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Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease, three major MDSC subpopulations can be defined as monocytic (M-MDSC), granulocytic [polymorphonuclear-MDSC (PMN-MDSC)], and early stage (e-MDSC), which lacks myeloid lineage markers of the former two subsets. The purpose of this study was to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer.Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T-cell–suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of patients with HNC.Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T-cell–suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC.Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Clin Cancer Res; 24(19); 4834–44. ©2018 AACR.

includes two suppl figures, suppl legends and suppl methods

Little is known about how many patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) receive on-demand and/or prophylactic treatment and what their clinical features are. Here, we estimated, using Delphi-based consensus, prevalence and treatment patterns in Germany as well as patient features linked to long-term prophylaxis.Eight experts, who together treat approximately 75% of all German HAE-C1-INH patients, participated in a classic, two-round Delphi survey. Consensus was defined as agreement between at least 75% of participants.Experts agreed that an estimated 1,350 patients in Germany have HAE-C1-INH, i.e. 1.62 per 100,000. One in four patients was estimated to receive long-term prophylaxis. Patient features linked to the use of prophylactic treatment included reduced quality of life, frequent swellings and swellings that affect the upper airways, andtwo attacks per month.The rate of prophylactic treatment in Germany is low, but is expected to increase. The level of disease activity and its impact and control are and should be considered in the choice for prophylactic treatment.

Zusammenfassung Hintergrund Schwannome sind seltene, benigne Tumore, die von den Gliazellen des peripheren Nervensystems (Schwannsche Zellen) ausgehen. Während es für intrakranielle Schwannome, insbesondere die des N. vestibularis, etablierte Therapiestrategien gibt, liegen zu den extrakraniellen Schwannomen weniger belastbare Daten vor. Methode Es wurde eine retrospektive Analyse von 20 Patienten mit histopathologisch gesicherten extrakraniellen Schwannomen im Kopf-Hals-Bereich mit einem Schwerpunkt auf Tumorlokalisation und postoperativem funktionellem Therapieergebnis durchgeführt. Ergebnisse Die Schwannome im vorliegenden Kollektiv entstammten vornehmlich dem N. facialis (n = 4), dem N. vagus (n = 4) oder dem sympathischen Grenzstrang (n = 3). Die häufigsten Primärsymptome waren Schwellungen (n = 12) und Schmerzen (n = 3). MRT (n = 13), Ultraschall (n = 12) und CT (n = 3) wurden zur Diagnostik eingesetzt. In 18 Fällen wurde ein chirurgischer Behandlungsansatz gewählt (n = 14 komplette Exstirpation, n = 3 Teilexstirpation, n = 1 unbekannter Resektionsumfang). Komplette Schwannomexstirpationen von motorisch-efferentenNerven (n = 10) machten ein Absetzen des Nervens häufiger erforderlich, wenn bereits präoperativ ein motorisches Defizit bestand (3 von 4 = 75 % bei präoperativem Defizit vs. 2 von 6 = 33 % ohne präoperatives Defizit). Schlussfolgerung Extrakranielle Schwannome stellen seltene, meist vom N. facialis, dem sympathischen Grenzstrang oder den kaudalen Hirnnerven ausgehende, benigne Tumore des HNO-Trakts dar, die in der Regel chirurgisch therapiert werden. Mit postoperativen motorischen Defiziten bei kompletten Exstirpationen muss insbesondere bei bereits präoperativ bestehenden Funktionsstörungen gerechnet werden.

ZusammenfassungDie therapeutischen Konzepte bei Kopf-Hals-Malignomen haben in den letzten 20 Jahren einen erheblichen Wandel erfahren, der mit einer zunehmenden Bedeutung nicht-chirurgischer Therapieverfahren einhergeht. Auch unter den Organerhaltungsprotokollen bzw. nach primärer Radiochemotherapie kommt es jedoch in erheblichem Umfang zum Auftreten von Tumorrezidiven. In dieser Situation stellt die Salvage- bzw. Rettungschirurgie im Kopf-Hals-Bereich häufig die einzig noch verbliebene kurative Option dar. Die Etablierung plastisch-rekonstruktiver Maßnahmen vor ca. 30 Jahren hat das operative Spektrum im Kopf-Hals-Bereich signifikant erweitert und neue Möglichkeiten der Salvage-Chirurgie bei rezidivierenden Karzinomen des Pharynx und Larynx eröffnet. Die Überlebensraten nach Salvage-Chirurgie hängen hierbei im Wesentlichen von der Art der Primärtherapie, der Lokalisation und dem Tumorstadium sowohl bei Erstdiagnose als auch zum Zeitpunkt des Rezidivs ab. Zur plastisch-rekonstruktiven Deckung kommen gestielte Lappen oder mikrovaskulär-anastomosierte Transplantate zum Einsatz. Die am häufigsten angewandten gestielten Lappen sind der M. pectoralis-major- und der Latissimus-dorsi-Lappen. Als freie Transplantate kommt meist das Radialis- oder ALT-Transplantat zum Einsatz. Durch Verwendung dieser Lappen und Transplantate wird nicht-bestrahltes Gewebe in die vorgeschädigten Regionen verlagert, um neben der Wiederherstellung der ursprünglichen Organfunktion auch gefürchtete postoperative Komplikationen, wie z. B. Speichelfisteln, zu reduzieren. Die Indikation zur Salvage-Chirurgie muss auch weiterhin in jedem Einzelfall vor dem Hintergrund der zu erwartenden Morbidität und einer realistischen Einschätzung der Erfolgsaussichten abgewogen werden. Die vorliegende Publikation möchte hierzu entsprechende Empfehlungen geben.

In the original publication of the article, first name and last names of all authors were swapped.

Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.

Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease, three major MDSC subpopulations can be defined as monocytic (M-MDSC), granulocytic [polymorphonuclear-MDSC (PMN-MDSC)], and early stage (e-MDSC), which lacks myeloid lineage markers of the former two subsets. The purpose of this study was to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer. Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T-cell–suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of patients with HNC. Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T-cell–suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC. Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Clin Cancer Res; 24(19); 4834–44. ©2018 AACR.

Zusammenfassung Hintergrund: Schnitt-, Stich- und Schussverletzungen der Kopf-Hals-Region stellen aufgrund der hohen Gefahr von vaskulären Läsionen ein potentiell lebensbedrohliches Krankheitsbild dar. Ein konsequentes, standardisiertes Notfallmanagement, in der Regel assoziiert mit einer operativen Exploration, ist Grundlage der effektiven Rettungskette. Methoden und Patienten: 11 Fälle selbst- oder fremdverschuldeter penetrierender Verletzungen der Kopf-Hals-Region werden hinsichtlich Alter, Geschlecht, Verletzungshergang, Art der Verletzung, beteiligter Strukturen, diagnostischen und operativen Vorgehens sowie Outcome beschrieben und der aktuellen Literatur und Leitlinien gegenübergestellt. Ergebnisse: Bei 10 von 11 Patienten wurde, im Rahmen eines interdisziplinären Schockraummanagements, nach einer klinischen Untersuchung eine CT-Angiografie durchgeführt. Bei 9 dieser Patienten wurde daraufhin eine chirurgische Exploration und Wundversorgung vorgenommen. In je 2 Fällen waren die Arteria carotis communis, die Arteria carotis externa sowie große venöse Blutgefäße des Halses verletzt. Keiner der Patienten verstarb oder litt unter bleibenden Schäden. Schlussfolgerung: Eine rasche, systematische und fächerübergreifende Versorgung in speziellen Trauma-Zentren hat einen wesentlichen Anteil daran dass Patienten mit penetrierenden Verletzungen im Kopf-Hals-Bereich seltener an ihren schwerwiegenden Verletzungen oder deren Folgen versterben.

Expression of the forkhead transcription factor (FoxP3)--an established marker of regulatory T cells--has been found in other cell types as well, including tumour cells. Recent studies indicated that high tumour FoxP3 expression might be associated with a poor outcome of patients with several types of solid cancers. Here, we investigated the role of FoxP3 expressed by the tumour cells in the prognosis of larynx and oro-hypopharynx squamous cell carcinoma (LSCC and OHSCC)--two major subtypes of head and neck cancer. To this end, we analysed by immunohistochemistry the expression of tumour FoxP3 in tissues from 83 LSCC and 89 OHSCC patients in relation to overall survival. In multivariate analysis we found that high tumour FoxP3 expression significantly associated with poor survival in OHSCC but not in LSCC patients. In further studies, we combined the prognostic value of FoxP3 with selected markers of inflammation (cyclooxygenase-2; COX2) or with markers of enhanced tumour migration/invasion (AHNAK and CORTACTIN). Interestingly, we found that the combination of FoxP3 and AHNAK (in LSCC) or FoxP3 and CORTACTIN (in OHSCC) had significantly stronger prognostic values than either marker analysed individually. Combination of FoxP3 and COX2 enhanced the prognostic accuracy only in OHSCC. Thus, our study identifies novel individual and combination markers that might have enhanced and distinct prognostic relevance in different subtypes of head and neck cancer.

Die transorale Roboter-assistierte Chirurgie entwickelte sich in den letzten Jahren insbesondere in Nordamerika zu einem chi­rurgischen Alternativverfahren bei der Resektion von Kopf-Hals-Tumoren. Als Schneidewerkzeuge stehen ein monopolarer Elektrokauter oder ein fasergefuhrter Tm:YAG-Laser zur Verfugung, die aufgrund ihrer Gewebewirkung eine breite Koagulations- und Vaporisationszone erzeugen. Mit dem Ziel der Verbesserung der Schneideeigenschaften kombinierten wir das da Vinci-System mit einer flexiblen CO 2 -Laserfaser. Im Zeitraum von Juli 2012 bis Oktober 2012 operierten wir im Rahmen einer prospektiven Untersuchung 6 Patienten mit T1 und T2 Oropharynxtumoren mit dem da Vinci-System unter Anwendung einer flexiblen CO 2 -Laser-Faser. Die Faser hatte einen Durchmesser von 1,2 mm und wurde mithilfe des Laser-Introducers des da Vinci-Systems gefuhrt. Wir evaluierten die klinische Anwendung in Hinblick auf Handhabung, Schneideeigenschaften, Geschwindigkeit der Resektion, Blutstillung sowie Nachblutung und untersuchten die Schnitt­rander histopathologisch. Es erfolgte ein klinischer Vergleich mit dem Elektrokauter und dem Tm:YAG-Laser, die in einer vorangegangenen Serie von 17 Patienten bereits analysiert wurden. Die CO 2 -Laser-Faser zeigte in Verbindung mit dem da Vinci-System sehr gute Schneideeigenschaften. Bei einer Laserleistung von 15 Watt ergab sich eine gunstige Schnitttiefe am Oropharynx bei guter Blutstillung. Die Resektionsrander zeigten geringere Koagulations- und Nekrosezonen als bei Resektionen mit dem Elektromesser oder dem Tm:YAG-Laser. Durch die Verwendung einer flexiblen CO 2 -Laser Faser lassen sich die Schneideeigenschaften des da Vinci-Systems verbessern. Weitere prospektive Vergleiche der verschiedenen Resektionsmodalitaten werden folgen.

Background The Flex Robotic System is a new robotic device specifically developed for transoral robotic surgery (TORS). Methods We performed a prospective clinical study, assessing the safety and efficacy of the Medrobotics Flex Robotic System. A total of 40 patients required a surgical procedure for benign lesions (n = 30) or T1 and T2 carcinomas (n = 10). Access and visualization of different anatomic subsites were individually graded by the surgeon. Setup times, access and visualization times, surgical results, as well as adverse events were documented intraoperatively. Results The lesions could be exposed and visualized properly in 38 patients (95%) who went on to have a surgical procedure performed with the Flex Robotic System, which were intraoperatively evaluated as successful. No serious adverse events occurred. Conclusion Lesions in the oropharynx, hypopharynx, or supraglottic larynx could be successfully resected using the Flex Robotic System, thus making the system a safe and effective tool in transoral robotic surgery. © 2016 Wiley Periodicals, Inc. Head Neck 39: 471–475, 2017

Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE.

The progression of epithelial cancer is associated with an intense immunological interaction between the tumor cells and immune cells of the host. However, little is known about the interaction between tumor cells and polymorphonuclear granulocytes (PMNs) in patients with head and neck squamous cell carcinoma (HNSCC). In our study, we investigated systemic PMN-related alterations in HNSCC, the role of tumor-infiltrating PMNs and their modulation by the tumor microenvironment. We assessed the infiltration of HNSCC tissue by PMNs (retrospectively) and systemic PMN-related alterations in blood values (prospectively) in HNSCC patients (n = 99 and 114, respectively) and control subjects (n = 41). PMN recruitment, apoptosis and inflammatory activity were investigated in an in vitro system of peripheral blood PMNs and a human HNSCC cell line (FaDu). HNSCC tissue exhibited considerable infiltration by PMNs, and strong infiltration was associated with poorer survival in advanced disease. PMN count, neutrophil-to-lymphocyte ratio and serum concentrations of CXCL8 (interleukin-8), CCL4 (MIP-1β) and CCL5 (RANTES) were significantly higher in the peripheral blood of HNSCC patients than in that of controls. In vitro, HNSCC-conditioned medium inhibited apoptosis of PMNs, increased chemokinesis and chemotaxis of PMNs, induced release of lactoferrin and matrix metalloproteinase 9 by PMNs and enhanced the secretion of CCL4 by PMN. Our findings demonstrate alterations in PMN biology in HNSCC patients. In vitro, tumor-derived factors modulate cellular functions of PMNs and increase their inflammatory activity. Thus, the interaction between HNSCC and PMNs may contribute to host-mediated changes in the tumor microenvironment.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that has been reported to enhance the aggressiveness and metastatic potential of tumor cells. However, the mechanisms through which MIF influences tumor development and progression are not understood. The objectives of our study were to assess the effects of tumor-derived MIF on neutrophils in head and neck cancer (HNC) and to identify possible feedback effects on tumor cells. To this end, we used an in vitro system to model the interaction between human HNC cells and neutrophils. In addition, we analyzed expression of MIF in tissues from HNC patients in relation to neutrophilic infiltration and clinical parameters. Our results show that human HNC is infiltrated by neutrophils proportional to the levels of tumoral MIF. Strong MIF expression by the tumor is associated with higher lymph node metastasis and reduced survival in HNC patients. In vitro, MIF modulated functions of human neutrophils by inducing chemokine CXC motif receptor 2(CXCR2)-dependent chemotaxis, enhancing neutrophil survival and promoting release of chemokine C-C Motif Ligand 4 (CCL4) and matrix metalloprotease 9(MMP9). Further, neutrophils activated with tumor-derived MIF enhanced migratory properties of HNC cells. In conclusion, our data indicate that the effects of tumor-derived MIF on neutrophils represent an additional mechanism by which MIF might contribute to tumor progression.