85% (n = 17/20), while in samples with
Published: 2024
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3. Regional outcome disparities in German head and neck cancer patients: Shorter survival in Eastern Germany

Author: Julius M. Vahl, Gabriele Nagel, Tsima Abou Kors, Matthias Brand, Adrian vonWitzleben, Michael Sonntag, Ayla Grages, Marie N. Theodoraki, Jens Greve, Michael Denkinger, Dhayana Dallmeier, Christian Idel, Stephan Stilgenbauer, Thomas K. Hoffmann, and Simon Laban
Subjects: age, cancer registry data, demographic change, socioeconomic health disparity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Introduction Demographics are important prognostic factors in malignant diseases. A nationwide analysis concerning the prognostic impact of demographics in head and neck cancer (HNC) patients (HNCP) has not been performed previously. Methods A retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) and the Federal Statistical Office (Destatis) between 2002 and 2017 was performed. A total of 212′920 HNCP were included. Incidence, tumor stage, age development, sex distribution, age‐, residence‐, and diagnosis‐time‐specific survival were examined. Results Mean age of HNCP increased more rapidly than in the general population (slope coefficient: 0.29 vs. 0.20; p 70 years was found. Furthermore, an OS disadvantage was observed for East Germany compared to West Germany (median 47 vs. 60 months; p
Published: 2023
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4. Machine Learning-assisted immunophenotyping of peripheral blood identifies innate immune cells as best predictor of response to induction chemo-immunotherapy in head and neck squamous cell carcinoma – knowledge obtained from the CheckRad-CD8 trial

Author: Markus Hecht, Benjamin Frey, Udo S. Gaipl, Xie Tianyu, Markus Eckstein, Anna-Jasmina Donaubauer, Gunther Klautke, Thomas Illmer, Maximilian Fleischmann, Simon Laban, Matthias G. Hautmann, Bálint Tamaskovics, Thomas B. Brunner, Ina Becker, Jian-Guo Zhou, Arndt Hartmann, Rainer Fietkau, Heinrich Iro, Michael Döllinger, Antoniu-Oreste Gostian, and Andreas M. Kist
Subjects: Chemotherapy, Immunotherapy, HNSCC, Induction therapy, Immune phenotyping, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Purpose: Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. Methods: The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. Results: The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. Conclusions: Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC.
Published: 2024
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5. Demographics and access to head and neck cancer care in rural areas compared to urban areas in Germany

Author: Julius M. Vahl, Gabriele Nagel, Ayla Grages, Matthias Brand, Adrian vonWitzleben, Michael Sonntag, Marie‐Nicole Theodoraki, Jens Greve, Tsima Aboukors, Michael Denkinger, Dhayana Dallmeier, Christian Idel, Thomas K. Hoffmann, and Simon Laban
Subjects: demographic change, East Germany, industrial country, peripheral region, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Demographic development in rural and urban areas differs substantially. Demographics and access to specialized head and neck cancer centers may affect head and neck cancer patients' (HNCP) outcomes. Here, we compare epidemiological indicators and outcomes of HNCP in rural and urban Germany. Patients and Methods In a retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) between 2002 and 2017, 212,920 HNCP were included. Incidence, demographics, travel distance to specialized centers, and ground values were compared between rural and urban areas with a focus on their association with patient outcomes. Results The mean age of HNCP was significantly higher in urban areas (mean difference = 1.4 years; p
Published: 2023
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6. Liquid biopsy: an examination of platelet RNA obtained from head and neck squamous cell carcinoma patients for predictive molecular tumor markers

Author: Lisa T. Huber, Johann M. Kraus, Jasmin Ezić, Amin Wanli, Marco Groth, Simon Laban, Thomas K. Hoffmann, Barbara Wollenberg, Hans A. Kestler, and Cornelia Brunner
Subjects: tumor educated platelets, liquid biopsy, head and neck, Internal medicine, RC31-1245
Abstract: Aim: Recently, a tumor cell-platelet interaction was identified in different tumor entities, resulting in a transfer of tumor-derived RNA into platelets, named further “tumor-educated platelets (TEP)”. The present pilot study aims to investigate whether such a tumor-platelet transfer of RNA occurs also in patients suffering from head and neck squamous cell carcinoma (HNSCC). Methods: Sequencing analysis of RNA derived from platelets of tumor patients (TPs) and healthy donors (HDs) were performed. Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for verification of differentially expressed genes in platelets from TPs and HDs in a second cohort of patients and HDs. Data were analyzed by applying bioinformatic tools. Results: Sequencing of RNA derived from the tumor as well as from platelets of TPs and HDs revealed 426 significantly differentially existing RNA, at which 406 RNA were more and 20 RNA less abundant in platelets from TPs in comparison to that of HDs. In TPs’ platelets, abundantly existing RNA coding for 49 genes were detected, characteristically expressed in epithelial cells and RNA, the products of which are involved in tumor progression. Applying bioinformatic tools and verification on a second TP/HD cohort, collagen type I alpha 1 chain (COL1A1) and zinc finger protein 750 (ZNF750) were identified as the strongest potentially platelet-RNA-sequencing (RNA-seq)-based biomarkers for HNSCC. Conclusions: These results indicate a transfer of tumor-derived messenger RNA (mRNA) into platelets of HNSCC patients. Therefore, analyses of a patient’s platelet RNA could be an efficient option for liquid biopsy in order to diagnose HNSCC or to monitor tumorigenesis as well as therapeutic responses at any time and in real time.
Published: 2023
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7. Treatment dependent impact of plasma-derived exosomes from head and neck cancer patients on the epithelial-to-mesenchymal transition

Author: Linda Hofmann, Marie Waizenegger, Ralph Röth, Stefanie Schmitteckert, Daphne Engelhardt, Patrick J. Schuler, Simon Laban, Thomas K. Hoffmann, Cornelia Brunner, and Marie-Nicole Theodoraki
Subjects: exosomes, HNSCC, EMT, conventional therapy, recurrence, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: BackgroundEpithelial to mesenchymal transition (EMT) is a key process in carcinogenesis of head and neck squamous cell carcinoma (HNSCC), contributing to tumor invasiveness, distant metastasis, and recurrence. Exosomes are known mediators and regulators of EMT. Here, we analyze the impact of exosomes that were primed by conventional therapy on EMT modulation.MethodsPlasmas of n = 22 HNSCC patients were collected before and after standard of care surgery and adjuvant or primary (chemo)radiotherapy. Exosomes were isolated by size exclusion chromatography. Upon co-incubation of exosomes with HNSCC cells, the cellular EMT profile was analyzed by flow cytometry and RT-qPCR. Wound healing assays were performed to evaluate migratory potential of exosome-treated cells.ResultsReduction of total exosome protein after therapy and in vitro exosome induced EMT profiles were dependent on the type of treatment. Exosomal TFG-β and miRNA cargo were partly responsible for observed exosome induced EMT changes. Exosomes from recurrent patients induced higher tumor cell migration after therapy than exosomes from disease-free patients.ConclusionsHNSCC patients’ exosomes from timepoints before and after therapy were able to confer therapy induced EMT modulation in vitro and have the potential to monitor the EMT process. Exosome induced changes in migratory potential emerged as discriminants of therapy outcome.
Published: 2023
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8. Influence of Bruton’s Tyrosine Kinase (BTK) on Epithelial–Mesenchymal Transition (EMT) Processes and Cancer Stem Cell (CSC) Enrichment in Head and Neck Squamous Cell Carcinoma (HNSCC)

Author: Franziska Leichtle, Annika C. Betzler, Carlotta Eizenberger, Kristina Lesakova, Jasmin Ezić, Robert Drees, Jens Greve, Patrick J. Schuler, Simon Laban, Thomas K. Hoffmann, Nils Cordes, Marialuisa Lavitrano, Emanuela Grassilli, and Cornelia Brunner
Subjects: BTK, HNSCC, EMT, CSC, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic isoforms of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial–mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC.
Published: 2023
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9. Comparison of plasma- and saliva-derived exosomal miRNA profiles reveals diagnostic potential in head and neck cancer

Author: Linda Hofmann, Tsima Abou Kors, Jasmin Ezić, Beate Niesler, Ralph Röth, Sonja Ludwig, Simon Laban, Patrick J. Schuler, Thomas K. Hoffmann, Cornelia Brunner, Valentin Medyany, and Marie-Nicole Theodoraki
Subjects: exosomes, miRNA, HNSCC, liquid biopsy, plasma, saliva, Biology (General), QH301-705.5
Abstract: Background: Head and neck squamous cell carcinomas (HNSCC) lack tumor-specific biomarkers. Exosomes from HNSCC patients carry immunomodulatory molecules, and correlate with clinical parameters. We compared miRNA profiles of plasma- and saliva-derived exosomes to reveal liquid biomarker candidates for HNSCC.Methods: Exosomes were isolated by differential ultracentrifugation from corresponding plasma and saliva samples from 11 HNSCC patients and five healthy donors (HD). Exosomal miRNA profiles, as determined by nCounter® SPRINT technology, were analyzed regarding their diagnostic and prognostic potential, correlated to clinical data and integrated into network analysis.Results: 119 miRNAs overlapped between plasma- and saliva-derived exosomes of HNSCC patients, from which 29 tumor-exclusive miRNAs, associated with TP53, TGFB1, PRDM1, FOX O 1 and CDH1 signaling, were selected. By intra-correlation of tumor-exclusive miRNAs from plasma and saliva, top 10 miRNA candidates with the strongest correlation emerged as diagnostic panels to discriminate cancer and healthy as well as potentially prognostic panels for disease-free survival (DFS). Further, exosomal miRNAs were differentially represented in human papillomavirus (HPV) positive and negative as well as low and high stage disease.Conclusion: A plasma- and a saliva-derived panel of tumor-exclusive exosomal miRNAs hold great potential as liquid biopsy for discrimination between cancer and healthy as well as HPV status and disease stage. Exosomal miRNAs from both biofluids represent a promising tool for future biomarker studies, emphasizing the possibility to substitute plasma by less-invasive saliva collection.
Published: 2022
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10. Cargo and Functional Profile of Saliva-Derived Exosomes Reveal Biomarkers Specific for Head and Neck Cancer

Author: Linda Hofmann, Valentin Medyany, Jasmin Ezić, Ramin Lotfi, Beate Niesler, Ralph Röth, Daphne Engelhardt, Simon Laban, Patrick J. Schuler, Thomas K. Hoffmann, Cornelia Brunner, Edwin K. Jackson, and Marie-Nicole Theodoraki
Subjects: exosomes, head and neck squamous cell carcinoma (HNSCC), saliva, liquid biopsy, miRNA, Medicine (General), R5-920
Abstract: BackgroundExosomes contribute to immunosuppression in head and neck squamous cell carcinoma (HNSCC), a tumor entity which lacks specific tumor biomarkers. Plasma-derived exosomes from HNSCC patients correlate with clinical parameters and have potential as liquid biopsy. Here, we investigate the cargo and functional profile of saliva-derived exosomes from HNSCC patients and their potential as non-invasive biomarkers for disease detection and immunomodulation.MethodsExosomes were isolated from saliva of HNSCC patients (n = 21) and healthy donors (HD, n = 12) by differential ultracentrifugation. Surface values of immune checkpoints and tumor associated antigens on saliva-derived exosomes were analyzed by bead-based flow cytometry using CD63 capture. Upon co-incubation with saliva-derived exosomes, activity and proliferation of T cells were assessed by flow cytometry (CD69 expression, CFSE assay). Adenosine levels were measured by mass spectrometry after incubation of saliva-derived exosomes with exogenous ATP. miRNA profiling of saliva-derived exosomes was performed using the nCounter® SPRINT system.ResultsSaliva-derived, CD63-captured exosomes from HNSCC patients carried high amounts of CD44v3, PDL1 and CD39. Compared to plasma, saliva was rich in tumor-derived, CD44v3+ exosomes and poor in hematopoietic cell-derived, CD45+ exosomes. CD8+ T cell activity was attenuated by saliva-derived exosomes from HNSCC patients, while proliferation of CD4+ T cells was not affected. Further, saliva-derived exosomes produced high levels of immunosuppressive adenosine. 62 HD- and 31 HNSCC-exclusive miRNAs were identified. Samples were grouped in “Healthy” and “Cancer” based on their saliva-derived exosomal miRNA profile, which was further found to be involved in RAS/MAPK, NF-κB complex, Smad2/3, and IFN-α signaling.ConclusionsSaliva-derived exosomes from HNSCC patients were enriched in tumor-derived exosomes whose cargo and functional profile reflected an immunosuppressive TME. Surface values of CD44v3, PDL1 and CD39 on CD63-captured exosomes, adenosine production and the miRNA cargo of saliva-derived exosomes emerged as discriminators of disease and emphasized their potential as liquid biomarkers specific for HNSCC.
Published: 2022
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11. Changes in Gene Expression Patterns in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma Under Chemoradiotherapy Depend on Response

Author: Johannes Doescher, Adrian von Witzleben, Konstantinos Boukas, Stephanie E. Weissinger, Gareth J. Thomas, Simon Laban, Jaya Thomas, Thomas K. Hoffmann, and Christian H. Ottensmeier
Subjects: head and neck squamous cell carcinoma, chemoradiotherapy, tumor microenvironment, tissue resident memory T cells, gene set enrichment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Chemoradiotherapy (CRT) is a standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Unfortunately, not all patients respond to this therapy and require further treatment, either salvage surgery or palliative therapy. The addition of immunotherapy to CRT is currently being investigated and early results describe a mixed response. Therefore, it is important to understand the impact of CRT on the tumor microenvironment (TME) to be able to interpret the results of the clinical trials. Paired biopsies from 30 HNSCC patients were collected before and three months after completion of primary CRT and interrogated for the expression of 1392 immune- and cancer-related genes. There was a relevant difference in the number of differentially expressed genes between the total cohort and patients with residual disease. Genes involved in T cell activation showed significantly reduced expression in these tumors after therapy. Furthermore, gene enrichment for several T cell subsets confirmed this observation. The analysis of tissue resident memory T cells (TRM) did not show a clear association with impaired response to therapy. CRT seems to lead to a loss of T cells in patients with incomplete response that needs to be reversed. It is not clear whether the addition of anti-PD-1 antibodies alone to CRT can prevent treatment failure, as no upregulation of the targets was measurable in the TME.
Published: 2022
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12. Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (TopROC)

Author: Lara Bußmann, Simon Laban, Claus Wittekindt, Carmen Stromberger, Silke Tribius, Nikolaus Möckelmann, Arne Böttcher, Christian Stephan Betz, Jens Peter Klussmann, Volker Budach, Adrian Muenscher, and Chia-Jung Busch
Subjects: Head and neck cancer, Oropharynx, Radiotherapy, Transoral surgery, Survival, Quality of life, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control. Methods TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1–2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program. Discussion This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine. Trial registration NCT03691441 Registered 1 October 2018 - Retrospectively registered.
Published: 2020
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13. Differential Requirement of Vav Proteins for Btk-dependent and –Independent Signaling During B Cell Development

Author: Annika C. Betzler, Sebastian Kieser, Katja Fiedler, Simon Laban, Marie-Nicole Theodoraki, Patrick J. Schuler, Thomas Wirth, Kerry Tedford, Klaus-Dieter Fischer, Thomas K. Hoffmann, and Cornelia Brunner
Subjects: BTK, bruton’s tyrosine kinase, VAV, B cell development, Ca2+ siganling, secondary lymphoid organs, Biology (General), QH301-705.5
Abstract: Btk and Vav proteins are all components of the signalosome that builds upon B cell receptor (BCR) activation. However, the role of Vav proteins within the signalosome is quite complex and not yet fully understood. Until now, studies of these have focused predominantly on a deficiency of Vav proteins alone or in combination with other Vav protein family members. Since a physical association of Btk with Vav was shown previously, we asked whether these molecules lie in the same or independent signaling pathways. By analyzing Vav1 and Vav3 single knock-out mice and generating double-knock-out animals deficient for either Vav1 or Vav3 and Btk, we observed, in line with previous publications, no severe B cell developmental defects when either Vav1 or Vav3 alone are not expressed. However, a simultaneous deficiency of Btk together with either Vav1 or Vav3 leads to a severe reduction of splenic B cells, which exhibit an immature phenotype. B cell developmental defects of Btk/Vav1-double deficient mice in the periphery were more severe than those observed in Btk-single-deficient animals. Additionally, morphological changes in splenic microarchitecture were observed in double- but also in single-knock-out mutants. These observations were accompanied by reduced BCR-induced Ca2+ mobilization, proliferation, germinal center formation and immunoglobulin secretion. Although deletion of Btk alone impaired Ca2+ mobilization upon BCR activation, the defect was even more severe when Vav1 or Vav3 were also mutated, indicating that Btk and the Vav proteins act in separate pathways that converge on Ca2+ signaling. In vitro ASC differentiation suggests that both B and T cells contribute to the observed phenotype of a Btk/Vav-double deficiency. Our results show that Vav proteins and Btk are both components of the BCR-activated signalosome but control separate signaling pathways important for B cell development.
Published: 2022
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14. Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

Author: Udo S Gaipl, Arndt Hartmann, Jian-Guo Zhou, Benjamin Frey, Markus Eckstein, Markus Hecht, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Matthias G Hautmann, Gunther Klautke, Simon Laban, Axel Hinke, Ina Becker, Sabine Semrau, Panagiotis Balermpas, Wilfried Budach, Heinrich Iro, Rainer Fietkau, Anna-Jasmina Donaubauer, Thomas B Brunner, Bálint Tamaskovics, and Antoniu-Oreste Gostian
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2022
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15. Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma to Individualize Treatment Decisions

Author: Adrian von Witzleben, Urs Müller-Richter, Katja Maurus, Stephanie Brändlein, Marie-Nicole Theodoraki, Cornelia Brunner, Simon Laban, Jochen Lennerz, Peter Möller, Thomas K. Hoffmann, Johannes Doescher, and Patrick J. Schuler
Subjects: head and neck squamous cell carcinoma, immunohistochemistry, targeted therapy, oncopanel, sequencing, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers and patients have limited therapy options if primary treatment fails. Therefore, additional information about the biology of the tumor is essential. Here we performed a feasibility study of concurrently applying two precision diagnostic tools in a consecutive series of HNSCC patients. We analyzed tumor samples of 31 patients using a genomic (oncomine) and a proteomic, immunohistochemical approach (oncopanel) and compared the result, also in the focus on their overlapping therapeutical targets. We found no strong correlation between the two approaches and observed a higher proportion of marker expression for the immunohistochemical panel. However, both panels show in our HNSCC cohort distinct patterns with druggable targets. The data suggest that both approaches complement one another and can be applied side-by-side to identify the best targets for the development of individual treatment options for HNSCC patients.
Published: 2022
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16. Performance of Different Diagnostic PD-L1 Clones in Head and Neck Squamous Cell Carcinoma

Author: Julika Ribbat-Idel, Franz F. Dressler, Rosemarie Krupar, Christian Watermann, Finn-Ole Paulsen, Patrick Kuppler, Luise Klapper, Anne Offermann, Barbara Wollenberg, Dirk Rades, Simon Laban, Markus Reischl, Karl-Ludwig Bruchhage, Christian Idel, and Sven Perner
Subjects: HNSCC, PD-L1, checkpoint inhibitors, TMA, harmonization, therapy prediction, Medicine (General), R5-920
Abstract: Background: The approval of immune checkpoint inhibitors in combination with specific diagnostic biomarkers presents new challenges to pathologists as tumor tissue needs to be tested for expression of programmed death-ligand 1 (PD-L1) for a variety of indications. As there is currently no requirement to use companion diagnostic assays for PD-L1 testing in Germany different clones are used in daily routine. While the correlation of staining results has been tested in various entities, there is no data for head and neck squamous cell carcinomas (HNSCC) so far.Methods: We tested five different PD-L1 clones (SP263, SP142, E1L3N, 22-8, 22C3) on primary HNSCC tumor tissue of 75 patients in the form of tissue microarrays. Stainings of both immune and tumor cells were then assessed and quantified by pathologists to simulate real-world routine diagnostics. The results were analyzed descriptively and the resulting staining pattern across patients was further investigated by principal component analysis and non-negative matrix factorization clustering.Results: Percentages of positive immune and tumor cells varied greatly. Both the resulting combined positive score as well as the eligibility for certain checkpoint inhibitor regimens was therefore strongly dependent on the choice of the antibody. No relevant co-clustering and low similarity of relative staining patterns across patients was found for the different antibodies.Conclusions: Performance of different diagnostic anti PD-L1 antibody clones in HNSCC is less robust and interchangeable compared to reported data from other tumor entities. Determination of PD-L1 expression is critical for therapeutic decision making and may be aided by back-to-back testing of different PD-L1 clones.
Published: 2021
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17. Correlation of HPV16 Gene Status and Gene Expression With Antibody Seropositivity and TIL Status in OPSCC

Author: Adrian von Witzleben, Eve Currall, Oliver Wood, Lindsey Chudley, Oluyemisi Akinyegun, Jaya Thomas, Kaïdre Bendjama, Gareth J. Thomas, Peter S. Friedmann, Emma V. King, Simon Laban, and Christian H. Ottensmeier
Subjects: oropharyngeal squamous cell carcinoma, human papillomavirus 16, antibody isotype, gene expression, immune response, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: IntroductionHuman papillomavirus 16 (HPV16) is the main cause of oropharyngeal squamous cell carcinoma (OPSCC). To date, the links between HPV16 gene expression and adaptive immune responses have not been investigated. We evaluated the correlation of HPV16 DNA, RNA transcripts and features of adaptive immune response by evaluating antibody isotypes against E2, E7 antigens and density of tumor-infiltrating lymphocytes (TIL).Material and MethodsFFPE-tissue from 27/77 p16-positive OPSCC patients was available. DNA and RNA were extracted and quantified using qPCR for all HPV16 genes. The TIL status was assessed. Immune responses against E2 and E7 were quantified by ELISA (IgG, IgA, and IgM; 77 serum samples pre-treatment, 36 matched post-treatment).ResultsAmounts of HPV16 genes were highly correlated at DNA and RNA levels. RNA co-expression of all genes was detected in 37% (7/19). E7 qPCR results were correlated with higher anti-E7 antibody (IgG, IgA) level in the blood. Patients with high anti-E2 IgG antibody (>median) had better overall survival (p=0.0311); anti-E2 and anti-E7 IgA levels had no detectable effect. During the first 6 months after treatment, IgA but not IgG increased significantly, and >6 months both antibody classes declined over time. Patients with immune cell-rich tumors had higher levels of circulating antibodies against HPV antigens.ConclusionWe describe an HPV16 qPCR assay to quantify genomic and transcriptomic expression and correlate this with serum antibody levels against HPV16 oncoproteins. Understanding DNA/RNA expression, relationship to the antibody response in patients regarding treatment and outcome offers an attractive tool to improve patient care.
Published: 2021
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18. Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Author: Udo S Gaipl, Carol I Geppert, Arndt Hartmann, Benjamin Frey, Markus Eckstein, Markus Hecht, Antoniu Oreste Gostian, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Matthias G Hautmann, Gunther Klautke, Simon Laban, Thomas Brunner, Axel Hinke, Ina Becker, Sabine Semrau, Panagiotis Balermpas, Wilfried Budach, Heinrich Iro, and Rainer Fietkau
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background To determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.Methods Patients received a single cycle of cisplatin 30 mg/m² on days 1–3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.Results A total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3–4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3–4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.Conclusions Single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.
Published: 2020
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19. Characterization and Differentiation of the Tumor Microenvironment (TME) of Orthotopic and Subcutaneously Grown Head and Neck Squamous Cell Carcinoma (HNSCC) in Immunocompetent Mice

Author: Matthias Brand, Simon Laban, Marie-Nicole Theodoraki, Johannes Doescher, Thomas K. Hoffmann, Patrick J. Schuler, and Cornelia Brunner
Subjects: tumor microenvironment, head and neck cancer, SCC VII orthotopic mouse model, SCC VII subcutaneous mouse model, regulatory B cells, CD4+ T cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: For the development and evaluation of new head and neck squamous cell carcinoma (HNSCC) therapeutics, suitable, well-characterized animal models are needed. Thus, by analyzing orthotopic versus subcutaneous models of HNSCC in immunocompetent mice, we evaluated the existence of adenosine-related immunosuppressive B- and T lymphocyte populations within the tumor microenvironment (TME). Applying the SCC VII model for the induction of HNSCC in immunocompetent C3H/HeN mice, the cellular TME was characterized after tumor initiation over time by flow cytometry. The TME in orthotopic grown tumors revealed a larger population of tumor-infiltrating lymphocytes (TIL) with more B cells and CD4+ T cells than the subcutaneously grown tumors. Immune cell populations in the blood and bone marrow showed a rather distinct reaction toward tumor induction and tumor location compared to the spleen, lymph nodes, or thymus. In addition, large numbers of immunosuppressive B- and T cells were identified within the TME but also in secondary lymphoid organs, independently of the tumor initiation site. The altered immunogenic TME may influence the response to any treatment attempt. Moreover, when analyzing the TME and other lymphoid organs of tumor-bearing mice, we observed conditions reflecting largely those of patients suffering from HNSCC suggesting the C3H/HeN mouse model as a suitable tool for studies aiming to target immunosuppression to improve anti-cancer therapies.
Published: 2020
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20. HNSCC: Tumour Antigens and Their Targeting by Immunotherapy

Author: Adrian von Witzleben, Chuan Wang, Simon Laban, Natalia Savelyeva, and Christian H. Ottensmeier
Subjects: HNSCC, cancer antigens, cancer testis antigens, viral antigens, HPV, Cytology, QH573-671
Abstract: Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.
Published: 2020
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21. Peripheral Cytokine Levels Differ by HPV Status and Change Treatment-Dependently in Patients with Head and Neck Squamous Cell Carcinoma

Author: Daphne Mytilineos, Jasmin Ezić, Adrian von Witzleben, Joannis Mytilineos, Ramin Lotfi, Daniel Fürst, Chrysanthi Tsamadou, Marie-Nicole Theodoraki, Angelika Oster, Gunnar Völkel, Hans A. Kestler, Cornelia Brunner, Patrick J. Schuler, Johannes Doescher, Thomas K. Hoffmann, and Simon Laban
Subjects: cytokines, head and neck cancer, human papillomavirus (HPV), longitudinal study, Fas, perforin, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion.
Published: 2020
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22. Immune Checkpoint Expression on Immune Cells of HNSCC Patients and Modulation by Chemo- and Immunotherapy

Author: Lisa K. Puntigam, Sandra S. Jeske, Marlies Götz, Jochen Greiner, Simon Laban, Marie-Nicole Theodoraki, Johannes Doescher, Stephanie E. Weissinger, Cornelia Brunner, Thomas K. Hoffmann, and Patrick J. Schuler
Subjects: HNSCC, head and neck cancer, immunotherapy, immune checkpoints, checkpoint inhibitors, immunomodulation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were isolated from head and neck squamous cell carcinoma (HNSCC) patients (n = 23) and compared to healthy donors (n = 23). Immune checkpoint expression (programmed cell death ligand 1 (PD-1), tumor necrosis factor receptor (TNFR)-related (GITR), CD137, tumor necrosis factor receptor superfamily member 4 (TNFRSF4) (OX40), t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG3)) was determined on immune cells by flow cytometry. PD-L1 expression was detected on tumor tissue by immunohistochemistry. Immune cells were treated with immuno- and chemotherapeutics to investigate treatment-specific change in immune checkpoint expression, in vitro. Specific changes of immune checkpoint expression were identified on PBL and TIL of HNSCC patients compared to healthy donors. Various chemotherapeutics acted differently on the expression of immune checkpoints. Changes of checkpoint expression were significantly less pronounced on regulatory T cells compared to other lymphocyte populations. Nivolumab treatment significantly reduced the receptor PD-1 on all analyzed T cell populations, in vitro. The specific immune checkpoint expression patterns in HNSCC patients and the investigated effects of immunomodulatory agents may improve the development and efficacy of targeted immunotherapy.
Published: 2020
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23. NF-κB and Its Role in Checkpoint Control

Author: Annika C. Betzler, Marie-Nicole Theodoraki, Patrick J. Schuler, Johannes Döscher, Simon Laban, Thomas K. Hoffmann, and Cornelia Brunner
Subjects: NF-κB, immune checkpoint expression, PD-L1, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade.
Published: 2020
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24. The HLA ligandome of oropharyngeal squamous cell carcinomas reveals shared tumour-exclusive peptides for semi-personalised vaccination

Author: Lena Mühlenbruch, Tsima Abou-Kors, Marissa L. Dubbelaar, Leon Bichmann, Oliver Kohlbacher, Martin Bens, Jaya Thomas, Jasmin Ezić, Johann M. Kraus, Hans A. Kestler, Adrian von Witzleben, Joannis Mytilineos, Daniel Fürst, Daphne Engelhardt, Johannes Doescher, Jens Greve, Patrick J. Schuler, Marie-Nicole Theodoraki, Cornelia Brunner, Thomas K. Hoffmann, Hans-Georg Rammensee, Juliane S. Walz, and Simon Laban
Subjects: Cancer Research, Oncology
Abstract: Background The immune peptidome of OPSCC has not previously been studied. Cancer-antigen specific vaccination may improve clinical outcome and efficacy of immune checkpoint inhibitors such as PD1/PD-L1 antibodies. Methods Mapping of the OPSCC HLA ligandome was performed by mass spectrometry (MS) based analysis of naturally presented HLA ligands isolated from tumour tissue samples (n = 40) using immunoaffinity purification. The cohort included 22 HPV-positive (primarily HPV-16) and 18 HPV-negative samples. A benign reference dataset comprised of the HLA ligandomes of benign haematological and tissue datasets was used to identify tumour-associated antigens. Results MS analysis led to the identification of naturally HLA-presented peptides in OPSCC tumour tissue. In total, 22,769 peptides from 9485 source proteins were detected on HLA class I. For HLA class II, 15,203 peptides from 4634 source proteins were discovered. By comparative profiling against the benign HLA ligandomic datasets, 29 OPSCC-associated HLA class I ligands covering 11 different HLA allotypes and nine HLA class II ligands were selected to create a peptide warehouse. Conclusion Tumour-associated peptides are HLA-presented on the cell surfaces of OPSCCs. The established warehouse of OPSCC-associated peptides can be used for downstream immunogenicity testing and peptide-based immunotherapy in (semi)personalised strategies.
Published: 2023

25. Supplementary Figure Legends from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

Author: Mascha Binder, Carsten Bokemeyer, Sonja Loges, Boris Fehse, Kristoffer Riecken, Rainald Knecht, Martin Trepel, Bruno Märkl, Elzbieta Jakubowicz, Steffen Goletz, Antje Danielczyk, Simon Laban, Ingke Braren, Isabel Ben Batalla, Anja Thalhammer, Markus Sack, Veronique Blanchard, Karina Biskup, Tobias Grob, Beate Habel, Minna Voigtlaender, Malte Kriegs, and Friederike Braig
Abstract: Supplementary Figure 1. Inhibitory effect of Cetuximab determined by western blot analysis of 12 HNSCC cell line lysates. Supplementary Figure 2. Time course of EGFR phosphorylation in HNSCC cell line UT-SCC 8. Supplementary Figure 3. Correlation of total and membrane exposed EGFR in HNSCC cell lines. Supplementary Figure 4. IL-3 dependent Ba/F3 cells can be transformed to EGF dependence by stable transduction with EGFR and EGFRK521 genes. Supplementary Figure 5. Far-UV CD spectra of Fc-EGFR and Fc-EGFRK521. Supplementary Figure 6. ADCC induction in EGFR-transduced Ba/F3 cells by Cetuximab and CetuGEX{trade mark, serif}.
Published: 2023

26. Supplementary Figure S3 from Antibody Responses to Cancer Antigens Identify Patients with a Poor Prognosis among HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma Patients

Author: Julia Butt, Tim Waterboer, Michael Pawlita, Thomas K. Hoffmann, Johannes Doescher, Marie-Nicole Theodoraki, Marlene C. Wigand, Patrick J. Schuler, Cornelia Brunner, Hans A. Kestler, Gunnar Völkel, Johann M. Kraus, Peter Möller, Ralf Marienfeld, Jasmin Ezić, Paolo Boscolo-Rizzo, Gerhard Dyckhoff, Christel C. Herold-Mende, Martina A. Broglie, Andreas Dietz, Gunnar Wichmann, Dirk Jäger, Inka Zörnig, Stefan B. Eichmüller, Lea Schroeder, Dana Holzinger, Dominik S. Gangkofner, and Simon Laban
Abstract: Overall survival by HPV-status. Overall survival stratified by HPV-status based on A) molecular HPV-status, B) seropositivity to HPV-16 E6, C) seropositivity to any high-risk HPV-types and D) by molecular HPV-status if available and seropositivity to any high-risk HPV-types if molecular HPV-status was unavailable. Overall survival was significantly longer regardless of the definition of HPV-status (p
Published: 2023

27. Supplementary Table 1 and 2 from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

Author: Mascha Binder, Carsten Bokemeyer, Sonja Loges, Boris Fehse, Kristoffer Riecken, Rainald Knecht, Martin Trepel, Bruno Märkl, Elzbieta Jakubowicz, Steffen Goletz, Antje Danielczyk, Simon Laban, Ingke Braren, Isabel Ben Batalla, Anja Thalhammer, Markus Sack, Veronique Blanchard, Karina Biskup, Tobias Grob, Beate Habel, Minna Voigtlaender, Malte Kriegs, and Friederike Braig
Abstract: Supplementary Table 1 Patient characteristics including EGFRK521 allele frequency. Supplementary Table 2 Characteristics and sequencing data of squamous cell carcinoma cell lines.
Published: 2023

28. Supplementary Table S1 from Antibody Responses to Cancer Antigens Identify Patients with a Poor Prognosis among HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma Patients

Author: Julia Butt, Tim Waterboer, Michael Pawlita, Thomas K. Hoffmann, Johannes Doescher, Marie-Nicole Theodoraki, Marlene C. Wigand, Patrick J. Schuler, Cornelia Brunner, Hans A. Kestler, Gunnar Völkel, Johann M. Kraus, Peter Möller, Ralf Marienfeld, Jasmin Ezić, Paolo Boscolo-Rizzo, Gerhard Dyckhoff, Christel C. Herold-Mende, Martina A. Broglie, Andreas Dietz, Gunnar Wichmann, Dirk Jäger, Inka Zörnig, Stefan B. Eichmüller, Lea Schroeder, Dana Holzinger, Dominik S. Gangkofner, and Simon Laban
Abstract: Patient characteristics (non-oropharyngeal patients)
Published: 2023

29. Supplemental Figures 1 to 6 from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

Author: Mascha Binder, Carsten Bokemeyer, Sonja Loges, Boris Fehse, Kristoffer Riecken, Rainald Knecht, Martin Trepel, Bruno Märkl, Elzbieta Jakubowicz, Steffen Goletz, Antje Danielczyk, Simon Laban, Ingke Braren, Isabel Ben Batalla, Anja Thalhammer, Markus Sack, Veronique Blanchard, Karina Biskup, Tobias Grob, Beate Habel, Minna Voigtlaender, Malte Kriegs, and Friederike Braig
Abstract: Supplemental Figures 1 to 6 from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism
Published: 2023

30. Data from Antibody Responses to Cancer Antigens Identify Patients with a Poor Prognosis among HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma Patients

Author: Julia Butt, Tim Waterboer, Michael Pawlita, Thomas K. Hoffmann, Johannes Doescher, Marie-Nicole Theodoraki, Marlene C. Wigand, Patrick J. Schuler, Cornelia Brunner, Hans A. Kestler, Gunnar Völkel, Johann M. Kraus, Peter Möller, Ralf Marienfeld, Jasmin Ezić, Paolo Boscolo-Rizzo, Gerhard Dyckhoff, Christel C. Herold-Mende, Martina A. Broglie, Andreas Dietz, Gunnar Wichmann, Dirk Jäger, Inka Zörnig, Stefan B. Eichmüller, Lea Schroeder, Dana Holzinger, Dominik S. Gangkofner, and Simon Laban
Abstract: Purpose:The identification of high-risk patients within human papillomavirus (HPV)-positive and -negative head and neck squamous cell carcinoma (HNSCC) is needed for improved treatment and surveillance strategies. In this study, we set out to discover antibody responses (AR) with prognostic impact in HNSCC stratified by HPV status.Experimental Design:A fluorescent bead–based multiplex serology assay on 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens, and 8 oncogenes) and 29 HPV antigens was performed in samples of 362 patients with HNSCC from five independent cohorts (153 HPV positive, 209 HPV negative). A multivariable Cox proportional hazard model with bootstrapping (M = 1000) was used for validation of prognostic antibody responses.Results:Antibody response to any of the cancer antigens was found in 257 of 362 patients (71%). In HPV-negative patients, antibody responses to c-myc, MAGE-A1, -A4, and Rhodopsin E2 (combined as ARhigh risk) were significantly associated with shorter overall survival. In HPV-positive patients, antibody responses to IMP-1 were discovered as a negative prognostic factor. ARhigh risk (HR = 1.76) and antibody responses to IMP-1 (HR = 3.28) were confirmed as independent markers for a poor prognosis in a multivariable Cox proportional hazard model with bootstrapping (M = 1000).Conclusions:We identified antibody responses to cancer antigens that associate with a dismal prognosis in patients with HNSCC beyond HPV-positive status. ARhigh risk may be used to detect HPV-negative patients with an extraordinarily bad prognosis. Most importantly, antibody response to IMP-1 may serve as a marker for a subgroup of HPV-positive patients who present with a poor prognosis similar to that in HPV-negative patients.
Published: 2023

31. Data from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

Author: Mascha Binder, Carsten Bokemeyer, Sonja Loges, Boris Fehse, Kristoffer Riecken, Rainald Knecht, Martin Trepel, Bruno Märkl, Elzbieta Jakubowicz, Steffen Goletz, Antje Danielczyk, Simon Laban, Ingke Braren, Isabel Ben Batalla, Anja Thalhammer, Markus Sack, Veronique Blanchard, Karina Biskup, Tobias Grob, Beate Habel, Minna Voigtlaender, Malte Kriegs, and Friederike Braig
Abstract: Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188–99. ©2016 AACR.
Published: 2023

32. BTK Isoforms p80 and p65 Are Expressed in Head and Neck Squamous Cell Carcinoma (HNSCC) and Involved in Tumor Progression

Author: Annika C. Betzler, Hannah Strobel, Tsima Abou Kors, Jasmin Ezić, Kristina Lesakova, Ronja Pscheid, Ninel Azoitei, Johanna Sporleder, Anna-Rebekka Staufenberg, Robert Drees, Stephanie E. Weissinger, Jens Greve, Johannes Doescher, Marie-Nicole Theodoraki, Patrick J. Schuler, Simon Laban, Toshiro Kibe, Michiko Kishida, Shosei Kishida, Christian Idel, Thomas K. Hoffmann, Marialuisa Lavitrano, Emanuela Grassilli, Cornelia Brunner, Betzler, A, Strobel, H, Abou Kors, T, Ezić, J, Lesakova, K, Pscheid, R, Azoitei, N, Sporleder, J, Staufenberg, A, Drees, R, Weissinger, S, Greve, J, Doescher, J, Theodoraki, M, Schuler, P, Laban, S, Kibe, T, Kishida, M, Kishida, S, Idel, C, Hoffmann, T, Lavitrano, M, Grassilli, E, and Brunner, C
Subjects: AVL-292, Cancer Research, Oncology, BTK, ibrutinib, head and neck cancer, ddc:610
Abstract: Here, we describe the expression of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC) cell lines as well as in primary HNSCC samples. BTK is a kinase initially thought to be expressed exclusively in cells of hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, particularly in B cells, we identified the 80 kDa and 65 kDa BTK isoforms in HNSCC, recently described as oncogenic. Importantly, we revealed that both isoforms are products of the same mRNA. By investigating the mechanism regulating oncogenic BTK-p80/p65 expression in HNSSC versus healthy or benign tissues, our data suggests that the epigenetic process of methylation might be responsible for the initiation of BTK-p80/p65 expression in HNSCC. Our findings demonstrate that chemical or genetic abrogation of BTK activity leads to inhibition of tumor progression in terms of proliferation and vascularization in vitro and in vivo. These observations were associated with cell cycle arrest and increased apoptosis and autophagy. Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients.
Published: 2023

33. Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients

Author: Ramin Lotfi, Theresa L. Whiteside, Cornelia Brunner, Simon Laban, Patrick J. Schuler, M-N Theodoraki, Tk. Hoffmann, Linda Hofmann, and Edwin K. Jackson
Subjects: Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, T cell, Early detection, Exosomes, Exosome, Article, Flow cytometry, medicine, Humans, Head and neck cancer, Early Detection of Cancer, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, Adenosine, Microvesicles, Surgery, medicine.anatomical_structure, Oncology, Head and Neck Neoplasms, Tumour immunology, Female, business, Adjuvant, medicine.drug
Abstract: Background Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. Methods Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. Results TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. Conclusions Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.
Published: 2021

34. Influence of travel burden on tumor classification and survival of head and neck cancer patients

Author: M-N Theodoraki, M Brand, A von Witzleben, Claudia Welke, Pj. Schuler, Tk. Hoffmann, J M Vahl, Johannes Doescher, Jens Greve, and Simon Laban
Subjects: medicine.medical_specialty, Pediatrics, Telemedicine, business.industry, Head and neck cancer, Cancer, General Medicine, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Otorhinolaryngology, Kilometer, 030220 oncology & carcinogenesis, Health care, Medicine, ddc:610, Neurosurgery, 030223 otorhinolaryngology, business, Psychosocial
Abstract: Cancer patients have to overcome various barriers to obtain diagnostics and treatment at head and neck cancer centers. Travel distance to a specialized hospital may result in psychosocial and financial distress, thus interfering with diagnostics, treatment, and follow-up care. In this study, we have aimed to analyze the association of travel distance with cTNM status, UICC stage at primary diagnosis, and survival outcomes of head and neck cancer (HNC) patients. We have analyzed data of 1921 consecutive HNC patients diagnosed between 2014 and 2019 at the head and neck cancer center of the Comprehensive Cancer Center Ulm (CCCU), Germany. Postal code-based travel distance calculation in kilometers, TNM status, and UICC stage were recorded at initial diagnosis. The assembly of travel distance-related groups (short, intermediate, long-distance) has been investigated. Moreover, group-related survival and recurrence analysis have been performed. In contrast to observations from overseas, no association of travel distance and higher cTNM status or UICC stage at primary diagnosis has been observed. Furthermore, no significant differences for recurrence-free survival and overall survival by travel distance were detected. In southern Germany, travel distance to head and neck cancer centers seems to be tolerable. Travel burden is not synonymous with travel distance alone but also involves sociodemographic, monetary, and disease-specific aspects as well as accessibility to proper infrastructure of transport and health care system.
Published: 2021

35. Occult lymph node metastases rate in sinonasal carcinoma

Author: Johannes Döscher, Charlotte Voigt, Patrick Schuler, Fabian Sommer, Simon Laban, Thomas Karl Hoffmann, and Marc Scheithauer
Published: 2022

36. Therapie fortgeschrittener Kopf-Hals-Karzinome mit Doppel-Checkpoint-Blockade gefolgt von Radioimmuntherapie – Ergebnisse der CheckRad-CD8 -Studie

Author: Antoniu-Oreste Gostian, Markus Eckstein, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Matthias G. Hautmann, Thomas B. Brunner, Simon Laban, Gunther Klautke, Balint Tamaskovics, Benjamin Frey, Arndt Hartmann, Wilfried Budach, Udo Gaipl, Heinrich Iro, Rainer Fietkau, and Markus Hecht
Published: 2022

37. The influence of immune checkpoint inhibitors on anti-tumor immunity in head and neck cancer

Author: Lisa Katharina Puntigam, Marlies Götz, Jochen Greiner, Marie-Nicole Theodoraki, Adrian von Witzleben, Simon Laban, Johannes Döscher, Cornelia Brunner, Thomas K. Hoffmann, and Patrick J. Schuler
Published: 2022

38. Rate okkulter Lymphknotenmetastasen bei sinunasalen Karzinomen

Author: Johannes Döscher, Charlotte Voigt, Patrick Schuler, Fabian Sommer, Simon Laban, Thomas Karl Hoffmann, and Marc Scheithauer
Published: 2022

39. Notfalldiagnosen in der Hals-Nasen-Ohrenheilkunde – eine retrospektive Auswertung über 72 Monate

Author: Janina Hahn, Robin Lochbaum, Siegfried Tewes, Simon Laban, Thomas Hoffmann, and Jens Greve
Published: 2022

40. Identification of a predictive marker signature for diagnosing HNSCC based on platelet RNAseq

Author: Cornelia Brunner, Lisa T. Huber, Johann M. Kraus, Jasmin Esic, Amin Wanli, Marco Groth, Simon Laban, Barbara Wollenberg, Hans A. Kestler, and Thomas K. Hoffmann
Published: 2022

41. Gewebsansässige Gedächtnis-T-Zellen (TRM) in primärem, metastasiertem und rezidivierendem Plattenepithelkarzinom des Kopfes und Halses (HNSCC)

Author: Adrian von Witzleben, Matthew Ellis, Gareth J. Thomas, Thomas K. Hoffmann, Simon Laban, and Christian H Ottensmeier
Published: 2022

42. Centralization, Specialization, and Outpatient Care for Head and Neck Tumor Patients – Challenges for Patients and Physicians

Author: Julius Malte Vahl, Felix Böhm, Matthias Brand, Adrian von Witzleben, Thomas Hoffmann, and Simon Laban
Published: 2022

43. Der Einfluss von Immun-Checkpoint-Inhibitoren auf die anti-Tumor-Immunität in Kopf-Hals-Tumoren

Author: Lisa Katharina Puntigam, Marlies Götz, Jochen Greiner, Marie-Nicole Theodoraki, Adrian von Witzleben, Simon Laban, Johannes Döscher, Cornelia Brunner, Thomas K. Hoffmann, and Patrick J. Schuler
Published: 2022

44. Tissue resident memory T cells (TRM) in primary, metastatic and recurrent head and neck squamous cell carcinoma (HNSCC) tissue

Author: Adrian von Witzleben, Matthew Ellis, Gareth J Thomas, Thomas K. Hoffmann, Simon Laban, and Christian H. Ottensmeier
Published: 2022

45. Zentralisierung, Spezialisierung und Ambulantisierung der Versorgung von Kopf-Hals-Tumorpatienten – Herausforderungen für Patienten und Ärzte

Author: Julius Malte Vahl, Felix Böhm, Matthias Brand, Adrian von Witzleben, Thomas Hoffmann, and Simon Laban
Published: 2022

46. Immune-mediated adverse events and their clinical management in head and neck cancer patients under anti-PD-1/PD-L1 immunotherapy

Author: Matthias Brand, Adrian von Witzleben, Julius Vahl, Johannes Döscher, Marie-Nicole Theodoraki, Thomas K. Hoffmann, and Simon Laban
Published: 2022

47. Immunvermittelte Arzneimittelwirkungen und deren klinisches Management bei Kopf-Hals-Tumorpatienten mit einer anti-PD-1/PD-L1 Immuntherapie

Author: Matthias Brand, Adrian von Witzleben, Julius Vahl, Johannes Döscher, Marie-Nicole Theodoraki, Thomas K. Hoffmann, and Simon Laban
Published: 2022

48. Therapy of advanced head and neck cancer with double checkpoint blockade followed by radioimmunotherapy – results of the CheckRad-CD8 study

Author: Antoniu-Oreste Gostian, Markus Eckstein, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Matthias G. Hautmann, Thomas B. Brunner, Simon Laban, Gunther Klautke, Balint Tamaskovics, Benjamin Frey, Arndt Hartmann, Wilfried Budach, Udo Gaipl, Heinrich Iro, Rainer Fietkau, and Markus Hecht
Published: 2022

49. Emergencies in Otorhinolaryngology – a 72-month retrospective Analysis

Author: Janina Hahn, Robin Lochbaum, Siegfried Tewes, Simon Laban, Thomas Hoffmann, and Jens Greve
Published: 2022

50. Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study

Author: Dmitri Nepogodiev, Joana Ff Simoes, Elizabeth Li, Maria Picciochi, James C Glasbey, Glauco Baiocchi, Ruth Blanco-Colino, Daoud Chaudhry, Ehab AlAmeer, Kariem El-Boghdadly, Funmilola Wuraola, Dhruva Ghosh, Rohan R Gujjuri, Ewen M Harrison, Herman Lule, Haytham Kaafarani, Mohammad Khosravi, Irmgard Kronberger, Sezai Leventoğlu, Harvinder Mann, Kenneth A Mclean, Mengistu Gebreyohanes Mengesha, Maria Marta Modolo, Faustin Ntirenganya, Lisa Norman, Oumaima Outani, Riinu Pius, Peter Pockney, Ahmad Uzair Qureshi, April Camilla Roslani, Sohei Satoi, Catherine Shaw, Aneel Bhangu, Omar M Omar, Waheed-Ul-Rahman Ahmed, Leah Argus, Alasdair Ball, Edward P Bywater, Amanpreet Brar, Brett E Dawson, Irani Duran, Muhammed Elhadi, Conor S Jones, Sivesh K Kamarajah, James M Keatley, Samuel Lawday, Ella J Marson, Riinu Ots, Irène Santos, Elliott H Taylor, Isobel M Trout, Chris Varghese, Mary L Venn, William Xu, Irida Dajti, Arben Gjata, Salah Eddine Oussama Kacimi, Luis Boccalatte, Daniel Cox, Philip Townend, Felix Aigner, Irmgard Elisabeth Kronberger, Elgun Samadov, Amer Alderazi, Kamral Hossain, Greg Padmore, Gabrielle van Ramshorst, Ismaïl Lawani, Anis Cerovac, Samir Delibegovic, Gustavo Mendonça Ataíde Gomes, Igor Lima Buarque, Muhammad Gohar, Mihail Slavchev, Chukwuemeka Nwegbu, Arnav Agarwal, Janet Martin, Joshua Ng-Kamstra, Maricarmen Olivos, Wenhui Lou, Dong-Lin Ren, Jose Andres Calvache, Carlos J Perez Rivera, Ana Danic Hadzibegovic, Tomislav Kopjar, Jakov Mihanovic, Pablo Mijahil Avilés Jiménez, Nikolaos Gouvas, Jaroslav Klat, René Novysedlák, Nicolas Amisi, Peter Christensen, Alaa El-Hussuna, Sylvia Batista, Eddy Lincango-Naranjo, Sameh Emile, Danilo Alfonso Arévalo Sandoval, Hailu Dhufera, Samuel Hailu, Mengistu G Mengesha, Joonas H Kauppila, Alexis P Arnaud, Zaza Demetrashvili, Markus Albertsmeier, Hans Lederhuber, Markus W Löffler, Daniel Kwesi Acquah, Bernard Ofori, Stephen Tabiri, Symeon Metallidis, Georgios Tsoulfas, Maria-Lorena Aguilera-Arevalo, Gustavo Recinos, Tamás Mersich, Dániel Wettstein, Gabriele Kembuan, Peiman Brouki Milan, Mohammad Hossein Khosravi, Masoud Mozafari, Ahmed Hilmi, Helen Mohan, Oded Zmora, Gaetano Gallo, Francesco Pata, Gianluca Pellino, Yuki Fujimoto, Naoto Kuroda, Mohamad K Abou Chaar, Faris Ayasra, Ildar Fakhradiyev, Intisar Hisham Said Hamdun, Jang Jin-Young, Mohammad Jamal, Lina Karout, Aiste Gulla, Fanjandrainy Rasoaherinomenjanahary, Luc Hervé Samison, Iran Irani Durán Sánchez, Diana Samantha Gonzalez, Laura Martinez, María José Martínez, Alejandra Nayen, Antonio Ramos-De la Medina, Jade Nunez, Pueya Rashid Nashidengo, Rakesh Shah, Ashish Lal Shrestha, Pascal Jonker, Schelto Kruijff, Milou Noltes, Pieter Steinkamp, Deborah Wright, Lukman Abdur-Rahman, Adesoji Ademuyiwa, Adewale Adisa, Babatunde Osinaike, Justina Seyi-Olajide, Omolara Williams, Emmanuel Williams, Sofija Pejkova, Zainab Al Balushi, Raza Sayyed, Mustafa Abo Mohsen, Sadi A Abukhalaf, Moises Cukier, Hugo Gomez-Fernandez, Sebastian Shu Yip, Ximena Paola Vasquez Ojeda, Marie Dione Sacdalan, Piotr Major, José Azevedo, Miguel F Cunha, Ahmad Zarour, Eduard-Alexandru Bonci, Ionut Negoi, Sergey Efetov, Viktor Kochetkov, Andrey Litvin, Jc Allen Ingabire, Georges Bucyibaruta, Ntirenganya Faustin, Sosthene Habumuremyi, Alphonsine Imanishimwe, Haragirimana Jean de Dieu, Emmanuel Munyaneza, Isaie Ncogoza, Ehab Alameer, Abdourahmane Ndong, Dejan Radenkovic, Min Hoe Chew, Frederick Koh, James Ngu, Arpád Panyko, Uros Bele, Jurij Aleš Košir, Hassan Daoud, Ana Maria Minaya Bravo, Umesh Jayarajah, Dakshitha Wickramasinghe, Mohammed Elmujtba Adam Essa Adam, Martin Rutegård, Malin Sund, Michel Adamina, Eleftherios Gialamas, Karoline Horisberger, Muhammad Alshaar, Abel Huang, Varut Lohsiriwat, Shane Charles, Haithem Jlassi, Arda Isik, Hervé Monka Lekuya, Slava Kopetskyi, Hayder Alsaadi, Sattar Alshryda, Osaid Alser, Brittany Bankhead-Kendall, Kerry Breen, Hassan Mashbari, Fernando Bonilla Cal, Hamza Al-Naggar, Mayaba Maimbo, Dennis Mazingi, Tom Abbott, Melika Akhbari, Ruth Benson, Shivam Bhanderi, Bruce Biccard, Edward Caruana, Sohini Chakrabortee, Reema Chapatwala, Ainhoa Costas-Chavarri, Andreas K Demetriades, Anant Desai, Salomone Di Saverio, Thomas Drake, John Edwards, Jonathan Evans, Marco Fiore, Samuel Ford, Christina Fotopoulou, Alexander Fowler, Kaori Futaba, Ian Ganly, Harelimana Grace James, Ewen Griffiths, Alessandro Gronchi, Peter Hutchinson, Gabriella Yael Hyman, Joseph Incorvia, Ritu Jain, Michael Jenkinson, Tabassum Khan, Stephen Richard Knight, Angelos Kolias, Søren Kudsk-Iversen, Tsun Yu Kwan, Elaine Leung, Julio Mayol, Siobhan McKay, John G Meara, Emily Mills, Susan Moug, Akshay Patel, Roberto Perinotti, Henry E Rice, Keith Roberts, Andrew Schache, Richard Shaw, Neil Smart, Matthew Stephens, Grant D Stewart, Ella Teasdale, Peter Vaughan-Shaw, Raghavan Vidya, Naomi Wright, Natalie Zimmelman, Ervis Agastra, Dariel Thereska, Sergio Martin Lucchini, Veronica Laudani, Carina Chwat, Ivana Ines Pedraza Salazar, Diana Alejandra Pantoja Pachajoa, Agustin Duro, José Alfredo Calderón Arancibia, Giuliana D'Aulerio, Nagendra Dudi-Venkata, Natasha Egoroff, Shebani Farik, Natalie Lott, Jana-Lee Moss, Sarah Rennie, Lorwai Tan, Uyen Giao Vo, David Watson, David Watters, Tim Bright, Paul Hollington, Xuanyu Zhou, Hidde M Kroon, Anthony Farfus, John Barker, Eleanor Watson, Sean Stevens, Haider Latif, Amanda Caroline Dawson, Alwin Chuan, Vijayaragavan Muralidharan, Enoch Wong, Travis Ackermann, Maurizio Pacilli, Russell Hodgson, Alexander Heriot, Peter Choong, Wendy Brown, Surjit Lidder, Justin Yeung, Luke Traeger, Guillermo Regalo, Ralph Gourlay, Sarit Badiani, Cherry Koh, Soni Putnis, Fayza Haider, Ashrarur Rahman Mitul, Niels Komen, Bert Dhondt, Serge Cappeliez, Manon Pigeolet, Martijn Schoneveld, Jasper Stijns, Wouter Oosterlinck, Nicolas Flamey, Cyrille Kpangon, Mouhamed Agbadebo, S Mèvo Romaric Tobome, Aldo Vieira Barros, Samuel Aguiar Júnior, Heloisa Galvão do Amaral Campos, Jefferson Gross, Felipe José Fernandez Coimbra, Luiz Paulo Kowalski, Fabiana Makdissi, Suely Nakagawa, Joao Pedreira Duprat Neto, Jose Guilherme Vartanian, Guilherme Yazbek, Stenio C Zequi, Ronald Flumignan, Natalia Jaworska, Angela Dell, Harsha Shanthanna, Abdollah Behzadi, Carolyn Nessim, Michelle Mozel, Pascal St-Germain, Crispin Russell, Gary Groot, Najib Safieddine, Duminda Wijeysundera, Antoine Eskander, Sami Chadi, Shawn MacKenzie, Alana Flexman, Fernando Heredia, Julio Villanueva, Sofia Waissbluth, Roberto Macchiavello, Mario I Escudero, Tyare Fuentes, Ximena Mimica, Dinimo Bolivar Saenz, Lina Caicedo, Juan Pablo Alzate, Joaquin Luna, Nestor Fabian Pedraza Alonso, Camilo Ortiz Silva, Juliana Rodriguez, Liliana Silva-Igua, Martha Luz Torres, Lina María Trujillo, Albaro José Nieto Calvache, Julián Balanta-Melo, Rafael Figueroa-Casanova, Oscar-Julián García-Montoya, Carlos Andres Marulanda Toro, Marcela Velez Botero, Maria Clara Mendoza Arango, Eneida Diaz Martinez, Valentina Gutiérrez Perdomo, Emileth Montenegro, Julia Rodriguez-Abreu, Dolores Mejía, Galal Abouelnagah, Sameh Shehata, Ahmed Hossam Eldin Fouad Rida, Ramy A Hassan, Mahmoud M Saad, Mohamed Reda Loaloa, Badr Mostafa, Mohamed Qassem, Mohamed Fahmy, Hesham Abozied, Ahmed Y Azzam, Sherief Ghozy, Asser Sallam, Ahmed Shehta, Mohamed Abdelkhalek, Rehab Samaka, Amr Morsy, Ahmed Elshawadfy Sherif, Abraham Negussie, Tigist Fisseha, Kibruyisfaw Shumbash, Metasebia Abebe, Seid Mohammed Yasin, Yemisirach Bizuneh Akililu, Abebe Megersa, Teshome Tefera, Melatework Assefa, Bahru Atnafu, Bereket Tsegaye, Yoseph Solomon Bezabih, Silamlak Sisay, Kebebe Bekele, Moa Jira, Habtamu Derilo, Eyueal Degefa, Anteneh Tadesse, Melkamu Nidaw, Elise Sarjanoja, Sylvie Testelin, Sophie Boucher, Lionel Jouffret, Zaher Lakkis, Alban Zarzavadjian Le Bian, Luke Harper, Marc Danguy des Déserts, Benoît André, Karem Slim, Romain Verhaeghe, Andrea Police, Edouard Girard, Alexandre Chebaro, Armande Subayi Nkembi, Laurent Arnalsteen, Quentin Ballouhey, Diane Mege, Clement Jeandel, Emilie Duchalais, Pierre-Alban Bouche, Gilles Manceau, Célia Crétolle, Erik Hervieux, Noémie Girard, Agathe Seguin-Givelet, Sebastien Gaujoux, Belinda De Simone, Matthieu Boisson, Damien Bergeat, Fabien Fredon, Francesco Nappi, Radwan Kassir, Aurélien Scalabre, Federico Migliorelli, Anne-Cecile Ezanno, Barbara Seeliger, Charlotte Vaysse, Helene Charbonneau, Vincent Misrai, Olivier Abbo, Martina Aida Angeles, Laurent Brunaud, Ali Modabber, Sebastian Wolf, Carsten Kamphues, Philipp Höhn, Tim R Glowka, Alexander Christopher Rokohl, Ulrich Bork, Georg Fluegen, Raymund E Horch, Andrea Schmedding, Andreas Schnitzbauer, Helge Eberbach, Daniel Schlager, Fritz Spelsberg, Lena Keppler, Andreas Hecker, Susanne Wolfer, Ulrich Ronellenfitsch, Christine Nitschke, Christian Peiper, Ibrahim Hakami, Stefan Welter, Karine Nikolaieva, Andreas Roth, Judith Lindert, Konstantinos Gousias, Anke Rissmann, Valerie Catherine Linz, Nuh Rahbari, Marie-Claire Rassweiler-Seyfried, Anna Eleonora Gut, Jens Gempt, Daniel Reim, Arthur Wagner, Alexander M Keppler, Mircea Gabriel Stoleriu, Tim Saier, Josef Stadler, Julia Christina Kaiser, Stefan M Brunner, Karin Pfister, Jonas Herzberg, Kai Nowak, Tobias Reinhard, Gregor A Stavrou, Alfred Königsrainer, Christian Konrads, Markus Quante, Simon Laban, Silke von Pusch, Markus Hirschburger, Johannes Doerner, Armin Wiegering, Ekaterini Christina Tampaki, Alitza Gutiérrez Ruiz, Alejandra Rodas, Ana Lucía Portilla, Jacqueline Carrera, Amalia Barrios Duarte, Megan Lowey, Sabrina Barillas, Atul Suroy, Dhaivat Vaishnav, Raghunandan Gorantlu Chowdappa, Irappa Madabhavi, Dhananjaya Bhat, Sunil Kumar Venkatappa, Sumit Thakar, Kavitha Jain, Aruna Kumar, Manoj Nagar, Tushar Mishra, Arunkumar Sekar, Anand Gupta, Lileswar Kaman, Madhivanan Karthigeyan, Manjul Tripathi, Ashwin Rammohan, Sudheer Othiyil Vayoth, Anupama Rajanbabu, Anbukkani Subbian, Rahul Gupta, Monish Raut, Nissi Evelyn, R Lavanya Kannaiyan, Anil Matai, Sanjeev Misra, Vishal Bhende, Sathish Muthu, Indranil Ghosh, Abhishek Sharma, Ankur Bajaj, Shiv Rajan, Gaurav Agarwal, Pranay Pawar, Philip Alexander, M Vijayakumar Vijayakumar, Zeeshan Hameed, L Badareesh, Navneet Kumar Chaudhry, Lipika Baliarsing, Satish Dharap, Amruta Kulkarni, Yuvaraja Thyavihally, Rahul Deo Sharma, C S Pramesh, Rajesh Soni, Surya Kumar Dube, Shilpa Sharma, Harvinder Singh, Lovenish Bains, Rahul Ghodke, Ashwani Kumar, Vivek Sodhai, Suvendu Maji, Somprakas Basu, Chandrashekhar Mahakalkar, Ravi Kannan, Asif Mehraj, N Ranganath, Ashish Phadnis, I Yadev, Alfie Kavalakat, Rohin Mittal, Karthik Chandra Vallam, Hamed Akhavizadegan, Esmaeil Rezghi Maleki, Naser Yousefzadeh Kandevani, Hilary Ikele, Catherine McNestry, Christina Fleming, Stephen O'Brien, Sami Abd Elwahab, Niall Davis, Mohsen Javadpour, Brendan McDonnell, Clare O Connor, Jarlath Bolger, Cillian Clancy, Stefanie M Croghan, Noel Donlon, Carolyn Cullinane, Ben Creavin, Muheilan Muheilan, Helen Earley, Syed Mohammad Umar Kabir, Muhammad Fahadullah, Éanna Ryan, Tara Connelly, Daisuke Hashimoto, Majdi Ali Alqudah, Amer Alajalen, Rand Y Omari, Abdulrahman Qasem, Yazan Alawneh, Amer Ahmad, Omar Aladawi, Bourhan Alrayes, Hanan Haidar, Shatha Husain, Faisal Qassem, Adnan Sumadi, Ala'a Abu Salhiyeh, Balqees Mahmoud Al-Manaseer, Zaid Alsunna, Hazim Ra'ed, Faten Reyad Bani Hamad, Amro Abuleil, Elmi Ahmed Mohamed Jimaale, Marah Abu-Mehsen, Noor Olaywah, Omar Wafi, Hazim Ababneh, Luai Abu-Ismail, Almu'atasim Khamees, Ahmad Alkhatib, Raikhan Bolatbekova, Mukhtar Kulimbet, Talgat Nurgozhin, Timur Saliev, Baurzhan Zhussupov, Ydyrys Almabayev, Dilyara Kaidarova, Khalil Tamoos, Ahmed Aqeelah, Alsnosy Abdullah Khalefa Mohammed, Faraj Al Maadany, Ghadah Alkadeeki, Milad Gahwagi, Wafa Aldressi, Mohamed Amnaina, Arowa Hassan Abdulrahman Alansari, Akram Alkaseek, Ghozlan Yagoub, Anass Ben Amer, Marwa Salem, Ayman Almugaddami, Dania Burgan, Mohammed Abdelkabir, Khayriyah Alshareef, Rayet Al Islam Ben Jouira, Ayman Meelad, Ahmad Bouhuwaish, Sumayya Essayah Dwaga, Houda Khalifa, Bushray Almiqlash, Taha Suliaman, Mohammed Alawami, Fras Elhajdawe, Hajir Aboazamazem, Ibrahim Ellojli, Ahmed Msherghi, Ismail Ali Saleh, Mohammed Alayan, Marcel Didier Ndayishyigikiye, Akutu Munyika, Philipp Plarre, David W Borowski, Cameron Wells, Rebecca Teague, Brodie Elliott, David Kieser, Omar Mohyieldin, Nick McIntosh, Cheyaanthan Haran, Jasmin King, Jeong Ha, Matthew James McGuinness, Opeoluwa Adesanya, Julius Olaogun, Akinola Akinmade, Kefas Bwala, Peter Agbonrofo, Akinwale Afolabi, Usang Usang, Sebastian Ekenze, Samson Olori, Taiwo Akeem Lawal, Abiodun Okunlola, Stephen Kache, Danjuma Sale, Lofty-John Anyanwu, Chukwuma Okereke, Musliu Adetola Tolani, Venko Filipce, Lazar Todorovic, Sotir Stavridis, John George Massoud, Sareyah Alsibai, Rizwan Sultan, Humera Naz Altaf, Abu Bakar Hafeez Bhatti, Shahzad Hussain Waqar, Aliya Aziz, Asad Ali Kerawala, Lajpat Rai, Mariyah Anwer, Aiman Tariq, Bushra Ayub, Sami Ullah Niazi, Muhammad Yasir Naseem, Muhammad Zeeshan Sarwar, Muhammad Imran Khokhar, Imdad Ahmad Zahid, Haroon Javaid Majid, Nabila Talat, Muhammad Asif, Muhammad Hamid Chaudhary, Umer Farooq, Siddique Ahmad, Waleed Mabood, Syed Imran Bukhari, Muhammad Tariq, Eesha Yaqoob, Saad Javed, Muhammad Usman Malik, Hassan Nawaz Yaqoob, Glenda Marina Falcon Pacheco, Robinson Mas Melendez, Arazzelly Del Pilar Paucar Urbina, Jose Rios Chiuyari, Carlos Eduardo Otiniano Alvarado, Lorena Fuentes Rivera Lau, Giuliano Borda-Luque, Milagros Niquen-Jimenez, Claudia Arias, Sergio Zegarra, Jenner Betalleluz Pallardel, Regina Amparo Ugarte Oscco, Gian Mendiola, Yahaira Tatiana Carpio Colmenares, Carlos Shiraishi Zapata, Maria Rosa Ortiz, Filipe Castro Borges, Octavio Viveiros, Pedro Serralheiro, Paulo Santos-Costa, Filipa Mendes, Miguel Rocha Melo, Paulo Cardoso, Ana Soares, Rita Gonçalves Pereira, Nelson Silva, André Caiado, Maria Luís Sacras, Pedro Azevedo, Rui Almeida-Reis, João Oliveira, Jorge Nogueiro, Mafalda Sampaio-Alves, Luciana Cidade Costa, Catarina Baía, Ana Cláudia Deus, Rita Branquinho, André Marçal, André Tojal, Silviu Tiberiu Makkai-Popa, Aurel Mironescu, Florin Grama, Elena Adelina Toma, Daniela Filipescu, Nicolae Bacalbasa, Natalia Motas, Sebastian Ionescu, Octav Ginghina, Radu Costea, Narcis Octavian Zarnescu, Radu Drasovean, Mihail-Gabriel Dimofte, Vlad Porumb, Mikhail Kirov, Yegor Molitvin, Vadim Pykhteev, Marianna Raevskaya, Aleksandr Butyrskii, Mushabab Alshahrani, Azah Althumairi, Nasser Alzerwi, Ahmed Al Ameer, Tariq Madkhali, Abddulrahman Saleh Almulhim, Salman Ghazwani, Abdu Ayoub, Othman Iskander, Mohammed Ghunaim, Mohammed Alharthi, Turki M Alzaidi, Mohammad Alyami, Abdulrahman Al Amri, Abdullah AlFakhri, Amal Alhefdhi, Sharfuddin Chowdhury, Thamer Nouh, Ameen Alshehri, Abdulrahman Alzahrani, Yousef Alalawi, Selmy Awad, Ibrahima Konate, Jacques Tendeng, Nan Zun Teo, Sabra Aqil, Cristina Barrena López, Ana Sánchez Mozo, Antonio Rodriguez Infante, Patricia Caja Vivancos, Mikel Prieto, Igor Alberdi San Roman, Laura Gomez Fernandez, Josep Maria Muñoz Vives, Anna Carreras-Castañer, Berta Díaz-Feijoo, Ramon Sieira-Gil, Victor Turrado-Rodriguez, Anna Sánchez López, Santiago Sánchez-Cabús, Marta Jimenez Toscano, MªPilar Canals Sin, Saura García Laura, Oriol Martin Sole, Pedro Palazon Bellver, Sonia Pérez-Bertólez, Jordi Prat-Ortells, Mireia Riba Martínez, Josep Rubio-Palau, Xavier Tarrado, Jorge Nuñez, Veronica Alonso Mendoza, Coro Bescós, Eloy Espin-Basany, Martin Espinosa-Bravo, Daniel Gil-Sala, Susana González-Suárez, Nuria Montferrer Estruch, Lucia Porteiro Mariño, Ana Rodríguez-Tesouro, Fabian Rojas Portilla, M Pilar Tormos Pérez, Inmaculada Vives, Unai Garcia De Cortazar, Kiara Tudela, Aitor Landaluce-Olavarria, Mercedes Estaire Gómez, Jorge Almoguera, Bakarne Ugarte-Sierra, Virginia Jimenez, Marta Bertrand, Laura Cárdenas Puiggrós, Olga Delisau-Puig, Jorge Garcia-Adamez, David Julià Bergkvist, Eloy Maldonado-Marcos, Lucia Diego García, Marta Roldón Golet, Iván Soto-Darias, Aida Cristina Rahy-Martín, Diego Enjuto, Adolfo Ramos-Luengo, Juan Delgado Fernandez, Carolina Lugo Duarte, Cristina Ojeda Thies, Lucila Marquez, Diana Crego Vita, Jana Dziakova, Jorge Caño Velasco, Olga Mateo-Sierra, Begoña Quintana-Villamandos, Cristina Rey Valcarcel, Javier Rio, Laura Román García de León, Marcello Di Martino, Jorge Prada, Javier Serrano González, Manuel Losada, Jose Tomas Castell Gomez, Ramon Corripio-Sanchez, Alexander Forero-Torres, José Manuel Morales-Puebla, Hanna Perez-Chrzanowska, Santiago Valderrabano Gonzalez, Alvaro Yebes, Ignacio Zapardiel, Manuel Diez Alonso, Nelson Morales Palacios, Alberto Cabañero Sánchez, Fátima Sánchez Fernández, Alfredo Abad Gurumeta, Ane Abad-Motos, Fernando Corella, Javier Ripollés-Melchor, Rosa Sanz-Gonzalez, Marta Alcaraz Fuentes, Maria Teresa Fernández Martín, Pablo Calvo Espino, Milagros Carrasco Prats, Antonio-José Fernández-López, Damián García Escudero, Vanesa Garcia Soria, Jesús Aarón Martínez Alonso, Miguel Ruiz-Marín, Beatriz Gómez Pérez, Joaquin Moya-Angeler, Daniel Fernández Martínez, Heura Llaquet Bayo, Enrique Colás-Ruiz, Susana Bella Romera, M Teresa Gavaldà Pellicé, Misericòrdia Jordà Solé, Enrique Jose Ruiz Velasquez, Bernardo Núñez, Raul Jimenez, Jon Zabaleta, Maria Jose González-Gimeno, Irene Ortega Vázquez, Antonio Perez Ferrer, Rubén Martín-Láez, Marcelo Moreno Suarez, Miguel Angel Freiria Eiras, Irene Ramallo-Solís, Juan-Carlos Gomez-Rosado, Jose Ramon Oliver Guillen, Mar Achalandabaso Boira, Juan Carlos Catalá Bauset, Julio Domenech, Rafael Badenes, Juan Carlos Bernal-Sprekelsen, Jorge Sancho-Muriel, Beatriz De Andrés-Asenjo, Francisco J Tejero-Pintor, Marc Vallve-Bernal, Alba Vazquez Melero, Laura Sánchez Blasco, Jorge Escartin, Victoria Duque Mallén, Selvaratnam Srishankar, Charitha Sooriyabandara, Oshan Basnayake, Nalaka Gunawansa, Prabuth Dulanjan Weeraddana, Thanusan Vimalakanthan, Shanthamoorthy Gishanthan, Pramodh Chandrasinghe, Marc-Olivier Sauvain, Ahmad Ghazal, Yusra Al-Sabbagh, Turki Alhassoun, Sara Maa Albared, Antoine Naem, Hareth Alnahr, Ghassan Jisry, Ali Hammed, Okedi Francis Xaviour, Gaston Turinawe, Isaac Mubezi, Franck K Sikakulya, Andrew Kakeeto, Wilberforce M Kabweru, Ronald Kiweewa, Paul Matovu, Otolia Isaac, Mohamed Mashhour, Amin El Helw, Safeena Kherani, Awadelkarim Mohamed, Ferial Mohamed Ali Abbas, Diary Mohammed, Ehab Aldlyami, Rakesh Kundra, Antony Louis Rex Michael, Kareem S Khalil, Rachel Dbeis, Shafaque Shaikh, Jenny Ferry, Aiman Jamal, Haleema Siddique, Rishi Das, Nikhil Ponugoti, Pornjittra Rattanasirivilai, Asma Sultana, Frances Mosley, Matthew Chan, Antony Bateman, Gareth Davies-Jones, Fanourios Georgiades, Navid Ahmadi, Aman Coonar, Mariam Baig, Chetan Khatri, Arthika Surendran, Julian Sonksen, Robert Sinnerton, Caitlin Brennan, Gemma Faulkner, Michael Greenhalgh, Hannah Emerson, Kiran Singisetti, Joshua Totty, Michael Wilson, Terence Lo, Harriet Corbett, Ijeoma Okonkwo, Gill Arbane, Cyrus Kerawala, Chetan Parmar, Michael Bath, Funlayo Odejinmi, Jayesh Sagar, Rishi Talwar, Samuel Newman, John Hammond, John Moir, Natalie Duric, Tamas Szakmany, Ahmar Iftikhar Talib, Mina Youssef, Christopher Lewis-Lloyd, Mariam Lami, Khurram Ayub, Benjamin Dean, Supriya Balasubramanya, Sathya Lakpriya, Luke Rogers, Paul Turner, Mark Maher, Kohila Sigamoney, Jihène El Kafsi, John Hardie, David Johnson, Christin Henein, Marianne Hollyman, Ketan Agarwal, Simon Powell, Govind Singh Chauhan, Rakesh Patel, Joel Gagnier, Heather Carmichael, Aurora, Kristofor A Olson, Eric Etchill, Sameer Hirji, Matthew Naunheim, Frederick Drake, Caroline Reinke, Anna Alecci, Dennis Vaysburg, Jennifer Rodriquez, Emily Shih, Vin Shen Ban, Julia Coleman, Krista Kaups-Fresno, Emmanouil Giorgakis, Maggie DiNome, Neal Bhutiani, Omar Alnachoukati, Taylor Aiken, Thomas Diehl, Ankush Gosain, Rishi Rattan, Muhammad Owais Abdul Ghani, Nensi Melissa Ruzgar, Anna Liveris, Nina Glass, Charu Paranjape, Theresa Chin, Antonio Meola, Kristina Nicholson, John Squiers, Stephanie Lueckel, Janani Reisenauer, Rachael Callcut, Ahmed Mansour, Allison Berndtson, Lucy Kornblith, Sara Seegert, Paulo Martins, Mohammed Al-Shehari, Ibrahim Al-Raimi, Allan Ngulube, Maphios Siamuchembu, Willard Mushiwokufa, Busisiwe Mlambo, Simbarashe Chinyowa, Enton Bollano, Kostandin Gjyli, Jola Kerpaci, Enxhi Vrapi, Lorena Zijaj, Bahraoui Djahida, Belabbes Fatima Zohra, Kouidri Khadidja, Oussama Bali, Nassim Benallel, Ismahene Lalmi, Meriem Abdoun, Nesrine Aouabed, Souad Bouaoud, Kamel Bouchenak, Assia Haif, Zineddine Soualili, Joaquin Bastet, Agustín Bianco, Daniel Capitaine, Jorge Centeno Lozada, Carlos Esquivel, Rodrigo Figueroa, Manuel Garcia, Pablo Martín García, José Ignacio Gerchunoff, Fernando Martinez Iascano, Jose Mondino, María Emilia Muriel, Carmignani Pablo, Martin Passadore, Alejandra Tornini, Rogelio Traverso, Lara Vargas, Gerardo Zanoni, Norberto Berber, Estefanía Cotta, Marcela Di Vincenzo, Esteban Sebastian Gallino, 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Kache, Danjuma Sale, Lofty-John Anyanwu, Chukwuma Okereke, Musliu Adetola Tolani, Venko Filipce, Lazar Todorovic, Sofija Pejkova, Sotir Stavridis, John George Massoud, Sareyah Alsibai, Rizwan Sultan, Humera Naz Altaf, Abu Bakar Hafeez Bhatti, Shahzad Hussain Waqar, Aliya Aziz, Asad Ali Kerawala, Lajpat Rai, Mariyah Anwer, Aiman Tariq, Bushra Ayub, Sami Ullah Niazi, Muhammad Yasir Naseem, Muhammad Zeeshan Sarwar, Muhammad Imran Khokhar, Imdad Ahmad Zahid, Haroon Javaid Majid, Nabila Talat, Muhammad Asif, Muhammad Hamid Chaudhary, Umer Farooq, Siddique Ahmad, Waleed Mabood, Syed Imran Bukhari, Muhammad Tariq, Eesha Yaqoob, Saad Javed, Saad Javed, Muhammad Usman Malik, Hassan Nawaz Yaqoob, Moises Cukier, Glenda Marina Falcon Pacheco, Robinson Mas Melendez, Arazzelly Del Pilar Paucar Urbina, Jose Rios Chiuyari, Carlos Eduardo Otiniano Alvarado, Lorena Fuentes Rivera Lau, Giuliano Borda-Luque, Milagros Niquen-Jimenez, Claudia Arias, Sergio Zegarra, Jenner Betalleluz Pallardel, Regina Amparo Ugarte Oscco, Gian Mendiola, Yahaira Tatiana Carpio Colmenares, Carlos Shiraishi Zapata, Maria Rosa Ortiz, Marie Dione Sacdalan, Piotr Major, Filipe Castro Borges, Octavio Viveiros, Pedro Serralheiro, Paulo Santos-Costa, Filipa Mendes, Miguel Rocha Melo, Paulo Cardoso, Ana Soares, José Azevedo, Rita Gonçalves Pereira, Nelson Silva, André Caiado, Maria Luís Sacras, Pedro Azevedo, Rui Almeida-Reis, Miguel F Cunha, João Oliveira, Jorge Nogueiro, Mafalda Sampaio-Alves, Luciana Cidade Costa, Catarina Baía, Ana Cláudia Deus, Rita Branquinho, André Marçal, André Tojal, Ahmad Zarour, Ahmad Zarour, Silviu Tiberiu Makkai-Popa, Aurel Mironescu, Florin Grama, Elena Adelina Toma, Ionut Negoi, Daniela Filipescu, Nicolae Bacalbasa, Natalia Motas, Sebastian Ionescu, Octav Ginghina, Radu Costea, Narcis Octavian Zarnescu, Radu Drasovean, Eduard-Alexandru Bonci, Mihail-Gabriel Dimofte, Vlad Porumb, Mikhail Kirov, Yegor Molitvin, Andrey Litvin, Vadim Pykhteev, Marianna Raevskaya, Sergey Efetov, Aleksandr Butyrskii, Mushabab Alshahrani, Azah Althumairi, Nasser Alzerwi, Ahmed Al Ameer, Ahmed Al Ameer, Tariq Madkhali, Abddulrahman Saleh Almulhim, Salman Ghazwani, Abdu Ayoub, Othman Iskander, Mohammed Ghunaim, Mohammed Alharthi, Turki M Alzaidi, Azah Althumairi, Mohammad Alyami, Abdulrahman Al Amri, Azah Althumairi, Abdullah AlFakhri, Amal Alhefdhi, Sharfuddin Chowdhury, Thamer Nouh, Ameen Alshehri, Abdulrahman Alzahrani, Yousef Alalawi, Selmy Awad, Ibrahima Konate, Abdourahmane Ndong, Jacques Tendeng, Nan Zun Teo, Frederick Koh, Jurij Aleš Košir, Uros Bele, Sabra Aqil, Cristina Barrena López, Ana Sánchez Mozo, Antonio Rodriguez Infante, Patricia Caja Vivancos, Mikel Prieto, Igor Alberdi San Roman, Laura Gomez Fernandez, Josep Maria Muñoz Vives, Anna Carreras-Castañer, Berta Díaz-Feijoo, Ramon Sieira-Gil, Victor Turrado-Rodriguez, Anna Sánchez López, Santiago Sánchez-Cabús, Marta Jimenez Toscano, MªPilar Canals Sin, Saura García Laura, Oriol Martin Sole, Pedro Palazon Bellver, Sonia Pérez-Bertólez, Jordi Prat-Ortells, Mireia Riba Martínez, Josep Rubio-Palau, Xavier Tarrado, Jorge Nuñez, Veronica Alonso Mendoza, Coro Bescós, Eloy Espin-Basany, Martin Espinosa-Bravo, Daniel Gil-Sala, Susana González-Suárez, Nuria Montferrer Estruch, Jorge Nuñez, Lucia Porteiro Mariño, Ana Rodríguez-Tesouro, Fabian Rojas Portilla, M Pilar Tormos Pérez, Inmaculada Vives, Unai Garcia De Cortazar, Kiara Tudela, Aitor Landaluce-Olavarria, Mercedes Estaire Gómez, Jorge Almoguera, Bakarne Ugarte-Sierra, Virginia Jimenez, Marta Bertrand, Laura Cárdenas Puiggrós, Olga Delisau-Puig, Jorge Garcia-Adamez, David Julià Bergkvist, Eloy Maldonado-Marcos, Lucia Diego García, Marta Roldón Golet, Iván Soto-Darias, Aida Cristina Rahy-Martín, Diego Enjuto, Adolfo Ramos-Luengo, Juan Delgado Fernandez, Carolina Lugo Duarte, Cristina Ojeda Thies, Lucila Marquez, Diana Crego Vita, Jana Dziakova, Ana Maria Minaya Bravo, Jorge Caño Velasco, Olga Mateo-Sierra, Begoña Quintana-Villamandos, Cristina Rey Valcarcel, Javier Rio, Laura Román García de León, Marcello Di Martino, Jorge Prada, Javier Serrano González, Manuel Losada, Jose Tomas Castell Gomez, Ramon Corripio-Sanchez, Alexander Forero-Torres, José Manuel Morales-Puebla, Hanna Perez-Chrzanowska, Santiago Valderrabano Gonzalez, Alvaro Yebes, Ignacio Zapardiel, Manuel Diez Alonso, Nelson Morales Palacios, Alberto Cabañero Sánchez, Fátima Sánchez Fernández, Alfredo Abad Gurumeta, Ane Abad-Motos, Fernando Corella, Javier Ripollés-Melchor, Rosa Sanz-Gonzalez, Marta Alcaraz Fuentes, Maria Teresa Fernández Martín, Pablo Calvo Espino, Milagros Carrasco Prats, Antonio-José Fernández-López, Damián García Escudero, Vanesa Garcia Soria, Jesús Aarón Martínez Alonso, Miguel Ruiz-Marín, Beatriz Gómez Pérez, Joaquin Moya-Angeler, Daniel Fernández Martínez, Heura Llaquet Bayo, Enrique Colás-Ruiz, Susana Bella Romera, M Teresa Gavaldà Pellicé, Misericòrdia Jordà Solé, Enrique Jose Ruiz Velasquez, Bernardo Núñez, Raul Jimenez, Jon Zabaleta, Maria Jose González-Gimeno, Irene Ortega Vázquez, Antonio Perez Ferrer, Rubén Martín-Láez, Marcelo Moreno Suarez, Miguel Angel Freiria Eiras, Irene Ramallo-Solís, Juan-Carlos Gomez-Rosado, Jose Ramon Oliver Guillen, Mar Achalandabaso Boira, Juan Carlos Catalá Bauset, Julio Domenech, Rafael Badenes, Juan Carlos Bernal-Sprekelsen, Jorge Sancho-Muriel, Beatriz De Andrés-Asenjo, Francisco J Tejero-Pintor, Marc Vallve-Bernal, Alba Vazquez Melero, Laura Sánchez Blasco, Jorge Escartin, Victoria Duque Mallén, Selvaratnam Srishankar, Umesh Jayarajah, Charitha Sooriyabandara, Oshan Basnayake, Nalaka Gunawansa, Dakshitha Wickramasinghe, Prabuth Dulanjan Weeraddana, Thanusan Vimalakanthan, Shanthamoorthy Gishanthan, Pramodh Chandrasinghe, Eleftherios Gialamas, Marc-Olivier Sauvain, Ahmad Ghazal, Yusra Al-Sabbagh, Turki Alhassoun, Sara Maa Albared, Antoine Naem, Hareth Alnahr, Ghassan Jisry, Ali Hammed, Arda Isik, Okedi Francis Xaviour, Gaston Turinawe, Isaac Mubezi, Franck K Sikakulya, Andrew Kakeeto, Wilberforce M Kabweru, Hervé Monka Lekuya, Ronald Kiweewa, Herman Lule, Paul Matovu, Otolia Isaac, Mohamed Mashhour, Amin El Helw, Sattar Alshryda, Safeena Kherani, Awadelkarim Mohamed, Ferial Mohamed Ali Abbas, Diary Mohammed, Ehab Aldlyami, Rakesh Kundra, Mohamed Mashhour, Mohamed Mashhour, Antony Louis Rex Michael, Hayder Alsaadi, Kareem S Khalil, Rachel Dbeis, Shafaque Shaikh, Jenny Ferry, Aiman Jamal, Haleema Siddique, Rishi Das, Nikhil Ponugoti, Sivesh K Kamarajah, Pornjittra Rattanasirivilai, Asma Sultana, Frances Mosley, Matthew Chan, Antony Bateman, Gareth Davies-Jones, Fanourios Georgiades, Grant D Stewart, Navid Ahmadi, Aman Coonar, Mariam Baig, Chetan Khatri, Arthika Surendran, Julian Sonksen, Robert Sinnerton, Caitlin Brennan, Gemma Faulkner, Michael Greenhalgh, Hannah Emerson, Kiran Singisetti, Joshua Totty, Michael Wilson, Terence Lo, Harriet Corbett, Ijeoma Okonkwo, Gill Arbane, Kariem El-Boghdadly, Cyrus Kerawala, Chetan Parmar, Tom Abbott, Michael Bath, Funlayo Odejinmi, Jayesh Sagar, Rishi Talwar, Samuel Newman, John Hammond, John Moir, Natalie Duric, Tamas Szakmany, Ahmar Iftikhar Talib, Mina Youssef, Christopher Lewis-Lloyd, Christopher Lewis-Lloyd, Mariam Lami, Khurram Ayub, Benjamin Dean, Supriya Balasubramanya, Sathya Lakpriya, Luke Rogers, Paul Turner, Mark Maher, Kohila Sigamoney, John Edwards, Jihène El Kafsi, John Hardie, David Johnson, Christin Henein, Marianne Hollyman, Ketan Agarwal, Simon Powell, Govind Singh Chauhan, Rakesh Patel, Joel Gagnier, Heather Carmichael, Aurora, Kristofor A Olson, Eric Etchill, Joseph Incorvia, Sameer Hirji, Matthew Naunheim, Frederick Drake, Haytham Kaafarani, Caroline Reinke, Anna Alecci, Dennis Vaysburg, Jennifer Rodriquez, Emily Shih, Vin Shen Ban, Julia Coleman, Henry E Rice, Krista Kaups-Fresno, Emmanouil Giorgakis, Maggie DiNome, Neal Bhutiani, Omar Alnachoukati, Brittany Bankhead-Kendall, Taylor Aiken, Thomas Diehl, Ankush Gosain, Rishi Rattan, Muhammad Owais Abdul Ghani, Nensi Melissa Ruzgar, Anna Liveris, Nina Glass, Charu Paranjape, Theresa Chin, Antonio Meola, Kristina Nicholson, John Squiers, Stephanie Lueckel, Janani Reisenauer, Rachael Callcut, Ahmed Mansour, Allison Berndtson, Lucy Kornblith, Sara Seegert, Paulo Martins, Hamza Al-Naggar, Mohammed Al-Shehari, Ibrahim Al-Raimi, Allan Ngulube, Maphios Siamuchembu, Willard Mushiwokufa, Busisiwe Mlambo, Simbarashe Chinyowa, Ervis Agastra, Enton Bollano, Kostandin Gjyli, Dariel Thereska, Irida Dajti, Jola Kerpaci, Enxhi Vrapi, Lorena Zijaj, Bahraoui Djahida, Belabbes Fatima Zohra, Kouidri Khadidja, Oussama Bali, Nassim Benallel, Ismahene Lalmi, Meriem Abdoun, Nesrine Aouabed, Souad Bouaoud, Kamel Bouchenak, Assia Haif, Zineddine Soualili, Joaquin Bastet, Agustín Bianco, Daniel Capitaine, Jorge Centeno Lozada, Carlos Esquivel, Rodrigo Figueroa, Manuel Garcia, Pablo Martín García, José Ignacio Gerchunoff, Fernando Martinez Iascano, Jose Mondino, María Emilia Muriel, Carmignani Pablo, Martin Passadore, Alejandra Tornini, Rogelio Traverso, Lara Vargas, Gerardo Zanoni, Norberto Berber, Estefanía Cotta, Marcela Di Vincenzo, Esteban Sebastian Gallino, Cecilia Gigena, Bianca Grassano, Veronica Laudani, Ignacio Lugones, Constanza Madrid, Maximiliano Maricic, Antonio Alberto Martinez, Andres Rosso, Pablo Scher, Sofia Tachella, Damaris Idara Anabel Zezular, Carla Abuawad, Agustin Albani Forneris, Carola Allemand, Laura Gisela Alvarez Calzaretta, Luis Boccalatte, Jorge G Boretto, Rocio Boudou, Rodrigo Brandariz, Martin Buljubasich, Arturo Burchakchi, Martin Buttaro, Juan Pablo Campana, Virginia Cano Busnelli, Tomas Carminatti, Agustina Florencia Castro Lalín, Julian Cereghini, María Sol Crespi Amor, Roberto Sebastián Croattini, Maria Sol Fernandez, Marcelo Figari, Uriel Fraidenraij, Diego Gallegos, Agustín Maria García-Mansilla, Marcos Gonzalez, Matias Ignacio Gonzalez, Esteban Gonzalez Salazar, Jeremias Goransky, Guillermo Hernandez Gauna, Felipe Higuera, Fernando Holc, Esteban Gabriel Jauregui, Juan Larrañaga, Juan Liyo, Lionel Llano, Pablo Lobos, Emilia Luzzi, Gustavo Mastroianni, Santiago Miguel Mata-Suarez, Horacio F Mayer, Santiago Mc Loughlin, Efrain Mendoza, Ricardo Esteban Mentz, Pedro Mercado, Pablo Moyano, Florencia Noll, Diego Odetto, Agustina Rene Oliva, Rafael Perez Vidal, Catalina Poggi, Eduardo Jorge Premoli, María Lourdes Ramos, Patricio Rosas, Luciano Rossi, Gustavo Rossi, Jose Saadi, Jordán Scherñuk, Pablo Slullitel, María Verona Stang, María Victoria Taboada, Sebastian Tirapegui, Constanza Uffelmann, Carlos Vaccaro, Roberto Vagni, Ana Clara Valerio, Celeste Soledad Zarratea, Carina Chwat, Silvina Montal, Brian Morris, Pedro Valdez, Fernando Diaz-Couselo,Ricci C, Casadei R, Fruscio, R, Ornaghi, S, Felice Pecoraro, Emanuele Cammarata, Sofia Campanella, Daniela Canzonieri, Adriana Cordova, Federico De Michele, Ettore Dinoto, Mara Franza, Leo Licari, Daniele Matta, Domenico Mirabella, Roberto Pirrello, Pierfrancesco Pugliese, Fernando Rosatti, Giuseppe Salamone, Francesca Toia, Massimiliano Tripoli, Vito Chiantera, Mariano Catello Di Donna, Collaborative, Covidsurg, Collaborative, Globalsurg, Palmisano, Silvia, de Manzini, Nicolo', Simoes, J, Rosati, R, on behalf of COVIDSurg Collaborative, GlobalSurg Collaborative, Aldrighetti, L, Mortini, P, Olmi, S, Medical Oncology, Assoc Surg Training ASiT, European Soc Coloproctology ESCP, EuroSurg, G4 Alliance, GlobalPaedSurg, GICS, ItSURG, ISRC, Italian Soc Colorectal Surg SICCR, PTSurg, S-ECCO, South African Soc, and SpainSurg
Subjects: Lung Diseases, Male, Internationality, SARS-Cov-2, COVID-19, surgery, pathways, pre-operative isolation, Settore MED/18 - CHIRURGIA GENERALE, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Lung Disease, ESTUDOS PROSPECTIVOS, Cohort Studies, Patient Isolation, Postoperative Complications, 80 and over, Prospective Studies, Prospective cohort study, 610 Medicine & health, Aged, 80 and over, Incidence (epidemiology), Treatment Outcome, Elective Surgical Procedures, Female, Elective Surgical Procedure, Cohort study, Human, medicine.medical_specialty, Isolation (health care), Preoperative care, NO, Anesthesiology, Preoperative Care, medicine, Humans, Elective surgery, LS7_4, Aged, business.industry, pathway, Surgery, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Prospective Studie, Anesthesiology and Pain Medicine, Human medicine, Postoperative Complication, Cohort Studie, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p=0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3days, with an OR (95%CI) at 4–7days or ≥8days of 1.25 (1.04–1.48), p=0.015 and 1.31 (1.11–1.55), p=0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p=0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3days, with an OR (95%CI) at 4–7days or ≥8days of 1.25 (1.04–1.48), p=0.015 and 1.31 (1.11–1.55), p=0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care.
Published: 2021

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