Effect of hypoglossal nerve stimulation on snoring: an evaluation using objective acoustic parameters.

STUDY OBJECTIVES: Hypoglossal nerve stimulation is an established therapy for sleep apnea syndrome. Whether or not this therapy on snoring and nighttime noise exposure is effective and how strong this effect may be has not been objectively investigated thus far and was the aim of this study. METHODS: In 15 participants (14 males; age: 30-72 years; mean: 51.7 years), polysomnography and acoustic measurements were performed before and after hypoglossal nerve stimulation. RESULTS: The therapy led to a significant improvement in sleep apnea (apnea-hypopnea index from 35.8 events/h to 11.2 events/h, P < .001). Acoustic parameters showed a highly significant reduction in the average sound pressure level (42.9 db[A] to 36.4 db[A], P < .001), averaged sound energy, A-weighted (LAeq; 33.1 db[A] to 28.7 db[A], P < .001), snoring index (1,068 to 506, P < .001), percentage snoring time (29.7-14.1%, P < .001), and psychoacoustic snore score, the latter being a measure of annoyance due to snoring (47.9 to 24.5, P < .001). CONCLUSIONS: This study was able to show for the first time by means of objective acoustic and psychoacoustic parameters that hypoglossal nerve stimulation can not only cause a significant improvement in sleep apnea but also has a positive effect on snoring and thus noise annoyance experienced by the bed partner. CLINICAL TRIAL REGISTRATION: Registry: German Clinical Trials Register; Name: Effect of Hypoglossal Nerve Stimulation on Snoring: An Evaluation Using Objective Acoustic Parameters; URL: https://drks.de/search/de/trial/DRKS00032354; Identifier: DRKS00032354. CITATION: Fischer R, Vielsmeier V, Kuehnel TS, et al. Effect of hypoglossal nerve stimulation on snoring: an evaluation using objective acoustic parameters. J Clin Sleep Med. 2024;20(3):363-370.

Correction: Schuderer et al. Risk Factors for Flap Loss: Analysis of Donor and Recipient Vessel Morphology in Patients Undergoing Microvascular Head and Neck Reconstructions. J. Clin. Med. 2023, 12, 5206.

In the original publication by Schuderer et al., there was a mistake in Table 1 as published [...].

Evidence-Based Approaches to Anticoagulation in Reconstructive Microsurgery-A Systematic Literature Review.

This systematic review addresses the crucial role of anticoagulation in microsurgical procedures, focusing on free flap reconstruction and replantation surgeries. The objective was to balance the prevention of thrombotic complications commonly leading to flap failure, with the risk of increased bleeding complications associated with anticoagulant use. A meticulous PubMed literature search following Evidence-Based-Practice principles yielded 79 relevant articles, including both clinical and animal studies. The full-texts were carefully reviewed and evaluated by the modified Coleman methodology score. Clinical studies revealed diverse perioperative regimens, primarily based on aspirin, heparin, and dextran. Meta-analyses demonstrated similar flap loss rates with heparin or aspirin. High doses of dalteparin or heparin, however, correlated with higher flap loss rates than low dose administration. Use of dextran is not recommended due to severe systemic complications. In animal studies, systemic heparin administration showed predominantly favorable results, while topical application and intraluminal irrigation consistently exhibited significant benefits in flap survival. The insights from this conducted systematic review serve as a foundational pillar towards the establishment of evidence-based guidelines for anticoagulation in microsurgery. An average Coleman score of 55 (maximum 103), indicating low overall study quality, however, emphasizes the need for large multi-institutional, randomized-clinical trials as the next vital step.

Risk Factors for Flap Loss: Analysis of Donor and Recipient Vessel Morphology in Patients Undergoing Microvascular Head and Neck Reconstructions.

In microvascular head and neck reconstruction, various factors such as diabetes, alcohol consumption, and preoperative radiation hold a risk for flap loss. The primary objective of this study was to examine the vessel morphology of both recipient and donor vessels and to identify predictors for changes in the diameters of H.E.-stained specimens associated with flap loss in a prospective setting. Artery and vein samples (N = 191) were collected from patients (N = 100), with sampling from the recipient vessels in the neck area and the donor vessels prior to anastomosis. External vessel diameter transverse (ED), inner vessel diameter transverse (ID), thickness vessel intima (TI), thickness vessel media (TM), thickness vessel wall (TVW), and intima-media ratio (IMR) for the recipient (R) and transplant site (T) in arteries (A) and veins (V) were evaluated using H.E. staining. Flap loss (3%) was associated with increased ARED (p = 0.004) and ARID (p = 0.004). Preoperative radiotherapy led to a significant reduction in the outer diameter of the recipient vein in the neck (p = 0.018). Alcohol consumption (p = 0.05), previous thrombosis (p = 0.007), and diabetes (p = 0.002) were associated with an increase in the total thickness of venous recipient veins in the neck. Diabetes was also found to be associated with dilation of the venous media in the neck vessels (p = 0.007). The presence of cardiovascular disease (CVD) was associated with reduced intimal thickness (p = 0.016) and increased total venous vessel wall thickness (p = 0.017) at the transplant site. Revision surgeries were linked to increased internal and external diameters of the graft artery (p = 0.04 and p = 0.003, respectively), while patients with flap loss showed significantly increased artery diameters (p = 0.004). At the transplant site, alcohol influenced the enlargement of arm artery diameters (p = 0.03) and the intima-media ratio in the radial forearm flap (p = 0.013). In the anterolateral thigh, CVD significantly increased the intimal thickness and the intima-media ratio of the graft artery (p = 0.01 and p = 0.02, respectively). Patients with myocardial infarction displayed increased thickness in the A. thyroidea and artery media (p = 0.003). Facial arteries exhibited larger total vessel diameters in patients with CVD (p = 0.03), while facial arteries in patients with previous thrombosis had larger diameters and thicker media (p = 0.01). The presence of diabetes was associated with a reduced intima-media ratio (p < 0.001). Although the presence of diabetes, irradiation, and cardiovascular disease causes changes in vessel thickness in connecting vessels, these alterations did not adversely affect the overall success of the flap.

Novel Three-Dimensional and Non-Invasive Diagnostic Approach for Distinction between Odontogenic Keratocysts and Ameloblastomas.

Aim of this study was to demonstrate the diagnostic ability to differentiate odontogenic keratocysts (OKCs) from ameloblastomas (AMs) based on computed tomography (CT) or cone beam computed tomography (CBCT) scans. Preoperative CT and CBCT scans from 2004 to 2019 of OKCs and AMs were analyzed in 51 participants. Lesions were three-dimensionally (3D) assessed and Hounsfield units (HU) as well as gray scale values (GSV) were quantified. Calculated HU spectra were compared within the same imaging modalities using unpaired t-tests and correlated with participants characteristics by calculating Pearsons correlation coefficients. Within the CT scans, AMs had highly significantly higher HU values compared to OKCs (43.52 HU and 19.79 HU, respectively; p < 0.0001). Analogous, within the CBCT scans, AMs had significantly higher GSV compared to OKCs (-413.76 HU and -564.76 HU, respectively; p = 0.0376). These findings were independent from participants' gender and age, anatomical site, and lesion size, indicating that the HU- and GSV-based difference reflects an individual configuration of the lesion. HU and GSV spectra calculated from CT and CBCT scans can be used to discriminate between OKCs and AMs. This diagnostic approach represents a faster and non-invasive option for preoperative diagnosis of such entities and has potential to facilitate therapeutic decision making.

Thin PDS Foils Represent an Equally Favorable Restorative Material for Orbital Floor Fractures Compared to Titanium Meshes.

Orbital floor fractures (OFFs) are common injuries of the midface and may result in long-term complications. The aim of this study was to compare two restoration materials, PDS foils and titanium meshes, with regards to (1) clinical outcome and (2) reduction in orbital volume. The monocentric discovery cohort was analyzed retrospectively and included 476 patients with OFFs treated between 2010 and 2020. A subcohort of 104 patients (study cohort) with isolated OFFs and available high-resolution imaging material was used for volume measurements. Postoperative complications were not significantly different between patients treated with different restoration materials. Prevalence of revision surgery was significantly higher in patients treated with thick PDS foils (25 mm). OFFs treated with PDS foils and titanium meshes showed a significant reduction in orbital volume (p = 0.0422 and p = 0.0056, respectively), however, this volume decrease was significantly less pronounced in patients treated with PDS foils alone (p = 0.0134). Restoration using PDS foil in an isolated OFF reduces the orbital volume to a lesser extent than titanium mesh. Class III patients according to the classification of Jaquiéry with a missing bony ledge medial to the infraorbital fissure particularly benefit from restoration with PDS foils due to a lower reduction in the orbital volume. Regarding short- and long-term postoperative complications, a PDS foil thickness of 0.15 mm appears equivalent to titanium mesh in the treatment of OFFs.

OSCC in Never-Smokers and Never-Drinkers Is Associated with Increased Expression of Tumor-Infiltrating Lymphocytes and Better Survival.

The aim of this study was to investigate the clinical, histopathologic, and immunologic differences of oral squamous cell carcinoma of never-smokers/never-drinkers and smokers/drinkers. Immunohistochemical staining for CD4, CD8, FoxP3, CD1a, and p16 was performed in 131 oral squamous cell carcinomas from smokers/drinkers and never-smokers/never-drinkers. Associations of smoking/drinking status with clinicopathologic data, immunohistochemical antibody expression, and survival were examined. Oral squamous cell carcinoma in never-smokers/never-drinkers was associated with the female gender (p < 0.001). Never-smokers/never-drinkers were older at diagnosis than smokers/drinkers (p < 0.001). Never-smokers/never-drinkers had more tumors in the maxilla, mandible, and tongue (p < 0.001). Pre-existing oral potentially malignant disorders appeared to be more common in never-smokers/never-drinkers (p < 0.001). Perineural invasion was more common in smokers/drinkers (p = 0.039). Never-smoking/never-drinking was associated with better overall survival (p = 0.004) and disease-specific survival (p = 0.029). High CD4+ T cell infiltration was associated with never-smoking/never-drinking (p = 0.008). Never-smokers/never-drinkers also showed increased CD8+ T cell infiltration (p = 0.001) and increased FoxP3+ Treg infiltration (p = 0.023). Furthermore, the total group of tumor-infiltrating lymphocytes was associated with never smoking/never drinking (p = 0.005). To conclude oral squamous cell carcinoma of the never-smokers/never-drinkers appears to be a distinct type of tumor, as it appears to have unique clinical and pathologic features and a more immunogenic microenvironment.

Direct Anthropometry Overestimates Cranial Asymmetry-3D Digital Photography Proves to Be a Reliable Alternative.

This study compared manual and digital measurements of plagiocephaly and brachycephaly in infants and evaluated whether three-dimensional (3D) digital photography measurements can be used as a superior alternative in everyday clinical practice. A total of 111 infants (103 with plagiocephalus and 8 with brachycephalus) were included in this study. Head circumference, length and width, bilateral diagonal head length, and bilateral distance from the glabella to the tragus were assessed by manual assessment (tape measure and anthropometric head calipers) and 3D photographs. Subsequently, the cranial index (CI) and cranial vault asymmetry index (CVAI) were calculated. Measured cranial parameters and CVAI were significantly more precise using 3D digital photography. Manually acquired cranial vault symmetry parameters were at least 5 mm lower than digital measurements. Differences in CI between the two measuring methods did not reach significance, whereas the calculated CVAI showed a 0.74-fold decrease using 3D digital photography and was highly significant (p < 0.001). Using the manual method, CVAI calculations overestimated asymmetry, and cranial vault symmetry parameters were measured too low, contributing to a misrepresentation of the actual anatomical situation. Considering consequential errors in therapy choices, we suggest implementing 3D photography as the primary tool for diagnosing deformational plagiocephaly and positional head deformations.

Two-Dimensional Post-Traumatic Measurements of Orbital Floor Blowout Fractures Underestimate Defect Sizes Compared to Three-Dimensional Approaches.

Orbital floor fractures represent a common fracture type of the midface and are standardly diagnosed clinically as well as radiologically using linear measurement methods. The aim of this study was to evaluate the accuracy of diagnostic measurements of isolated orbital floor fractures based on two-dimensional (2D) and three-dimensional (3D) measurement techniques. A cohort of 177 patients was retrospectively and multi-centrically evaluated after surgical treatment of an orbital floor fracture between 2010 and 2020. In addition to 2D and 3D measurements of the fracture area, further fracture-related parameters were investigated. Calculated fracture areas using the 2D measurement technique revealed an average area of 287.59 mm2, whereas the 3D measurement showed fracture areas with a significantly larger average value of 374.16 mm2 (p < 0.001). On average, the 3D measurements were 1.53-fold larger compared to the 2D measurements. This was observed in 145 patients, whereas only 32 patients showed smaller values in the 3D-based approach. However, the process duration of the 3D measurement took approximately twice as long as the 2D-based procedure. Nonetheless, 3D-based measurement of orbital floor defects provides a more accurate estimation of the fracture area than the 2D-based procedure and can be helpful in determining the indication and planning the surgical procedure.

Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release. Expression levels of two recently described gene sets were determined in The Cancer Genome Atlas Head and Neck Cancer cohort (n = 522) and validated in the GSE65858 dataset (n = 250) as well as a recently published single-cell RNA sequencing dataset (n = 18). Clustering into HPV(+) and HPV(-) patients was performed in all cohorts for further analysis. Potential associations between gene expression levels, immune cell infiltration, and patient overall survival were analyzed using GEPIA2, TISIDB, TIMER, and the UCSC Xena browser. Compared to normal control tissues, vesiculation-related genes were upregulated in HNSCC cells. Elevated gene expression levels positively correlated (P < 0.01) with increased abundance of CD4(+) T cells, macrophages, neutrophils, and dendritic cells infiltrating tumor tissues but were negatively associated (P < 0.01) with the presence of B cells and CD8(+) T cells in the tumor. Expression levels of immunosuppressive factors NT5E and TGFB1 correlated with the vesiculation-related genes and might explain the alterations of the anti-tumor immune response. Enhanced expression levels of vesiculation-related genes in tumor tissues associates with the immunosuppressive tumor milieu and the reduced infiltration of B cells and CD8(+) T cells into the tumor.

Statin Use Ameliorates Survival in Oral Squamous Cell Carcinoma-Data from a Population-Based Cohort Study Applying Propensity Score Matching.

The anti-cancer properties of statins have attracted much attention recently, but little is known about the prognostic role of statins in oral squamous cell carcinoma (OSCC). In a retrospective approach, we analyzed a population-based cohort of 602 OSCC patients with primary curative tumor resection to negative margins and concomitant neck dissection between 2005-2017. Long-term medication with statins was correlated with overall survival (OAS) as well as recurrence-free survival (RFS) using uni- and multivariable Cox regression. Additionally, propensity score matching was applied to adjust for confounders. Statin use was present in 96 patients (15.9%) at a median age of 65.7 years. Statin treatment correlated with ameliorated survival in multivariable Cox regression in the complete cohort (OAS: HR 0.664; 95% CI 0.467-0.945, p = 0.023; RFS: HR 0.662; 95% CI 0.476-0.920, p = 0.014) as well as matched-pair cohort of OSCC patients (OAS: HR 0.691; 95% CI 0.479-0.997, p = 0.048; RFS: HR 0.694; 95% CI 0.493-0.976, p = 0.036) when compared to patients not taking statins at time of diagnosis. These findings were even more pronounced by sub-group analysis in the matched-pair cohort (age < 70 years). These data indicate that statin use might ameliorate the oncological outcome in primarily resected OSCC patients, but prospective clinical trials are highly recommended.

TGFß carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Contributions of TGFß to cancer progression are well documented. However, plasma TGFß levels often do not correlate with clinicopathological data. We examine the role of TGFß carried in exosomes isolated from murine and human plasma as a contributor to disease progression in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The 4-nitroquinoline-1-oxide (4-NQO) mouse model was used to study changes in TGFß expression levels during oral carcinogenesis. In human HNSCC, TGFß and Smad3 protein expression levels and TGFB1 gene expression were determined. Soluble TGFß levels were evaluated by ELISA and TGFß bioassays. Exosomes were isolated from plasma using size exclusion chromatography, and TGFß content was quantified using bioassays and bioprinted microarrays. RESULTS: During 4-NQO carcinogenesis, TGFß levels in tumour tissues and in serum increased as the tumour progressed. The TGFß content of circulating exosomes also increased. In HNSCC patients, TGFß, Smad3 and TGFB1 were overexpressed in tumour tissues and correlated with increased soluble TGFß levels. Neither TGFß expression in tumours nor levels of soluble TGFß correlated with clinicopathological data or survival. Only exosome-associated TGFß reflected tumour progression and correlated with tumour size. CONCLUSIONS: Circulating TGFß+ exosomes in the plasma of patients with HNSCC emerge as potential non-invasive biomarkers of disease progression in HNSCC.

Elective Tracheotomy in Patients Receiving Mandibular Reconstructions: Reduced Postoperative Ventilation Time and Lower Incidence of Hospital-Acquired Pneumonia.

Elective tracheotomy (ET) secures the airway and prevents adverse airway-related events as unplanned secondary tracheotomy (UT), prolonged ventilation (PPV) or nosocomial infection. The primary objective of this study was to identify factors predisposing for airway complications after reconstructive lower ja surgery. We reviewed records of patients undergoing mandibulectomy and microvascular bone reconstruction (N = 123). Epidemiological factors, modus of tracheotomy regarding ET and UT, postoperative ventilation time and occurrence of hospital-acquired pneumonia HAP were recorded. Predictors for PPV and HAP, ET and UT were identified. A total of 82 (66.7%) patients underwent tracheotomy of which 12 (14.6%) were performed as UT. A total of 52 (42.3%) patients presented PPV, while 19 (15.4%) developed HAP. Increased operation time (OR 1.004, p = 0.005) and a difficult airway (OR 2.869, p = 0.02) were predictors, while ET reduced incidence of PPV (OR 0.054, p = 0.006). A difficult airway (OR 4.711, p = 0.03) and postoperative delirium (OR 6.761, p = 0.01) increased UT performance. HAP increased with anesthesia induction time (OR 1.268, p = 0.001) and length in ICU (OR 1.039, p = 0.009) while decreasing in ET group (HR 0.32, p = 0.02). OR for ET increased with mounting CCI (OR 1.462, p = 0.002) and preoperative radiotherapy (OR 2.8, p = 0.018). ET should be strongly considered in patients with increased CCI, preoperative radiotherapy and prolonged operation time. ET shortened postoperative ventilation time and reduced HAP.

A20 as a Potential New Tool in Predicting Recurrence and Patient's Survival in Oral Squamous Cell Carcinoma.

A20, known as a potent inhibitor of NF-κB signaling, has been characterized in numerous clinical as well as preclinical studies. Recently, especially in various malignant diseases, the prognostic and therapeutic relevance of A20 was investigated. In oral squamous cell carcinoma (OSCC) however, the characterization of A20 is uncharted territory. We analyzed a tissue microarray (TMA) of 229 surgically-treated OSCC patients (2003-2013). Immunohistochemical (IHC) stainings were performed for A20 and CD3; additionally, standard haematoxylin-eosin staining was applied. IHC findings were correlated with a comprehensive dataset, comprising clinical and pathohistological information. A20 expression was analyzed in tumor cells as well as in tumor infiltrating lymphocytes (TILs) and correlated with the overall survival (OS) and recurrence-free survival (RFS) using uni- and multivariable Cox regression. The median follow-up time was 10.9 years and the A20 expression was significantly decreased in CD3+ TILs compared to mucosa-infiltrating lymphocytes (MILs). In the Kaplan-Meier analyses, higher A20 expression in TILs was correlated with better OS (p = 0.017) and RFS (p = 0.020). In the multivariable survival analysis, A20 overexpression correlated with improved OS (HR: 0.582; 95% CI 0.388-0.873, p = 0.009) and RFS (HR 0.605; 95% CI 0.411-0.889, p = 0.011). Our results indicate a novel prognostic role for A20 in OSCC. Due to its elevated expression in TILs, further research is highly desirable, which therefore could offer new therapeutic opportunities for patients suffering from OSCC.

Negative Pressure Wound Therapy with Instillation: Analysis of the Rinsing Fluid as a Monitoring Tool and Approach to the Inflammatory Process: A Pilot Study.

BACKGROUND: Negative pressure wound therapy with instillation (NPWTi) is an established wound conditioning tool. Previous investigations discovered that the rinsing fluid is a suitable monitoring tool containing various cells and cytokines. METHODS: The aim of this pilot study was to analyze rinsing fluid samples from patients treated with NPWTi and link them to the clinical course, including microbiological contamination. In 31 consecutive patients with acute and chronic wounds, laboratory analysis was performed to evaluate IL-6, IL-8, bFGF, Tnf-a, and VEGF. RESULTS: IL-6 showed a significant increase to 1540 pg/mL on day two and 860 pg/mL on day four (p = 0.01 and p = 0.04, resp.). IL-8 steadily increased from a median of 2370 pg/mL to a maximum of 19,400 pg/mL on day three (p = 0.01). The median bFGF showed a steady decline from 22 pg/mL to 10 pg/m (p = 0.35) on day three. The median Tnf-a increased from 11 pg/mL to 44 pg/mL (p = 001). The median VEGF values fluctuated but showed an overall increase from 35 pg/mL to 250 pg/mL (p = 0.07). Regarding IL-8, diabetic and non-diabetic patients both showed a gradual increase with non-significant higher median values for the diabetics. The subgroup analysis of IL-6 showed increasing and higher values in cases with bacterial superinfections (p = 0.07). CONCLUSION: We were able to use an established wound conditioning tool to gather important information about the inflammatory response during NPWTi treatment. Cytokine and cell courses were mostly consistent with the literature, especially in diabetic patients, and should be further investigated.

TIGIT Expression on Intratumoral Lymphocytes Correlates with Improved Prognosis in Oral Squamous Cell Carcinoma.

(1) Background: T-cell immunoglobulin and ITIM domain (TIGIT) is a potential immunotherapeutic target in a variety of malignant entities, and antibody-based treatments are currently under investigation in clinical trials. While promising results were observed in patients with lung cancer, the role of TIGIT in oral squamous cell carcinoma (OSCC) as a biomarker as well as a therapeutic target remains elusive. Therefore, we evaluated the role of TIGIT as a prognostic factor in OSCC. (2) Methods: Here, we describe the results of a retrospective tissue microarray (TMA) OSCC cohort. Using immunohistochemistry, TIGIT expression was correlated with overall and recurrence-free survival (OAS and RFS, respectively). Additionally, in silico analysis was performed based on the TCGA Head and Neck Squamous Cell Carcinoma (HNSCC) cohort in order to correlate patients' survival with TIGIT and CD274 (encoding for PD-L1) gene expression levels. (3) Results: Database analysis revealed a beneficial outcome in OAS for tumor patients with high intraepithelial CD3-TIGIT-expression (n = 327). Hereby, OAS was 53.9 months vs. 30.1 months for patients with lower TIGIT gene expression levels (p = 0.033). In our retrospective OSCC-TMA cohort, elevated TIGIT levels on CD3+ cells correlated significantly with improved OAS (p = 0.025) as well as distant RFS (p = 0.026). (4) Conclusions: This study introduces TIGIT as a novel prognostic factor in OSCC, indicating the improved outcome of OSCC patients relative to their increased TIGIT expression. TIGIT might provide therapeutic implications for future immunotherapy in advanced-stage OSCC patients.

Prognostic Relevance of Type 2 Diabetes and Metformin Treatment in Head and Neck Melanoma: Results from a Population-Based Cohort Study.

BACKGROUND: Type 2 Diabetes (DM2) and the consecutively daily use of antidiabetic medication are characterized by a frequent prevalence worldwide and were shown to impact the initiation and progression of malignant diseases. While these effects were observed in a variety of malignancies, comprehensive data about the role of DM2 and antidiabetic drugs in the outcome of head and neck melanoma (HNM) patients are missing. METHODS: This retrospective population-based cohort study included 382 HNM patients from Eastern Bavaria having received tumor resection to negative margins between 2010 and 2017. Recurrence-free survival (RFS) was evaluated with regard to DM2 and routine metformin intake. Statistical analysis was performed by uni- and multivariate analyses. The median follow-up time was 5.6 years. RESULTS: DM2 was diagnosed in 68 patients (17.8%), routine metformin intake was found in 39 cases (10.2%). The univariate survival analysis revealed impaired 5-year RFS in HNM patients with DM2 compared to non-diabetic controls (p = 0.016; 64.0% and 74.5%, respectively). The multivariate Cox regression substantiated this effect (HR = 1.980, 95% CI = 1.108-3.538, p = 0.021). In detail, the cumulative locoregional recurrence rate displayed the most far-reaching negative effect on the RFS of diabetic HNM patients (HR = 4.173, 95% CI = 1.628-10.697, p = 0.003). For metformin intake, a profound positive effect on the RFS in multivariate statistics was observed, both in the complete cohort (HR = 0.396, 95% CI = 0.177-0.884, p = 0.024) as well as in the cohort of diabetic HNM patients (HR = 0.352, 95% CI = 0.135-0.913, p = 0.032). CONCLUSIONS: This study emphasizes that DM2 is a relevant comorbid condition in HNM patients, impairing patient survival. Metformin intake was associated with a favorable outcome in HNM patients, providing possible therapeutic implications for future adjuvant treatment regimes.

TGFß+ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.

Transforming growth factor ß (TGFß) is a major component of tumor-derived small extracellular vesicles (TEX) in cancer patients. Mechanisms utilized by TGFß+ TEX to promote tumor growth and pro-tumor activities in the tumor microenvironment (TME) are largely unknown. TEX produced by head and neck squamous cell carcinoma (HNSCC) cell lines carried TGFß and angiogenesis-promoting proteins. TGFß+ TEX stimulated macrophage chemotaxis without a notable M1/M2 phenotype shift and reprogrammed primary human macrophages to a pro-angiogenic phenotype characterized by the upregulation of pro-angiogenic factors and functions. In a murine basement membrane extract plug model, TGFß+ TEX promoted macrophage infiltration and vascularization (p < 0.001), which was blocked by using the TGFß ligand trap mRER (p < 0.001). TGFß+ TEX injected into mice undergoing the 4-nitroquinoline-1-oxide (4-NQO)-driven oral carcinogenesis promoted tumor angiogenesis (p < 0.05), infiltration of M2-like macrophages in the TME (p < 0.05) and ultimately tumor progression (p < 0.05). Inhibition of TGFß signaling in TEX with mRER ameliorated these pro-tumor activities. Silencing of TGFß emerges as a critical step in suppressing pro-angiogenic functions of TEX in HNSCC.

Postoperative Delirium after Reconstructive Surgery in the Head and Neck Region.

Postoperative delirium (POD) is an acute and serious complication following extended surgery. The aim of this study was to identify possible risk factors and scores associated with POD in patients undergoing reconstructive head and neck surgery. A collective of 225 patients was retrospectively evaluated after receiving reconstructive surgery in the head and neck region, between 2013 to 2018. The incidence of POD was examined with regards to distinct patient-specific clinical as well as perioperative parameters. Uni- and multivariate statistics were performed for data analysis. POD occurred in 49 patients (21.8%) and was strongly associated with an increased age-adjusted Charlson Comorbidity Index (ACCI) and a prolonged stay in the ICU (p = 0.009 and p = 0.000, respectively). Analogous, binary logistic regression analysis revealed time in the ICU (p < 0.001), an increased ACCI (p = 0.022) and a Nutritional Risk Screening (NRS) score ≠ 0 (p = 0.005) as significant predictors for a diagnosis of POD. In contrast, the extent of reconstructive surgery in terms of parameters such as type of transplant or duration of surgery did not correlate with the occurrence of POD. The extension of reconstructive interventions in the head and neck region is not decisive for the development of postoperative delirium, whereas patient-specific parameters such as age and comorbidities, as well as nutritional parameters, represent predictors of POD occurrence.