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1. 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

2. Zentralisierung, Spezialisierung und Ambulantisierung der Versorgung von Kopf-Hals-Tumorpatienten

Author

Julius Malte Vahl, Felix Böhm, Matthias Brand, Adrian von Witzleben, Thomas Karl Hoffmann, and Simon Laban

Subjects
Otorhinolaryngology
Abstract

ZusammenfassungDemografisch zeigt sich eine alternde, morbider werdende deutsche Bevölkerung. Gleichzeitig werden Urbanisierungstendenzen, medizinische Überkapazitäten und steigende, auch innovationsbedingte Versorgungskosten bei einem knappen Gesundheitsetat beobachtet. Zentralisierung, Spezialisierung und Ambulantisierung sollen Abhilfe verschaffen und können durch Modifikationen der Vergütung mitgesteuert werden. Dieser Umbruch birgt für Patient*innen und Ärzt*innen neue Herausforderungen, welche exemplarisch am Kopf-Hals-Tumor (KHT)-Zentrum des Universitätsklinikums Ulm analysiert wurden. Dabei handelt es sich um eine retrospektive, monozentrische Kohortenstudie zur Entwicklung des Patientenaufkommens, Einzugsgebiets, der Behandlungsmodalität und Demografie unter Einschluss von 2070 KHT-Patient*innen zwischen den Jahren 2011 und 2020 der HNO-Klinik. Es wurde beobachtet, dass die Anzahl (Neudiagnosen 2011: 134 vs. 2020: 204) und das Durchschnittsalter (2011: 61,5 Jahre vs. 2020: 65,8 Jahre; p

Published
2022

3. 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

4. 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

5. 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

6. 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

7. Supplementary Figure S4 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

Prognostic impact of antibody responses to cancer antigens stratified by HPV-status. Overall survival was significantly shorter for patients with {greater than or equal to}2 AR, AR to c-myc, MAGåE-A1, MAGE-A4 and Rhodopsin E2 in the HPV-negative cohort and IMP-1 in the HPV-positive cohort. Overall survival was calculated using the Kaplan-Meier method and p-values were determined using logrank tests. Results were corrected for multiple testing with a false discovery rate of 15%.

Published
2023

8. 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

9. 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

10. Supplementary Figure 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

Consort diagram of the study cohort.

Published
2023

11. 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

14. 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
Cancer Research, Oncology
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

15. 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

16. 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
Inorganic Chemistry, head and neck squamous cell carcinoma, immunohistochemistry, targeted therapy, oncopanel, sequencing, Organic Chemistry, General Medicine, ddc:610, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
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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17. 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

18. 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
General Medicine
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

19. 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
Cell Biology, Developmental Biology
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

20. [Centralization, Specialization, and Outpatient Care for Head and Neck Tumor Patients]

Author

Julius Malte, Vahl, Felix, Böhm, Matthias, Brand, Adrian, von Witzleben, Thomas Karl, Hoffmann, and Simon, Laban

Abstract

Demographically, the German population is aging and becoming more morbid. At the same time, urbanization trends, medical overcapacities, and increasing care costs are being observed in association with a tight healthcare budget. Centralization, specialization, and outpatient care are intended to provide a remedy and can be controlled by modifications to remuneration. This upheaval poses new challenges for patients and physicians, which were analyzed exemplarily at the Head and Neck Tumor (HNC) Center of the University Hospital Ulm. This is a retrospective, monocentric cohort study on the development of patient volume, catchment area, treatment modality, and demographics including 2070 HNC patients at the ENT clinic between the years 2011 and 2020. It was observed that the number (new diagnoses 2011: 134 vs. 2020: 204) and the average age (2011: 61.5 years vs. 2020: 65.8 years; p0.0001) of HNC patients increased over time. In addition, patients tended to travel longer distances (2011: 54.4 km vs. 2020: 64.4 km; p = 0.05). At the same time, the mean number of consultations and treatments per patient per 5-year follow-up interval grew (at initial diagnosis in 2011: 7.8 vs. 2016: 10.4; p = 0.0003), with the proportion of outpatient contacts increasing from 58.9 % to 62.4 % (p = 0.09) from 2011 to 2020. Accordingly, clinical centers are expected to become more important in the care of HNC patients as the healthcare system becomes more specialized, and centralized with a growing outpatient setting. The following consequences for patient care should be considered in restructuring strategies.Demografisch zeigt sich eine alternde, morbider werdende deutsche Bevölkerung. Gleichzeitig werden Urbanisierungstendenzen, medizinische Überkapazitäten und steigende, auch innovationsbedingte Versorgungskosten bei einem knappen Gesundheitsetat beobachtet. Zentralisierung, Spezialisierung und Ambulantisierung sollen Abhilfe verschaffen und können durch Modifikationen der Vergütung mitgesteuert werden. Dieser Umbruch birgt für Patient*innen und Ärzt*innen neue Herausforderungen, welche exemplarisch am Kopf-Hals-Tumor (KHT) -Zentrum des Universitätsklinikums Ulm analysiert wurden. Dabei handelt es sich um eine retrospektive, monozentrische Kohortenstudie zur Entwicklung des Patientenaufkommens, Einzugsgebiets, der Behandlungsmodalität und Demografie unter Einschluss von 2070 KHT-Patient*innen zwischen den Jahren 2011 und 2020 der HNO-Klinik. Es wurde beobachtet, dass die Anzahl (Neudiagnosen 2011: 134 vs. 2020: 204) und das Durchschnittsalter (2011: 61,5 Jahre vs. 2020: 65,8 Jahre; p0,0001) der KHT-Patient*innen im zeitlichen Verlauf anstiegen. Außerdem nahmen die Patient*innen hierbei tendenziell größere Anfahrtswege auf sich (2011: 54,4km vs. 2020: 64,4km; p=0,05). Gleichzeitig wuchs die mittlere Anzahl an Konsultationen und Behandlungen pro Patient*in und 5-Jahres-Nachsorgeintervall (bei Erstdiagnose 2011: 7,8 vs. 2016: 10,4; p=0,0003), wobei sich der Anteil ambulanter Patientenkontakte von 2011–2020 von 58,9% auf 62,4% (p=0,09) erhöhte. Dementsprechend ist zu erwarten, dass klinische Zentren im Zuge der Spezialisierung, Ambulantisierung und Zentralisierung des Gesundheitssystems an Bedeutung bei der Versorgung von KHT-Patient*innen gewinnen. Daraus folgende Konsequenzen für die Patientenversorgung sollten bei Umstrukturierungsstrategien berücksichtigt werden.

Published
2022

21. 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

37. 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, 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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

38. Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

Author

Markus Hecht, Markus Eckstein, Sandra Rutzner, Jens von der Grün, Thomas Illmer, Gunther Klautke, Simon Laban, Matthias G Hautmann, Thomas B Brunner, Bálint Tamaskovics, Axel Hinke, Jian-Guo Zhou, Benjamin Frey, Anna-Jasmina Donaubauer, Ina Becker, Sabine Semrau, Arndt Hartmann, Panagiotis Balermpas, Wilfried Budach, Udo S Gaipl, Heinrich Iro, Antoniu-Oreste Gostian, and Rainer Fietkau

Subjects
Male, Cancer Research, Immunology, CD8-Positive T-Lymphocytes, Radioimmuntherapie, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Immunology and Allergy, ddc:610, Immune Checkpoint Inhibitors, RC254-282, Aged, Clinical/Translational Cancer Immunotherapy, Pharmacology, Squamous Cell Carcinoma of Head and Neck, Patient Selection, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Induction Chemotherapy, Middle Aged, Radioimmunotherapy, Oncology, Head and Neck Neoplasms, Molecular Medicine, Female, DDC 610 / Medicine & health
Abstract

PurposeThe first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed.MethodsPatients with stage III–IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1–3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%.ResultsBetween September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3–4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%).ConclusionsThe trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS.Trial registration numberThe trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST)., publishedVersion

Published
2022

39. Early relapse detection by monitoring of circulating cell-free DNA in patients with localized head and neck squamous cell carcinoma: a subgroup analysis of the multicenter randomized clinical trial IMSTAR-HN [Letter]

Author

Hanna Jonas, Donjete Simnica, Lara Bußmann, Henrike Zech, Johannes Doescher, Simon Laban, Chia-Jung Busch, and Mascha Binder

Subjects
Cancer Research, Oncology, Head and Neck Neoplasms, Squamous Cell Carcinoma of Head and Neck, Humans, ddc:610, Neoplasm Recurrence, Local, Oral Surgery, Cell-Free Nucleic Acids
Published
2022

40. [Immunotherapy of head and neck cancer : Highlights of the ASCO and ESMO annual meetings 2021]

Author

Marie-Nicole, Theodoraki, Simon, Laban, and Thomas K, Hoffmann

Subjects
Head and Neck Neoplasms, Squamous Cell Carcinoma of Head and Neck, Humans, Immunotherapy, Neoplasm Recurrence, Local, Medical Oncology
Abstract

This year's American Society of Clinical Oncology (ASCO) meeting included interesting data on first-line therapy of nasopharyngeal carcinomas with PD‑1 inhibitors and on checkpoint inhibition in various clinical constellations. At the European Society of Medical Oncology (ESMO) meeting, the results of the CheckMate-651 study were presented.All abstracts and presentations from the ASCO and ESMO meetings 2021 on immunotherapy in head and neck cancer (HNSCC) were evaluated for their relevance. The most interesting studies are elaborated upon herein.Studies on locally advanced HNSCC showed an improved response after neoadjuvant pembrolizumab administration. A second cycle did not improve the response rate, but the proportion of patients with a good response was almost doubled. The CheckRad CD8 study showed an improvement in progression-free survival by induction chemoimmunotherapy with tremelimumab and durvalumab followed by stratification according to the CD8 immune cell infiltrate. Two studies were presented on first-line treatment of recurrent/metastatic nasopharyngeal carcinomas. Chemoimmunotherapy showed a higher response rate and prolonged progression-free survival with a similar adverse event profile. In recurrent/metastatic HNSCC, the CheckMate 651 study showed an increased duration of response with nivolumab and ipilimumab and higher response rates than pembrolizumab alone. The primary endpoints for overall survival were not achieved.PD‑1 inhibition has great potential to change the therapeutic landscape for nasopharyngeal carcinomas in the future. In HNSCC, CD8 tumor infiltrate presents a promising predictive marker for selecting patients who can benefit from radioimmunotherapy. The combination of nivolumab and ipilimumab did not improve overall survival in palliative first-line therapy; thus, no change in the current standard is expected.HINTERGRUND: Beim diesjährigen American Society of Clinical Oncology(ASCO)-Treffen gab es interessante Daten zur Erstlinientherapie nasopharyngealer Karzinome mit PD-1-Inhibitoren und zur Checkpointinhibition in verschiedenen klinischen Konstellationen. Beim European Society of Medical Oncology(ESMO)-Meeting wurden die Ergebnisse der CheckMate-651-Studie vorgestellt.Alle Abstracts und Präsentationen der ASCO- und ESMO-Kongresse 2021 zur Immuntherapie von Kopf-Hals-Tumoren (HNSCC) wurden bezüglich Relevanz beurteilt. Die interessantesten Studien wurden aufgearbeitet.Lokal fortgeschrittene HNSCC zeigten ein besseres Ansprechen nach neoadjuvanter Pembrolizumab-Gabe. Die Ansprechrate wurde durch einen zweiten Zyklus nicht erhöht, jedoch wurde der Anteil an Patienten mit stärkerem Ansprechen fast verdoppelt. Die CheckRad-CD8-Studie zeigte eine Verbesserung des progressionsfreien Überlebens durch eine Induktions-Chemoimmuntherapie mit Tremelimumab und Durvalumab sowie Stratifizierung nach dem CD8-Immuninfiltrat. Außerdem wurden Studien zur Erstlinientherapie von rezidivierten/metastasierten Nasopharynxkarzinomen vorgestellt. Eine Chemoimmuntherapie wies eine höhere Ansprechrate bei ähnlichem Nebenwirkungsprofil auf. Bei fortgeschrittenen HNSCC verfehlte die Kombination aus Nivolumab und Ipilimumab die primären Endpunkte für das Gesamtüberleben, wobei die Kombination höhere Ansprechraten im Vergleich zur Pembrolizumab-Monotherapie aufwies.Eine PD-1-Inhibition dürfte zukünftig bei der Behandlung des Nasopharynxkarzinoms eine Rolle spielen. Eine CD8-Infiltration des Tumors stellt einen potenziellen prädiktiven Marker zur Auswahl von Patienten dar, die von einer Radioimmuntherapie profitieren könnten. Die Kombination von Nivolumab und Ipilimumab führte zu keiner Verbesserung des Gesamtüberlebens in der palliativen Erstlinientherapie, weshalb hier aktuell keine Zulassungsänderung des bisherigen Standards zu erwarten ist.

Published
2021

41. Erratum to: Analysis, identification and visualization of subgroups in genomics

Author

Hans A. Kestler, Cornelia Brunner, Hartmut Döhner, Verena I. Gaidzik, Nensi Ikonomi, Axel Fürstberger, Simon Laban, Johann M. Kraus, Donna Neuberg, Thomas K. Hoffmann, Silke D. Kühlwein, and Gunnar Völkel

Subjects
AcademicSubjects/SCI01060, Genome, Human, Computer science, Gene Expression Profiling, Computational Biology, Genomics, Computational biology, Visualization, Gene Expression Regulation, Neoplastic, Neoplasms, Mutation, Humans, Identification (biology), Erratum, Precision Medicine, Molecular Biology, Algorithms, Information Systems
Abstract

Cancer is a complex and heterogeneous disease involving multiple somatic mutations that accumulate during its progression. In the past years, the wide availability of genomic data from patients' samples opened new perspectives in the analysis of gene mutations and alterations. Hence, visualizing and further identifying genes mutated in massive sets of patients are nowadays a critical task that sheds light on more personalized intervention approaches.Here, we extensively review existing tools for visualization and analysis of alteration data. We compare different approaches to study mutual exclusivity and sample coverage in large-scale omics data. We complement our review with the standalone software AVAtar ('analysis and visualization of alteration data') that integrates diverse aspects known from different tools into a comprehensive platform. AVAtar supplements customizable alteration plots by a multi-objective evolutionary algorithm for subset identification and provides an innovative and user-friendly interface for the evaluation of concurrent solutions. A use case from personalized medicine demonstrates its unique features showing an application on vaccination target selection.AVAtar is available at: https://github.com/sysbio-bioinf/avatar.hans.kestler@uni-ulm.de, phone: +49 (0) 731 500 24 500, fax: +49 (0) 731 500 24 502.

Published
2021

43. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048)

Author

Barbara Burtness, Kevin J Harrington, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G M Hughes, Ricard Mesía, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Ruey-Long Hong, René González Mendoza, Ananya Roy, Yayan Zhang, Burak Gumuscu, Jonathan D Cheng, Fan Jin, Danny Rischin, Guillermo Lerzo, Marcelo Tatangelo, Mirta Varela, Juan Jose Zarba, Michael Boyer, Hui Gan, Bo Gao, Brett Hughes, Girish Mallesara, Anne Taylor, Martin Burian, Carlos Henrique Barrios, Dalvaro Oliveira de Castro Junior, Gilberto Castro, Fabio Andre Franke, Gustavo Girotto, Iane Pinto Figueiredo Lima, Ulisses Ribaldo Nicolau, Gustavo Dix Junqueira Pinto, Lucas Santos, Ana-Paula Victorino, Neil Chua, Felix Couture, Richard Gregg, Aaron Hansen, John Hilton, Joy McCarthy, Denis Soulieres, Rodrigo Ascui, Pablo Gonzalez, Luis Villanueva, Marco Torregroza, Angela Zambrano, Petra Holeckova, Zdenek Kral, Bohuslav Melichar, Jana Prausova, Milan Vosmik, Maria Andersen, Niels Gyldenkerne, Hannes Jurgens, Kadri Putnik, Petri Reinikainen, Viktor Gruenwald, Simon Laban, Gerasimos Aravantinos, Ioannis Boukovinas, Vassilis Georgoulias, Dora Kwong, Yousuf Al-Farhat, Tibor Csoszi, Jozsef Erfan, Geza Horvai, Laszlo Landherr, Eva Remenar, Agnes Ruzsa, Judit Szota, Salem Billan, Iris Gluck, Orit Gutfeld, Aron Popovtzer, Marco Benasso, Simona Bui, Vittorio Ferrari, Lisa Licitra, Franco Nole, Takashi Fujii, Yasushi Fujimoto, Nobuhiro Hanai, Hiroki Hara, Koji Matsumoto, Kenji Mitsugi, Nobuya Monden, Masahiro Nakayama, Kenji Okami, Nobuhiko Oridate, Kiyoto Shiga, Yasushi Shimizu, Masashi Sugasawa, Masanobu Takahashi, Shunji Takahashi, Kaoru Tanaka, Tsutomu Ueda, Hironori Yamaguchi, Tomoko Yamazaki, Ryuji Yasumatsu, Tomoya Yokota, Tomokazu Yoshizaki, Iveta Kudaba, Zinaida Stara, Soon Keat Cheah, Jose Aguilar Ponce, Rene Gonzalez Mendoza, Carlos Hernandez Hernandez, Francisco Medina Soto, Jan Buter, Ann Hoeben, S. Oosting, Karijn Suijkerbuijk, Aase Bratland, Marianne Brydoey, Renzo Alvarez, Luis Mas, Priscilla Caguioa, John Querol, Eugenio Emmanuel Regala, Maria Belen Tamayo, Ellie May Villegas, Andrzej Kawecki, Andrey Karpenko, Arkadiy Klochikhin, Alexey Smolin, Oleg Zarubenkov, Boon Cher Goh, Graham Cohen, Johanna du Toit, Christa Jordaan, Gregory Landers, Paul Ruff, Waldemar Szpak, Neonyana Tabane, Irene Brana, Lara Iglesias Docampo, Javier Lavernia, Ricard Mesia, Edvard Abel, Valentina Muratidu, Niels Nielsen, Valerie Cristina, Sacha Rothschild, Hung-Ming Wang, Muh-Hwa Yang, Su-Peng Yeh, Chia-Jui Yen, Nopadol Soparattanapaisarn, Virote Sriuranpong, Sercan Aksoy, Irfan Cicin, Meltem Ekenel, Hakan Harputluoglu, Ozgur Ozyilkan, Kevin Harrington, Sanjiv Agarwala, Haythem Ali, Robert Alter, Daniel Anderson, Justine Bruce, Nicholas Campbell, Miguel Conde, John Deeken, William Edenfield, Lawrence Feldman, Elizabeth Gaughan, Basem Goueli, Balazs Halmos, Upendra Hegde, Brian Hunis, Robert Jotte, Anand Karnad, Saad Khan, Noel Laudi, Douglas Laux, Danko Martincic, Steven McCune, Dean McGaughey, Krzysztof Misiukiewicz, Deborah Mulford, Eric Nadler, Johannes Nunnink, James Ohr, Meaghan O'Malley, Brian Patson, Doru Paul, Elizabeta Popa, Steven Powell, Rebecca Redman, Vincent Rella, Chaio Rocha Lima, Abirami Sivapiragasam, Yungpo Su, Ammar Sukari, Stuart Wong, Emrullah Yilmaz, Jeffrey Yorio, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, Male, Humanized/therapeutic use, Antimetabolites, Cetuximab, Phases of clinical research, Pembrolizumab, 030204 cardiovascular system & hematology, Antineoplastic/therapeutic use, Cetuximab/therapeutic use, Antineoplastic Agents, Immunological, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Monoclonal, Squamous Cell Carcinoma of Head and Neck/drug therapy, 030212 general & internal medicine, Antineoplastic Agents, Immunological/therapeutic use, education.field_of_study, General Medicine, Middle Aged, Antimetabolites, Antineoplastic/therapeutic use, Progression-Free Survival, Antibodies, Monoclonal, Humanized/therapeutic use, Head and Neck Neoplasms, Female, Fluorouracil, medicine.drug, Antimetabolites, Antineoplastic, medicine.medical_specialty, Population, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Fluorouracil/therapeutic use, Antibodies, 03 medical and health sciences, Immunological/therapeutic use, Internal medicine, medicine, Humans, Progression-free survival, education, Aged, Performance status, Squamous Cell Carcinoma of Head and Neck, business.industry, Head and Neck Neoplasms/drug therapy, medicine.disease, Interim analysis, Head and neck squamous-cell carcinoma, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Published
2019

44. Die Laryngektomie – noch zeitgemäß?

Author

Tk. Hoffmann, J M Vahl, Simon Laban, Jens Greve, Andreas Knopf, and Pj. Schuler

Subjects
Gynecology, Human papilloma virus, medicine.medical_specialty, business.industry, medicine.medical_treatment, Laryngectomy, 03 medical and health sciences, 0302 clinical medicine, Otorhinolaryngology, 030220 oncology & carcinogenesis, medicine, Head and neck surgery, 030223 otorhinolaryngology, business
Abstract

Die Kehlkopfentfernung (Laryngektomie) bietet fur Patienten mit fortgeschrittenen Larynx- und Hypopharynxkarzinomen ohne Fernmetastasen einen kurativen Ansatz. Insbesondere bei Vorliegen eines cT4a-Karzinoms ist die Laryngektomie der primaren Radio(chemo)therapie prognostisch (retrospektiv) uberlegen. Weitere wichtige Indikationen fur eine Laryngektomie stellen eine tumorbedingte Larynxdysfunktion wie Schluckunfahigkeit bzw. Aspirationsneigung und ein Rezidiv nach vorausgegangener Radio(chemo)therapie dar. Das operative Verfahren ist hoch standardisiert und ausreichend sicher. Der mit einer Laryngektomie einhergehende Stimmverlust ist durch eine funktionelle Rehabilitation (Ruktus, Stimmprothese) zu kompensieren. Die vorliegende Arbeit verschafft einen Uberblick hinsichtlich Indikation, praoperativer Diagnostik, operativem Verfahren, moglichen Komplikationen, alternativer Behandlungsansatze sowie Rehabilitation und Prognose. Die Laryngektomie gehort auch weiterhin zum bewahrten Standardrepertoire der modernen Kopf-Hals-Onkologie.

Published
2019

45. Therapie der rezidivierten und fernmetastasierten Plattenepithelkarzinome des Kopf-Hals-Bereichs

Author

Simon Laban, Lara Bussmann, Chia-Jung Busch, HB Zech, Christian Stephan Betz, and P. Schafhausen

Subjects
Oncology, medicine.medical_specialty, business.industry, Treatment outcome, medicine.disease, Head and neck squamous-cell carcinoma, Biological tumor markers, stomatognathic diseases, Otorhinolaryngology, Antibodies monoclonal, Internal medicine, medicine, In patient, business
Abstract

This year also saw a great number of phase II and III studies presented at the ASCO Annual Meeting, in which new drugs (monoclonal antibodies, small molecules) were investigated as an alternative to or in combination with established mono- and polychemotherapy in patients with recurrences or distance metastases from head and neck squamous cell carcinoma (R/M-HNSCC). The studies now presented here describe the different concepts being applied to drug-based treatment of R/M-HNSCC and illustrate the variety of therapeutic approaches to treatment of recurrences and metastases.

Published
2019

46. Update zu HPV-assoziierten Kopf-Hals-Karzinomen – Highlights der ASCO-Jahrestagung 2019

Author

Jens Peter Klussmann, Shachi Jenny Sharma, Thomas K. Hoffmann, N. Würdemann, Simon Laban, and Silke Tribius

Subjects
Gynecology, medicine.medical_specialty, business.industry, 03 medical and health sciences, 0302 clinical medicine, Otorhinolaryngology, 030220 oncology & carcinogenesis, Radiation oncology, Head and neck surgery, Head and neck oncology, Medicine, Human papillomavirus, 030223 otorhinolaryngology, business
Abstract

Beim diesjahrigen Kongress der Amerikanischen Gesellschaft fur Onkologie (ASCO, American Society for Clinical Oncology) fanden sich unter der Stichwortsuche „HPV-associated head and neck cancer“ 920 Treffer – 74 % der Treffer zum Stichwort humane Papillomaviren (HPV). Dies zeigt die Relevanz des Themas: Das Spektrum reichte von der Validierung und Trennung der Prognosegruppen von Patienten mit einem HPV-assoziierten Oropharynxkarzinom (OPSCC) nach TNM 8 uber die Charakterisierung neuer Tumormarker und Tumormutationslast zu moglichen Deeskalationsstrategien zur Vermeidung von Toxizitat multimodaler Therapiestandards. So wurde u. a. gezeigt, dass die Trennung p16-positiver OPSCC im Stadium I nach Union Internationale Contre le Cancer (UICC) von denen im Stadium II mit der aktuellen TNM 8-Klassifikation ohne weitere Marker nicht ausreichend gelingt, um Deeskalationsstrategien zu rechtfertigen. Nach Veroffentlichung der Ergebnisse der De-ESCALaTE- und der RTOG-1016-Studie 2018, die den aktuellen Standard auch fur p16-positive OPSCC bestatigen, wurden keine weiteren Phase-III-Studien zum Thema der Deeskalation prasentiert. In einer vorgestellten prospektiven Phase-II-Studie (NCT 02281955) wurde die Strahlentherapiedosis auf kumulativ 60 Gy reduziert, wobei die simultane Chemotherapie mit Cisplatin 30 mg/m2 wochentlich nicht dem Standard entspricht und alternativ zu Cisplatin Cetuximab gegeben werden konnte. Einige Arbeiten beschaftigten sich mit der oralen und Darmmikrobiota als prognostischem Marker bzw. deren therapiebedingte Veranderungen, insbesondere unter Immuntherapie. Eine Modifikation scheint den Therapieerfolg positiv zu beeinflussen. Belastbare Daten fur die verschiedenen Modifikationen der Therapie von HPV-assoziierten OPSCC fehlen jedoch weiterhin, um diese in der taglichen Praxis umzusetzen.

Published
2019

47. Strahlentherapeutische Studien bei Kopf-Hals-Tumoren

Author

S. Ott, Thomas Wiegel, Silke Tribius, Cordula Petersen, Tk. Hoffmann, and Simon Laban

Subjects
Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Otorhinolaryngology, business.industry, 030220 oncology & carcinogenesis, medicine, 030223 otorhinolaryngology, business
Published
2019

48. Immuntherapie von Kopf-Hals-Tumoren

Author

Barbara Wollenberg, Chia-Jung Busch, Andreas Dietz, Pj. Schuler, N. Würdemann, Tk. Hoffmann, Johannes Doescher, and Simon Laban

Subjects
Gynecology, medicine.medical_specialty, Otorhinolaryngology, business.industry, medicine, ddc:610, business
Published
2019

49. Onkoimmunologie im Alter

Author

Janina Hahn, Patrick J. Schuler, Simon Laban, Marlene C. Wigand, Tk. Hoffmann, S Jeske, and Johannes Doescher

Subjects
Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Otorhinolaryngology, business.industry, 030220 oncology & carcinogenesis, Immune checkpoint inhibitors, Head and neck surgery, Medicine, ddc:610, 030223 otorhinolaryngology, business
Abstract

Physiologische Alterungsprozesse des Immunsystems gehen mit einer erhohten Anfalligkeit fur Infektionskrankheiten, Autoimmun- und Tumorerkrankungen einher. Entsprechend der allgemeinen demographischen Entwicklung steigt auch die Anzahl der Tumorpatienten mit fortgeschrittenem Lebensalter zunehmend. Ein Ende dieser Entwicklung ist bislang nicht absehbar. Bei der Tumorbehandlung gewinnt die Immuntherapie mit Checkpoint-Inhibitoren stetig an Bedeutung, allerdings existieren bislang nur wenige Studien zu Wirksamkeit und Nebenwirkungsprofil bei alteren Patienten. In dieser Ubersichtsarbeit werden die Veranderungen des Immunsystems im Alter und ihr Einfluss auf die Karzinogenese erortert. Daruber hinaus wird auf den aktuellen Forschungsstand zur Immuntherapie von Patienten im fortgeschrittenen Lebensalter mit einem Kopf-Hals-Tumor eingegangen.

Published
2019

50. Rising mean age of head and neck squamous cell carcinoma patients in a German tertiary referral center during a 15-year observation period

Author

A von Witzleben, TK Hoffmann, M Brand, Ralf Marienfeld, Pj. Schuler, Peter Möller, Jens Greve, J M Vahl, Michael Denkinger, Peter Kuhn, J Döscher, Dhayana Dallmeier, Cornelia Brunner, Marlene C. Wigand, Christian Idel, C Steiger, Simon Laban, and Claudia Welke

Subjects
German, medicine.medical_specialty, business.industry, General surgery, Observation period, language, Medicine, Referral center, Mean age, business, medicine.disease, Head and neck squamous-cell carcinoma, language.human_language
Published
2021

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