Abdominal ultrasound in head and neck squamous cell carcinoma staging: yes or no?

PURPOSE: Abdominal ultrasound is a diagnostic staging procedure for distant metastases in head and neck squamous cell carcinoma (HNSCC). However, currently performed abdominal staging procedures do not follow consistent standards. Therefore, this retrospective study on 498 patients aimed at investigating on abdominal ultrasound as a staging procedure in HNSCC. MATERIALS AND METHODS: A retrospective analysis of 498 head and neck cancer patients treated in our Department of Head and Neck Surgery between 2008 and 2015 was performed. Disease-related data were collected over a mean follow-up time of 30.3 months, and results of abdominal ultrasound were analyzed. RESULTS: 426 patients received abdominal ultrasound as a staging procedure. 7% (29) were suspicious for metastases. In 19 cases (66%), the detected abnormalities were masses of the liver. In four patients, abdominal metastases were confirmed at the time of initial diagnosis. 16 patients developed abdominal metastases in the course of the disease (on average 623 days after initial diagnosis). 19 out of 20 patients with abdominal metastases had an N2/N3 cervical lymph node status. In this study, the negative predictive value of abdominal ultrasound for HNSCC staging was 99.03%, while the positive predictive value yielded 5.88% (N2/N3-patients). CONCLUSION: Only in patients with locally advanced lymph-node-status (N2/N3), abdominal ultrasound can be useful as a staging investigation to exclude abdominal metastasis in HNSCC patients. For N0/N1 patients, abdominal ultrasound might be dispensed. Of note, in case of a positive result, further diagnostic procedures are mandatory.

A semiparametric model for between-subject attributes: Applications to beta-diversity of microbiome data.

The human microbiome plays an important role in our health and identifying factors associated with microbiome composition provides insights into inherent disease mechanisms. By amplifying and sequencing the marker genes in high-throughput sequencing, with highly similar sequences binned together, we obtain operational taxonomic units (OTUs) profiles for each subject. Due to the high-dimensionality and nonnormality features of the OTUs, the measure of diversity is introduced as a summarization at the microbial community level, including the distance-based beta-diversity between individuals. Analyses of such between-subject attributes are not amenable to the predominant within-subject-based statistical paradigm, such as t-tests and linear regression. In this paper, we propose a new approach to model beta-diversity as a response within a regression setting by utilizing the functional response models (FRMs), a class of semiparametric models for between- as well as within-subject attributes. The new approach not only addresses limitations of current methods for beta-diversity with cross-sectional data, but also provides a premise for extending the approach to longitudinal and other clustered data in the future. The proposed approach is illustrated with both real and simulated data.

Improving interinstitutional and intertechnology consistency of pulmonary SBRT by dose prescription to the mean internal target volume dose.

PURPOSE: Dose, fractionation, normalization and the dose profile inside the target volume vary substantially in pulmonary stereotactic body radiotherapy (SBRT) between different institutions and SBRT technologies. Published planning studies have shown large variations of the mean dose in planning target volume (PTV) and gross tumor volume (GTV) or internal target volume (ITV) when dose prescription is performed to the PTV covering isodose. This planning study investigated whether dose prescription to the mean dose of the ITV improves consistency in pulmonary SBRT dose distributions. MATERIALS AND METHODS: This was a multi-institutional planning study by the German Society of Radiation Oncology (DEGRO) working group Radiosurgery and Stereotactic Radiotherapy. CT images and structures of ITV, PTV and all relevant organs at risk (OAR) for two patients with early stage non-small cell lung cancer (NSCLC) were distributed to all participating institutions. Each institute created a treatment plan with the technique commonly used in the institute for lung SBRT. The specified dose fractionation was 3â€¯× 21.5 Gy normalized to the mean ITV dose. Additional dose objectives for target volumes and OAR were provided. RESULTS: In all, 52 plans from 25 institutions were included in this analysis: 8 robotic radiosurgery (RRS), 34 intensity-modulated (MOD), and 10 3D-conformal (3D) radiation therapy plans. The distribution of the mean dose in the PTV did not differ significantly between the two patients (median 56.9 Gy vs 56.6 Gy). There was only a small difference between the techniques, with RRS having the lowest mean PTV dose with a median of 55.9 Gy followed by MOD plans with 56.7 Gy and 3D plans with 57.4 Gy having the highest. For the different organs at risk no significant difference between the techniques could be found. CONCLUSIONS: This planning study pointed out that multiparameter dose prescription including normalization on the mean ITV dose in combination with detailed objectives for the PTV and ITV achieve consistent dose distributions for peripheral lung tumors in combination with an ITV concept between different delivery techniques and across institutions.

Vertebral osteomyelitis is characterised by increased RANK/OPG and RANKL/OPG expression ratios in vertebral bodies and intervertebral discs.

Vertebral osteomyelitis (VO) is an infection of the spine mainly caused by bacterial pathogens. The pathogenesis leading to destruction of intervertebral discs (IVDs) and adjacent vertebral bodies (VBs) is poorly described. The present study aimed at investigating the connection between infection and bone/disc metabolism in VO patients. 14 patients with VO (infection group) and 14 patients with burst fractures of the spine (fracture group; control) were included prospectively. Tissue biopsies from affected IVDs and adjacent VBs were analysed by RT-qPCR for mRNA-expression levels of 18 target genes including chemokines, adipokines and genes involved in bone metabolism. Most importantly, the receptor activator of NF-κB/osteoprotegerin (RANK/OPG) expression ratio was drastically elevated in both VBs and IVDs of the infection group. In parallel, expression of genes of the prostaglandin-E2-dependent prostanoid system was induced. Such genes regulate tissue degradation processes via the triad OPG/RANK/RANKL as well as via the chemokines IL-8 and CCL-20, whose expression was also found to be increased upon infection. The gene expression of the adipokine leptin, which promotes inflammatory tissue degradation, was higher in IVD tissue of the infection group, whereas the transcription of omentin and resistin genes, whose functions are largely unknown in the context of infectious diseases, was lower in infected VBs. In summary, similar expression patterns of pro-inflammatory cytokines and pro-osteoclastogenic factors were identified in VBs and IVDs of patients suffering from VO. This suggests that common immuno-metabolic pathways are involved in the mechanisms leading to tissue degradation in VBs and IVDs during VO.

Applicability of radiomics in interstitial lung disease associated with systemic sclerosis: proof of concept.

OBJECTIVE: To retrospectively evaluate if texture-based radiomics features are able to detect interstitial lung disease (ILD) and to distinguish between the different disease stages in patients with systemic sclerosis (SSc) in comparison with mere visual analysis of high-resolution computed tomography (HRCT). METHODS: Sixty patients (46 females, median age 56 years) with SSc who underwent HRCT of the thorax were retrospectively analyzed. Visual analysis was performed by two radiologists for the presence of ILD features. Gender, age, and pulmonary function (GAP) stage was calculated from clinical data (gender, age, pulmonary function test). Data augmentation was performed and the balanced dataset was split into a training (70%) and a testing dataset (30%). For selecting variables that allow classification of the GAP stage, single and multiple logistic regression models were fitted and compared by using the Akaike information criterion (AIC). Diagnostic accuracy was evaluated from the area under the curve (AUC) from receiver operating characteristic (ROC) analyses, and diagnostic sensitivity and specificity were calculated. RESULTS: Values for some radiomics features were significantly lower (p < 0.05) and those of other radiomics features were significantly higher (p = 0.001) in patients with GAP2 compared with those in patients with GAP1. The combination of two specific radiomics features in a multivariable model resulted in the lowest AIC of 10.73 with an AUC of 0.96, 84% sensitivity, and 99% specificity. Visual assessment of fibrosis was inferior in predicting individual GAP stages (AUC 0.86; 83% sensitivity; 74% specificity). CONCLUSION: The correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features indicating severity of SSc-ILD on HRCT, which are not recognized by visual analysis. KEY POINTS: • Radiomics features can predict GAP stage with a sensitivity of 84% and a specificity of almost 100%. • Extent of fibrosis on HRCT and a combined model of different visual HRCT-ILD features perform worse in predicting GAP stage. • The correlation of radiomics with GAP stage, but not with the visually defined features of ILD-HRCT, implies that radiomics might capture features on HRCT, which are not recognized by visual analysis.

The Role of Visceral Obesity, Sarcopenia and Sarcopenic Obesity on Surgical Outcomes After Liver Resections for Colorectal Metastases.

BACKGROUND: The impact of body compositions on surgical results is controversially discussed. This study examined whether visceral obesity, sarcopenia or sarcopenic obesity influence the outcome after hepatic resections of synchronous colorectal liver metastases. METHODS: Ninety-four consecutive patients with primary hepatic resections of synchronous colorectal metastases were identified from a single center database between January 2013 and August 2018. Patient characteristics and 30-day morbidity were retrospectively analyzed. Body fat and skeletal muscle were calculated by planimetry from single-slice CT images at the level of L3. RESULTS: Fifty-nine patients (62.8%) underwent minor hepatectomies, and 35 patients underwent major resections (37.2%). Postoperative complications occurred in 60 patients (62.8%) including 35 patients with major complications (Clavien-Dindo grade III-V). The mortality was nil at 30 days and 2.1% at 90 days. The body mass index showed no influence on postoperative outcomes (p = 1.0). Visceral obesity was found in 66 patients (70.2%) and was significantly associated with overall and major complication rates (p = .002, p = .012, respectively). Sarcopenia was observed in 34 patients (36.2%) without a significant impact on morbidity (p = .461), however, with longer hospital stay. Sarcopenic obesity was found in 18 patients (19.1%) and was significantly associated with postoperative complications (p = .014). Visceral obesity, sarcopenia and sarcopenic obesity were all identified as significant risk factors for overall postoperative complications. CONCLUSION: Visceral obesity, sarcopenic obesity and sarcopenia are independent risk factors for overall complications after resections of CRLM. Early recognition of extremes in body compositions could prompt to perioperative interventions and thus improve postoperative outcomes.

[Chronic pancreatitis : Characterization and differentiation from pancreatic cancer]. / Chronische Pankreatitis : Charakterisierung und Differenzierung zum Pankreaskarzinom.

CLINICAL/METHODOLOGICAL ISSUE: Chronic pancreatitis (CP) is a long-lasting inflammation of the pancreas that changes the normal structure and function of the organ. There are a wide range of inflammatory pancreatic diseases, of which some entities, such as focal pancreatitis (FP) or "mass-forming pancreatitis," can mimic pancreatic ductal adenocarcinoma (PDAC). As a consequence, a misdiagnosis can lead to avoidable and unnecessary surgery or delay of therapy. STANDARD RADIOLOGICAL METHODS: The initial imaging method used in pancreatic diseases is ultrasound due to its availability and low cost, followed by contrast-enhanced computed tomography (CE-CT), which is considered a workhorse in the diagnostic work-up of diseases of the pancreas. Magnetic resonance imaging (MRI) and/or MR cholangiopancreatography (MRCP) can be used as a problem-solving tool to distinguish between solid and cystic lesions, and to rule out abnormalities in the pancreatic ducts, such as those associated with recurrent acute pancreatitis (AP) or to show early signs of CP. MRCP has essentially replaced diagnostic endoscopic retrograde cholangiopancreatography (ERCP) in the initial assessment before any therapeutic intervention. PRACTICAL RECOMMENDATION: The following review article summarizes the relevant features of CT and MRI that can help to make the diagnosis of CP and to aid in the differentiation between focal pancreatitis and PDAC, even in difficult cases.

[Perioperative medical prophylaxis of venous thromboembolic events in head and neck surgery : A retrospective study and recommendations]. / Medikamentöse Thromboseprophylaxe bei Kopf-Hals-Operationen : Eine retrospektive Analyse und Handlungsempfehlung.

BACKGROUND: In the authors' department, a newly implemented clinical algorithm for application of perioperative thrombosis prophylaxis in head and neck surgery recommends restrictive handling of anticoagulants. This retrospective study aims to evaluate the algorithm by comparing incidences of venous thromboembolic events (VTE) and surgical revisions due to postoperative hemorrhage. MATERIALS AND METHODS: Perioperative incidences of deep vein thrombosis and pulmonary embolism as well as surgical revisions due to postoperative hemorrhage after head and neck surgery were determined based on all patients operated in the department over a period of 36 months. The incidences before (group I) and after (group II) implementation of the restrictive algorithm were compared. RESULTS: A total of 9276 patients were included. The incidences of VTE (0.12%) and surgical revisions due to postoperative hemorrhage (1.4%) were low. Incidences of VTE were non-significantly higher in group II (0.16%) than in group I (0.08%; p > 0.45, chi-square-test). Case analysis revealed that this difference was not due to implementation of the restrictive algorithm. The incidence of surgical revision due to postoperative hemorrhage was identical in the two groups (1.4%). CONCLUSION: After restricting the indication for thrombosis prophylaxis, the incidence of VTE or surgical revision due to postoperative hemorrhage did not change significantly. The provided clinical algorithm represents a low-risk and low-cost strategy of perioperative risk stratification.

[Effects of the SARS-CoV­2 pandemic on the otolaryngology university hospitals in the field of research, student teaching and specialist training]. / Auswirkungen der SARS-CoV­2-Pandemie auf die universitäre Hals-Nasen-Ohren-Heilkunde im Bereich der Forschung, Lehre und Weiterbildung.

BACKGROUND: From spring 2020, SARS-CoV­2 began to spread worldwide, with what is now known as the first wave of the pandemic, starting in March 2020. This resulted in restructuring and shift of resources at many hospitals. The aim of our work was to detect the effects of the pandemic on the german Oto-Rhino-Laryngology (ORL) university hospitals in terms of research, student teaching and further specialist training. MATERIAL AND METHODS: The chairmen of the 39 ORL university hospitals in Germany were asked about the effects of the pandemic on research, student teaching and ORL specialist training (residency) in the period from March to April 2020 using a structured online survey. RESULTS: All 39 chairmen took part in the survey. Of these, 74.4% (29/39) stated that their research activities had deteriorated as a result of the pandemic. In 61.5% (24/39) pandemic-related research issues were addressed. All hospitals reported a restriction for in-house teaching and 97.5% (38/39) introduced new digital teaching methods. During the observation period, 74.4% of the chairmen did not see ORL specialist training (residency)at risk. CONCLUSION: Our results provide an insight into the heterogeneous effects of the pandemic. The fast processing of pandemic-related research topics and the introduction of innovative digital concepts for student teaching impressively demonstrates the great innovative potential and the ability of the ORL university hospitals to react quickly in order to maintain their tasks in research, student teaching and ORL specialist training in the best possible way even during the pandemic.

A career start in the Third Reich : The pathologist and Rudolf Virchow Award recipient Walter Müller (1907-1983).

The pathologist Walter Müller is undoubtedly one of the most prominent post-war representatives of his profession. He became full professor and founding dean in Essen, and in 1983 the German Society for Pathology (DGP) awarded him the Rudolf Virchow Medal - the highest distinction of the society - for his merits to the field of pathology.But this glorious career was by no means predetermined. Rather, after the end of the Second World War there were signs of a career break that were still largely unknown. After fleeing Königsberg from the approaching Red Army, Müller had to fear for his professional existence and his scientific advancement, as he was threatened with a ban on his profession in connection with denazification. As a young assistant doctor, Müller had joined the Berlin SA soon after the National Socialists took power and had also applied for membership of the NSDAP in 1937.Using Müller as an example, this article deals with the political influences and effects of National Socialism on young scientists and their career development. It poses the question of typical political barriers and overarching patterns of adaptation.On the basis of the personal written estate, personal archive sources, and a reanalysis of the available secondary literature, existing self-portrayals and narratives of Walter Müller are critically reviewed and supplemented. Several examples show that Müller's career development was characterized by a willingness to adapt politically. After a brief career slump in the years 1946/47, he succeeded in consolidating his career thanks to a mild denazification process and subsequently became one of the leading experts in German-language pathology.

[Primary cutaneous CD4+ small to medium-sized T-cell lymphoma in an adolescent patient]. / Primäres kutanes CD4+ klein- bis mittelgroßzelliges T-Zell-Lymphom bei einem Jugendlichen.

A rare finding of primary cutaneous CD4+ small to medium-sized T­cell lymphoma (SMPTCL) in a fifteen-year-old patient is reported. This is a rare tumor entity for which there is currently no standardized treatment recommendation. At the interdisciplinary tumor board, the decision was made to resect the tumor and reconstruct the defect with a nasolabial advancement flap in a two-stage process. Follow-up examinations, currently over 3 years, have shown the patient to be free of recurrences.

[Comparison of T cell response in the tumor milieu of patients with HPV+ and HPV- head and neck cancer]. / Vergleich der T-Zell-Antwort im Tumormilieu von Patienten mit HPV+- und HPV−-Kopf-Hals-Karzinom.

BACKGROUND: The incidence of HPV-associated squamous cell carcinoma of the head and neck region (HNSCC) has increased dramatically in recent years. Despite a similar localization (oropharyngeal squamous cell epithelia) to smoking- and alcohol-associated cancers, HPV-associated carcinomas are considered to represent a distinct entity. Reasons for the different therapeutic responses of the two tumor entities are not yet fully understood. METHODS AND OBJECTIVE: This review investigates the importance of tumor-infiltrating lymphocytes in HPV+ and HPV- HNSCC by means of articles and publications concerning the tumor micromilieu, effects on prognosis, and patients' therapeutic responses. RESULTS: HNSCC patients with a positive HPV status and increased frequencies of CD8+ T cells (CD, cluster of differentiation) demonstrated an improved therapeutic response and improved outcomes. Decreased expression of the EGF (epidermal growth factor) receptor correlates with increased TH1 cytokine secretion by CD4+ T cells, which, in their role as T helper cells, can activate macrophages, dendritic cells, and cytotoxic T cells, amongst others. Regulatory T cells (Treg) execute an immune-suppressive effect in the tumor micromilieu through different metabolic and signaling pathways (IL[interleukin]­4, IL-10, TGF­ß ["transforming growth factor­ß"]). CONCLUSION: The importance of the adaptive immune response for treatment response and patients' prognosis has been supported by different investigations. Understanding the immunological processes in the tumor environment plays an important role for the development of new treatment approaches.

[The role of surgery and salvage surgery in the era of HPV-associated oropharyngeal carcinomas]. / Rolle der Chirurgie und Salvage-Chirurgie in der Ära HPV-assoziierter Oropharynxkarzinome.

The incidence of human papillomavirus (HPV)-positive oropharyngeal carcinomas is increasing worldwide. Due to a markedly different response to treatment compared to HPV-negative oropharyngeal carcinomas, determining the ideal therapeutic approach can be challenging. Particularly in never-smokers, HPV-positive oropharyngeal carcinomas respond well to primary radiation therapy; at the same time recent studies indicate comparable survival after primary surgery. For stage I tumors according to TNM­8, retrospective analyses show very good oncologic outcomes after surgery alone, and no added benefit of adjuvant radio- or chemotherapy. Results of prospective treatment deintensification trials are expected in the coming years. Minimally invasive transoral surgical approaches for selected oropharyngeal cancers can improve preservation of postoperative function and quality of life. For both HPV-positive and HPV-negative oropharyngeal carcinomas, salvage surgery is the treatment of choice for resectable recurrent locoregional disease and resectable distant metastases.

[Neutrophils in the tumor microenvironment-foes or friends?] / Neutrophile Granulozyten im Tumormikromilieu ­ Feind oder Freund?

Neutrophils are the most abundant white blood cells in the human circulation and are usually associated with inflammation and with fighting infections. In recent years, the role of these cells during cancer progression has been a matter of increasing interest. Tumor-associated neutrophils (TANs) accumulate in cancer patients and represent an important negative prognostic marker in a broad variety of neoplasms. Accordingly, TANs represent a highly attractive therapeutic target. TAN may exhibit tumor-promoting or -inhibiting functions. Pro-tumor neutrophils support tumor angiogenesis and growth and promote metastatic dissemination of tumors via establishment of the premetastatic niche. Studies in animal models have already shown that the depletion of TANs or the inhibition of their migration bears therapeutic potential. Multiple pathways and mediators that induce pro-tumoral functions in neutrophils have been identified. In this review, we provide an up-to-date overview of the pro- and anti-tumor properties of neutrophils as well as the environmental cues that regulate these distinct functions. We also report on our own work that comprehensively investigated the role of neutrophils in head and neck cancer.

[Transoral resection of supraglottic laryngeal tumors with the Flex Robotic System]. / Transorale Resektion von supraglottischen Larynxkarzinomen mit dem Flex Robotic System.

The Flex Robotic System (Medrobotics, Raynham, MA, USA) allows flexible transoral endoscopic resection of head and neck tumors. The current article presents functional and first oncologic experiences with flexible transoral robot-assisted surgery for resection of supraglottic laryngeal tumors. From July 2014 to February 2020, supraglottic cancers in 32 patients (T1 = 11, T2 = 20, T3 = 1) were resected using the Flex Robotic System in the authors' clinic. Within a prospective clinical study, the feasibility, complications, and oncologic results were assessed. Tumors could be exposed, visualized, and successfully resected in all patients. In difficult-to-reach anatomic regions such as the aryepiglottic fold or petiole, the system provided a very good surgical overview. No serious adverse events occurred. Overall survival and local tumor control after 2 years were 88 and 94%, respectively. In conclusion, supraglottic tumors in difficult-to-reach areas have been successfully resected using the Flex Robotic System, with excellent local tumor control.

[Head and neck cancer in the elderly-current aspects]. / Tumorerkrankungen des Kopf-Hals-Bereichs im höheren Lebensalter ­ aktuelle Aspekte.

BACKGROUND: The treatment of head and neck cancer is dominated by surgery and radiochemotherapy, which is in part associated with high morbidity. In elderly patients, however, the otorhinolaryngologist often has to question the rationality of invasive treatment. Although the proportion of geriatric patients with head and neck tumors is increasing, the paucity of data means that there are few consistent standards and recommendations in the literature and guidelines. OBJECTIVE: The aim of this paper is to provide concrete clinical recommendations for geriatric patients with head and neck tumors based on a systematic literature search. MATERIALS AND METHODS: A keyword-based literature search was performed to present the current level of evidence and provide a clinical algorithm. RESULTS: In addition to age, the pretreatment dispositional evaluation of geriatric patients should include psychosocial, functional, and medical (patient history) comorbidities. For pretreatment risk stratification, an algorithm was created on the basis of these data for individual evaluation of the patient's pretreatment risk. CONCLUSION: Pretreatment risk stratification of geriatric patients with head and neck malignancies is of high relevance for the individual decision for or against invasive treatment, but the currently available evidence is limited. This paper is based on a systematic literature review and provides a clinical algorithm for otorhinolaryngologists and head and neck surgeons.

[Exosomes as immune regulators in head and neck cancer]. / Exosomen als Immunregulatoren in Kopf-Hals-Karzinomen.

Exosomes, virus-sized nanovesicles, are utilized as messenger systems of our body to communicate with other body cells and regulate immune functions. Almost all cells produce exosomes and are able to interact with immune cells in the blood stream and peripheral body areas. Different markers on the surface of exosomes are necessary for immune cell adhesion and interaction. Furthermore, many types of exosome-immune cell interaction, such as surface receptor contact and phagocytosis, are known. As carriers of different cargos, exosomes affect different immune cell types in head and neck cancers: So far, T cells, natural killer cells, macrophages, and dendritic cells have been described in this context. For diagnostic purposes, a combined analysis of different parameters including protein amount, nucleic acid/protein expression, and the immunosuppressive impact of exosomes could empower exosomes as useful tools for evaluation of tumor promotion and progression in the future.

[The microbiome in head and neck tumors-initial findings and outlook]. / Das Mikrobiom bei Kopf-Hals-Tumoren ­ erste Erkenntnisse und Ausblick.

Technical progress in molecular biology has allowed for a more detailed analysis of the composition of the human microbiome in recent years. Inter- and intraindividual differences in microbiome composition have been demonstrated, which in part correlate with the occurrence of certain diseases. For some of the so-called oncomicrobes, a direct relationship between their effect on the host organism and carcinogenesis has been demonstrated, predominantly for gastrointestinal cancers. Initial results for head and neck cancer show inter- and intraindividual differences in the local microbiota of the tumor environment, with certain bacterial strains over- or underrepresented. Our results confirm these findings, e.g., by showing a relative abundance of fusobacteria in tumor tissue while streptococci were relatively reduced. Currently available results show a high degree of inter- and intraindividual variation, thus requiring larger patient cohorts for functional analyses.

[Tumor microenvironment in salivary gland carcinomas: Consequences for new therapeutic concepts]. / Das Tumormikromilieu bei Speicheldrüsenkarzinomen ­ mögliche Konsequenzen für neue Therapiekonzepte.

INTRODUCTION: Salivary gland carcinomas (SGCs) are rare tumors which represent a challenge for diagnosis and therapy due to their histological diversity and the different disease courses depending on the respective subtype. Little is known about the composition of the tumor microenvironment in SGCs. A more comprehensive understanding of the relevant molecular changes and immunological processes of the tumor and surrounding stroma could help to improve therapeutic efficiency, for example by adjuvant immunomodulation. METHODS: This manuscript highlights recent studies analyzing the composition of the tumor microenvironment in salivary gland carcinomas. RESULTS: The tumor microenvironment displays a significant diversity in the composition of immune cells among different tumor entities. In one third of the SGCs, an expression of cell surface molecule LAG3 on tumor infiltrating lymphocytes could be observed. LAG3-similar to CTLA­4 and PD-1-inhibits cellular proliferation, activation, and homeostasis of antitumor-effective T cells. Especially, prognostically less favorable entities such as salivary duct carcinomas and adenocarcinomas NOS (not otherwise specified) yielded higher expressions. CONCLUSIONS: LAG3 is particularly detectable in aggressive entities and advanced tumors. Hence, LAG3 inhibition poses a potential targeted therapy for advanced and metastatic SGCs.

[Stimulatory and inhibitory signaling pathways of the T cell-APC interaction and the effect of TLR agonists on APCs]. / Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ.

BACKGROUND: CD8+ cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8+ T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs). OBJECTIVE: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction. MATERIALS AND METHODS: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48 h of CD14+ cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8+ T cells were stimulated for 72 h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD­1, Tim­3, CTLA4, and Lag3 by flow cytometry. RESULTS: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD­1 checkpoint blockade. CONCLUSION: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8+ T cell exhaustion. The effect of PD­1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.