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An esthetic implant-supported rehabilitation continues to be a major challenge in patients with a thin periodontium. Ridge preservation and immediate implant placement are intended to preserve the hard tissue volume and prevent preimplant bone loss following tooth extraction. Since these techniques are almost always combined with bone grafting, primary wound closure is indispensable. Therefore, a technique for reliable wound closure was developed. This technique employs a combined epithelized-subepithelial connective tissue graft, leaves the mucogingival line in its place, and has the added advantage of thickening the buccal soft tissue with the resultant local conversion of a thin marginal gingiva to a thick marginal gingiva. [ABSTRACT FROM AUTHOR]

Objectives Early detection of oral cancer is a major health issue. The objective of this pilot study was to analyze the deformability of healthy and cancer cells using a microfluidic optical stretcher ( OS). Material and Methods Different cancer cell lines, primary oral cancer cells, and their healthy counterparts were cultivated and characterized, respectively. A measurable deformation of the cells along the optical axis was detected, caused by surface stress, which is optically induced by the laser power. Results All cells revealed a viscoelastic extension behavior and showed a characteristic deformation response under laser light exposure. The CAL-27/-33 cells exhibited the highest relative deformation. All other cells achieved similar values, but on a lower level. The cytoskeleton reacts sensitively of changing environmental conditions, which may be influenced by growth behavior of the cancer specimens. Nevertheless, the statistical analysis showed significant differences between healthy and cancer cells. Conclusion Generally, malignant and benign cells showed significantly different mechanical behavior. Cancer-related changes influence the composition of the cytoskeleton and thus affect the deformability, but this effect may be superimposed by cell cultivation conditions or cell doubling time. These influences had to be substituted by brush biopsies to minimize confounders in pursuing investigations. [ABSTRACT FROM AUTHOR]

During the last decade, oral cytology has once again become the focus of scientific research. This new interest is due to the introduction of a cytobrush for cell collection as well as a computer-assisted analysis (Oral CDx). Although promising, the sensitivity and specificity of conventional oral brush cytology remains limited. To circumvent the problems and improve the accuracy, various adjunctive analytical methods have been attempted. DNA analysis, immunocytochemical and molecular analysis are suggested methodological cytology approaches to improve the validity of oral brush cytology. An increase in sensitivity (up to 100%) and specificity (up to 100%) of oral brush biopsy has been reported on localized pre-malignant and malignant lesions. Oral brush biopsy probably will not replace histopathology in the definitive diagnosis of oral cancer, but it might be valuable for the prevention of misdiagnosis of clinically doubtful oral lesions and for the monitoring of lesions that might proceed on to oral cancer. [ABSTRACT FROM AUTHOR]

Background: Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation.Methods/design: The present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients rejecting randomization will be treated as preferred and enrolled in a prospective observational study (comprehensive cohort design) after giving informed consent. This observational part of the trial will be performed with maximum consistency to the treatment and observation protocol of the RCT. Because the impact of patient preference for a certain treatment option is not calculable, parallel design of RCT and observational study may provide a maximum of evidence and efficacy for evaluation of treatment outcome. Secondary clinical endpoints are as follows: incidence and time to tumor relapse (locoregional relapse, lymph node involvement and distant metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module), and time from operation to orofacial rehabilitation. All tumors represent a homogeneous clinical state and therefore additional investigation of protein expression levels within resection specimen may serve for establishment of surrogate parameters of patient outcome.Conclusion: The inherent challenges of a rare clinical condition (pN1) and two substantially different therapy arms would limit the practicality of a classical randomized study. The concept of a Comprehensive Cohort Design combines the preference of a randomized study, with the option of careful data interpretation within an observational study.Trial Registration: ClinicalTrials.gov: NCT00964977. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the disparities in PD-1 and PD-L1 expression among oral squamous cell carcinomas (OSCCs) in individuals categorized as never-smokers/never-drinkers versus smokers/drinkers., Methods: Immunohistochemical staining for PD-1 and PD-L1, along with PDCD1LG2/cen9 dual color probe analysis, was conducted on 130 OSCC specimens from both smoker/drinker and never-smoker/never-drinker cohorts. Associations between smoking/drinking status, clinicopathologic data, immunohistochemical antibody expression, fluorescence in situ hybridization, and survival outcomes were assessed., Results: OSCC in never-smokers/never-drinkers exhibited significantly elevated PD-1 expression (p = 0.003), increased PD-L1-TPS expression (p = 0.044), and elevated PD-L1-CPS expression (p < 0.001). High PD-L1-ICS expression was more prevalent in never-smokers (p = 0.042). Moreover, never-smokers and never-drinkers demonstrated augmented PD-L1 gene copy numbers (p = 0.081 and p = 0.054, respectively). Increased PD-L1 gene copy number, particularly amplification, correlated with PD-L1-TPS (p = 0.039 and p < 0.001). Conversely, PD-L1 gene copy loss was associated with negative PD-L1-CPS (p = 0.023). Notably, positive PD-L1-CPS was significantly linked with improved overall survival (p = 0.023)., Conclusions: OSCC arising in never-smokers/never-drinkers exhibit heightened PD-1/PD-L1 signaling, suggesting potential efficacy of immune checkpoint therapy in this subgroup of tumors., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Literature suggests that intravenous prophylaxis exceeding 48 h offers no additional benefit in preventing surgical site infections (SSI) in patients with microvascular head and neck reconstruction. However, protocols for antibiotic therapy duration post-reconstruction are not standardized. This study identifies factors predicting prolonged intravenous antibiotic use and antibiotic escalation in patients receiving free flap head neck reconstruction. A retrospective analysis of 446 patients receiving free flap reconstruction was conducted, examining predictors for antibiotic therapy > 10 days and postoperative escalation. 111 patients (24.8%) experienced escalation, while 159 patients (35.6%) received prolonged therapy. Multivariate regression analysis revealed predictors for escalation: microvascular bone reconstruction (p = 0.008, OR = 2.0), clinically suspected SSI (p < 0.001, OR = 5.4), culture-positive SSI (p = 0.03, OR = 2.9), extended ICU stay (p = 0.01, OR = 1.1) and hospital-acquired pneumonia (p = 0.01, OR = 5.9). Prolonged therapy was associated with bone reconstruction (p = 0.06, OR = 2.0), preoperative irradiation (p = 0.001, OR = 1.9) and culture-positive SSI (p < 0.001, OR = 3.5). The study concludes that SSIs are a primary factor driving the escalation of perioperative antibiotic use. Clinical suspicion of infection often necessitates escalation, even in the absence of confirmed microbiological evidence. Microvascular bone reconstruction was a significant predictor for both the escalation and extension of antibiotic therapy beyond 10 days. Furthermore, preoperative radiation therapy, hospital-acquired pneumonia, and prolonged ICU stay were associated with an increased likelihood of escalation, resulting in significantly extended antibiotic administration during hospitalization. Antibiotic stewardship programmes must be implemented to reduce postoperative antibiotic administration time.Trial registration The study was registered approved by the local Ethics Committee (Nr: 18-1131-104)., (© 2024. The Author(s).)

Background: The aim of this study was to evaluate the difference between pre- and post-operative radiotherapy on the progress of ossification after free fibula flap reconstruction of the mandible using three-dimensional (3D) analysis. Methods: A total of 38 free fibula reconstructions of the mandible were evaluated retrospectively for ossification between bone segments by measuring Hounsfield Units (HU) in at least two postoperative computer tomography scans (average of 2.4 scans per patient; around the 5th, 12th, 16th, and 19th month postoperative). Three subgroups were created according to the time of irradiation: preoperative radiotherapy (preORT) ( n = 11), postoperative radiotherapy (postORT) ( n = 16), and patients without any radiation therapy ( n = 11) as the control group (noRT). HU in eight regions of interest (ROI) and overlapping surfaces between segments per contact point, as well as influencing factors, were analyzed. Results: The fastest progress in gain of HU ossification with a difference of 0.30 HU/day was observed in noRT compared to preORT ( p = 0.002). postORT was -0.24 HU/day slower than preORT ( p = 0.005). Original and grafted bone showed a significantly slower HU uptake than between two graft segments with -84.18 HU/day ( p < 0.001). Moreover, a larger initial overlapping surface between the segments in cm 2 resulted in a higher rise of HU/day ( p < 0.001). Conclusions: 3D analysis of post-reconstructive CT scans shows prolonged ossification of mandible reconstructions by free fibula after head and neck radiation. The effect is distinct in cases with post-operative adjuvant radiotherapy. The effects of radiotherapy on ossification may be minimized by a larger initial contact surface and improved operational techniques. Moreover, HU longitudinal measurements and 3D analysis offer new perspectives for clinical evaluation of successful bony healing.

Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with a 5-year overall survival rate of around 50%, stagnant for decades. A tumour-induced immunosuppressive microenvironment contributes to HNSCC progression, with the adenosine (ADO) pathway and an upregulated expression of inhibitory immune checkpoint regulators playing a key role in this context. The correlation between high neutrophil-to-lymphocyte ratio (NLR) with advanced tumour staging suggests involvement of neutrophils (NØ) in cancer progression. Interestingly, we associated a high NLR with an increased intracellular PD-L1 localization in primary HNSCC samples, potentially mediating more aggressive tumour characteristics and therefore synergistically favouring tumour progression. Still, further research is needed to harness this knowledge for effective treatments and overcome resistance. Since it is hypothesized that the tumour microenvironment (TME) may be influenced by small extracellular vesicles (sEVs) secreted by tumours (TEX), this study aims to investigate the impact of HNSCC-derived TEX on NØ and blockade of ADO receptors as a potential strategy to reverse the pro-tumour phenotype of NØ. UMSCC47-TEX exhibited CD73 enzymatic activity involved in ADO signalling, as well as the immune checkpoint inhibitor PD-L1. Data revealed that TEX induce chemotaxis of NØ and the sustained interaction promotes a shift into a pro-tumour phenotype, dependent on ADO receptors (P1R), increasing CD170 high subpopulation, CD73 and PD-L1 expression, followed by an immunosuppressive secretome. Blocking A3R reduced CD73 and PD-L1 expression. Co-culture experiments with HNSCC cells demonstrated that TEX-modulated NØ increase the CD73/PD-L1 axis, through Cyclin D-CDK4/6 signalling. To support these findings, the CAM model with primary tumour was treated with NØ supernatant. Moreover, these NØ promoted an increase in migration, invasion, and reduced cell death. Targeting P1R on NØ, particularly A3R, exhibited potential therapeutic strategy to counteract immunosuppression in HNSCC. Understanding the TEX-mediated crosstalk between tumours and NØ offers insights into immunomodulation for improving cancer therapies., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background: The aim of this study was to investigate the effect of antiresorptive agents on the ossification of reconstructed mandibles by free bone grafts for the first time., Methods: A total of 38 reconstructions of the jaw were retrospectively evaluated for ossification between bone segments by two raters based on postoperative panoramic radiographs. The study group (n = 13) had segmental resection of the mandible and free bone flap reconstruction due to medication-related osteonecrosis of the jaw (MRONJ). The control group (noMRONJ, n = 25) comprised segmental mandibular resections and free bone flap reconstructions due to tumors, chronic osteomyelitis, or trauma without any radiation. Ossification time and influencing factors were evaluated., Results: Both duration of surgery (346 ± 90 min. vs. 498 ± 124 min.; p < 0.001) and hospitalization (8.7 ± 2.8 days vs. 13.4 ± 5.3 days, p = 0.006) were shorter in the MRONJ group compared to the noMRONJ group. Ossification after mandibular reconstruction was significantly faster in the MRONJ study group [224 days, interquartile range (IQR) 175-287] compared to the control group (288 days, IQR 194-445; p < 0.001). Moreover, good initial contact between the segments resulted in faster ossification (p < 0.001) in the MRONJ group. Ossification rate between original and grafted bone or between grafted bone segments only did not differ in both the study and control groups (MRONJ, p = 0.705 vs. control, p = 0.292). The type of antiresorptive agent did not show any significance for ossification. The rate of wound healing disturbances did also not differ between the study and control groups (p = 0.69)., Conclusion: Advanced MRONJ (stage 3) can be resected and reconstructed safely with free microvascular bone flaps. Antiresorptive agents enhance the ossification of the bone segments. Optimal initial contact of the bone segments accelerates bone healing. Surgery and hospitalization are markedly shortened in this vulnerable group of MRONJ patients compared to oncologic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gottsauner, Meier, Eichberger, Eckmüller, Schuderer, Fiedler, Maurer, Reichert and Ettl.)

Late-onset infection of an inserted temporomandibular joint prosthesis is a difficult complication to treat. Most treatment protocols for late prosthetic infections include device replacement. A 40-year-old female patient with an infected and exposed temporomandibular joint prosthesis presented 3 years after implant placement. The patient was treated with prosthesis revision including fistula coverage with a temporalis muscle flap and prolonged antibiotic therapy for 10 weeks. Since completion of treatment, the patient has been infection-free., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background : The aim of this study is to assess patients' subjective perception of treatment outcome after extracapsular fractures of the mandibular condyle. Methods : A questionnaire survey regarding facial nerve palsy (FNP), malocclusion, pain, reduction in maximum mouth opening (MMO) and further discomfort after 3, 6, and 12 months was carried out. Patients aged 18 or more presenting with an extracapsular condylar fracture between 2006 and 2020 were identified by purposive sampling Questionnaires were received from 115 patients. Fractures were classified on the basis of the pre-treatment imaging, the way of treatment was obtained from patients' medical records. Data were analyzed using Pearsons' chi-square-test, descriptive statistics and Student's t -test. Results : 93.0% of the fractures were treated by open reduction and internal fixation (ORIF). MMO reduction was the most common post-treatment complication (55.6%). ORIF was associated with less pain after 3 months ( p = 0.048) and lower VAS scores compared to conservative treatment ( p = 0.039). Comminuted fractures were more frequently associated with post-treatment malocclusion ( p = 0.048), FNP ( p = 0.016) and MMO reduction ( p = 0.001). Bilateral fractures were significantly accompanied by malocclusion ( p = 0.029), MMO reduction ( p = 0.038) and pain occurrence ( p < 0.001). Conclusions : Patients report less pain after ORIF. Comminuted and bilateral fractures seem to be major risk factors for complications. Subjective perception of complications after extracapsular condylar fractures differs from objectively assessed data.

The programmed cell death 1 ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD-L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD-L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD-L1 in various cellular compartments of six well-characterized head and neck cancer (HNC) cell lines, including the nucleus. Via Western blotting, we detected PD-L1 in its well-known glycosylated/deglycosylated state at 40-55 kDa. In addition, we detected previously unknown PD-L1 variants with a molecular weight at approximately 70 and > 150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD-L1 variant expression is cell-cycle-dependent. Immunofluorescence staining of PD-L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD-L1 trafficking remain less understood; however, proximity ligation assays showed a cell-cycle-dependent interaction of the cytoskeletal protein vimentin with PD-L1, whereas vimentin could serve as a potential shuttle for nuclear PD-L1 transportation. Mass spectrometry after PD-L1 co-immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD-L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD-L1 and multiple tumor cell-intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: The utilization of three-dimensional (3D) surface imaging for facial anthropometry is a significant asset for patients undergoing maxillofacial surgery. Notably, there have been recent advancements in smartphone technology that enable 3D surface imaging.In this study, anthropometric assessments of the face were performed using a smartphone and a sophisticated 3D surface imaging system., Methods: 30 healthy volunteers (15 females and 15 males) were included in the study. An iPhone 14 Pro (Apple Inc., USA) using the application 3D Scanner App (Laan Consulting Corp., USA) and the Vectra M5 (Canfield Scientific, USA) were employed to create 3D surface models. For each participant, 19 anthropometric measurements were conducted on the 3D surface models. Subsequently, the anthropometric measurements generated by the two approaches were compared. The statistical techniques employed included the paired t-test, paired Wilcoxon signed-rank test, Bland-Altman analysis, and calculation of the intraclass correlation coefficient (ICC)., Results: All measurements showed excellent agreement between smartphone-based and Vectra M5-based measurements (ICC between 0.85 and 0.97). Statistical analysis revealed no statistically significant differences in the central tendencies for 17 of the 19 linear measurements. Despite the excellent agreement found, Bland-Altman analysis revealed that the 95% limits of agreement between the two methods exceeded ±3 mm for the majority of measurements., Conclusion: Digital facial anthropometry using smartphones can serve as a valuable supplementary tool for surgeons, enhancing their communication with patients. However, the proposed data suggest that digital facial anthropometry using smartphones may not yet be suitable for certain diagnostic purposes that require high accuracy., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.)

Background/aim: Mandibular condylar fractures represent 25%-35% of all mandibular fractures. Despite profound research, there is still a controverse debate about treating these fractures conservatively or by open reduction and internal fixation (ORIF). The aim of this study is to analyse the outcome after open and closed treatment of extracapsular mandibular condyle fractures regarding general characteristics, post-treatment malocclusion, facial nerve palsy (FNP), maximum mouth opening (MMO) and parotid complications., Methods: A retrospective cohort of 377 fractures (350 open, 27 closed treatment) was reviewed by reference to clinical and radiological pre- and postoperative documentation. Follow-up period was 12 months. Pearsons' chi-square-test, correlations, Kruskal-Wallis test and t-test were carried out for statistical analysis., Results: The dominant type of fracture was type II in Spiessl and Schroll classification (50.1%). In the open treated fractures, the most common approach was retromandibular transparotid (91.7%). Post-treatment malocclusion occurred in 18.0% and was significantly increased in bilateral fractures (p = .039), in luxation fractures (p = .016) and in patients with full dentition (p = .004). After open reduction and internal fixation (ORIF), temporary FNP was documented in 7.1% whereas a permanent paresis occurred in 1.7%. FNP was significantly associated with high fractures (p = .001), comminution (p = .028) and increased duration of surgery (p = .040). Parotid complications were significantly associated with revision surgery (p = .009). Post-treatment reduction of MMO mainly occurred in female patients (p < .001) as well as in patients with bilateral fractures (p < .001), high fractures (p = .030) and concomitant mandibular (p = .001) and midfacial fractures (p = .009)., Conclusion: Malocclusion seems to be the most frequent long-term complication after open reduction and osteosynthesis of extracapsular mandibular condyle fractures. We suggest ORIF by a transparotid approach to be an appropriate treatment with a low complication rate regarding especially FNP for extracapsular fractures of the mandibular condyle., (© 2023 The Authors. Dental Traumatology published by John Wiley & Sons Ltd.)

The treatment of bite wounds to the face is discussed controversially in relation to surgery and antibiotics. The aim of this study is a retrospective evaluation of 111 cases of animal bite injuries to the face that presented to our unit of oral and maxillofacial surgery over a 13-year period. Children under 10 years of age were predominantly involved. A total of 94.5% of the assessed injuries were caused by dogs. Wound infections occurred in 8.1%. Lackmann type II was the most common type of injury (36.9%). The perioral area was affected most frequently (40.5%). Primary wound closure was carried out in 74.8% of the cases. In 91.9% of the cases, antibiotic prophylaxis was prescribed. The most often administered type of antibiotic was amoxicillin with clavulanic acid (62.1%). Patients without antibiotics showed an increased infection rate without significance. Wound infections occurred significantly more frequently in wounds to the cheeks ( p = 0.003) and when local flap reconstruction was necessary ( p = 0.048). Compared to the other surgical treatment options, primary closure showed the lowest infection rates (4.8%, p = 0.029). We recommend antibiotic prophylaxis using amoxicillin with clavulanic acid and wound drains for wounds of Lackmann class II or higher. Primary closure seems to be the treatment of choice whenever possible.

When research on osteogenic differentiation in dental follicle cells (DFCs) began, projects focused on bone morphogenetic protein (BMP) signaling. The BMP pathway induces the transcription factor DLX3, whichh in turn induces the BMP signaling pathway via a positive feedback mechanism. However, this BMP2/DLX3 signaling pathway only seems to support the early phase of osteogenic differentiation, since simultaneous induction of BMP2 or DLX3 does not further promote differentiation. Recent data showed that inhibition of classical protein kinase C (PKCs) supports the mineralization of DFCs and that osteogenic differentiation is sensitive to changes in signaling pathways, such as protein kinase B (PKB), also known as AKT. Small changes in the lipidome seem to confirm the participation of AKT and PKC in osteogenic differentiation. In addition, metabolic processes, such as fatty acid biosynthesis, oxidative phosphorylation, or glycolysis, are essential for the osteogenic differentiation of DFCs. This review article attempts not only to bring the various factors into a coherent picture of osteogenic differentiation in DFCs, but also to relate them to recent developments in other types of osteogenic progenitor cells.

(1) Background Oral squamous cell carcinomas (OSCC) are a common malignancy of the oral cavity and are often diagnosed when they have already spread to the regional lymph nodes. Advanced stages of cancer are characterized by the development of distant metastases. Angiogenesis, a hallmark of cancer, is known to contribute to cancer progression and metastasis. High microvessel density (MVD) has been linked to poor clinical outcomes in various types of cancer. (2) Methods: In this study, we aimed to investigate the spatial heterogeneity of blood vessels by comparing the tumor center and invasion front and to evaluate its prognostic value in OSCC. A total of 71 OSCC patient specimens were collected. The tissue was immunohistochemically stained using CD31 antibody to assess the MVD in the tumor center and the invasion front. Furthermore, the associations between the histopathological parameters, including MVD, disease-free survival (DFS), and overall survival (OS) were computed. (3) Results: In our study, we found a significantly higher presence of blood vessels at the invasion front of OSCCs compared to the tumor center. However, we did not observe any significant differences in MVD between different tumor stages. High intratumoral MVD was shown to be a positive prognostic factor for DFS ( p = 0.047). (4) Conclusions: To the best of our knowledge, we were the first to analyze MVD as a prognostic factor by considering its spatial heterogeneity in OSCC. However, further studies are warranted to further elucidate the complexity of microvascular spatial heterogeneity and its influence on prognosis.

In recent research, the tumor microenvironment has been shown to attract mesenchymal stromal cells (MSCs), which is of particular interest due to its implications for cancer progression. The study focused on understanding the interaction between bone marrow-derived MSCs (BMSCs) and head and neck cancer (HNC) cells. This interaction was found to activate specific markers, notably the osteogenic marker alkaline phosphatase and the oncogene Runx2. These activations corresponded with the release of collagenase enzymes, MMP9 and MMP2. To gain insights into bone resorption related to this interaction, bovine bone slices were used, supporting the growth of "heterogeneous spheroids" that contained both BMSCs and HNC cells. Through scanning electron microscopy and energy-dispersive X-ray (EDX) analysis, it was observed that these mixed spheroids were linked to a notable increase in bone degradation and collagen fiber exposure, more so than spheroids of just BMSCs or HNC cells. Furthermore, the EDX results highlighted increased nitrogen content on bone surfaces with these mixed clusters. Overall, the findings underscore the significant role of BMSCs in tumor growth, emphasizing the need for further exploration in potential cancer treatment strategies.

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.

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.

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.

Cholesteatoma is a temporal bone disease characterized by dysfunctions of keratinocytes. MicroRNAs (miRNAs) are evolutionary conserved noncoding RNAs that regulate mRNA expression. They can be packaged into exosomes and transported to target cells that can be used in the future therapy of cholesteatoma. This study aimed to collect knowledge on the role of miRNAs and exosomal miRNAs in cholesteatoma and was conducted according to the PRISMA guidelines for systematic reviews. Four databases were screened: Pubmed/MEDLINE, Web of Science, Scopus, and the Cochrane Library. The last search was run on the 6th of June 2023. We included full-text original studies written in English, which examined miRNAs in cholesteatoma. The risk of bias was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool, modified for the needs of this review. We identified 118 records and included 18 articles. Analyses revealed the downregulation of exosomal miR-17 as well as miR-10a-5p, miR-125b, miR-142-5p, miR34a, miR-203a, and miR-152-5p and the overexpression of exosomal miR-106b-5p as well as miR-1297, miR-26a-5p, miR-199a, miR-508-3p, miR-21-3p, miR-584-5p, and miR-16-1-3p in cholesteatoma. The role of differentially expressed miRNAs in cholesteatoma, including cell proliferation, apoptosis, the cell cycle, differentiation, bone resorption, and the remodeling process, was confirmed, making them a potential therapeutic target in this disease.

Introduction: Hyperbaric oxygen (HBO 2 ) therapy involves the inhalation of pure oxygen in a pressure chamber under increased ambient pressure. Recent research indicates that circulating small extracellular vesicles (sEVs) play important roles in human physiology and pathology. Therefore, the objective of this pilot study was to monitor the impact of HBO 2 therapy on the levels of circulating sEVs in the serum of patients with necrotizing soft-tissue infections (NSTI), aseptic bone necrosis (ABN) or idiopathic sudden sensory neural hearing loss (ISSNHL)., Material and Methods: Serum-derived sEVs were isolated and quantified in 80 patients before and after HBO 2 therapy applied for NSTI, ISSNHL and ABN patients as well as in normal controls who received neither HBO 2 therapy nor steroids., Results: We observed a significant increase of circulating sEVs in patients with ISSNHL after HBO 2 therapy ( p < 0.05), as well as significantly elevated levels of sEVs after HBO 2 therapy compared to patients with NSTI ( p < 0.05) and ABN ( p < 0.01)., Conclusions: The increase in the levels of sEVs in ISSNHL may be evidence for both the intended reduction of inflammation as a result of steroid therapy and the inhibitory effect of oxidative stress induced by HBO 2 therapy. Thus, sEVs released during HBO 2 therapy might play an important biological role in mediating the response to therapy and might be a promising approach to gain further insights into the therapeutic efficacy of HBO 2 therapy., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Termedia & Banach.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Short telomeres and genomic DNA damage are causes of cellular senescence in dental follicle cells (DFCs)., Design: This study examined the role of the DNA damage response (DDR) during cellular senescence of DFCs by β-galactosidase activity and DNA damage by comet assay. Expression of genes/proteins was determined by Western Blots and reverse transcription-quantitative polymerase chain reaction, while glycolysis was enzymatically estimated. Cell cycle stages and reactive oxygen species (ROS) were investigated by flow cytometry., Results: During the induction of cellular senescence gene expression of DDR genes were down-regulated, while DNA double-strand breaks occurred at the same time. Furthermore, inhibition of DNA protein kinase (DNA-PK) reduced senescence and ROS, both of which are associated with cellular senescence. In contrast, while these data suggest that inhibition of DDR is associated with the induction of cellular senescence, inhibition of DNA-PK did not result in renewal of DFCs, as inhibition resulted in typical features of depleted cells such as increased cell size and reduced cell proliferation rate. DNA-PK repression inhibited both osteogenic differentiation potential and glycolysis, which are typical features of cellular exhaustion. Moreover, DNA-PK affects cellular senescence via activation of AKT1 (protein kinase B)., Conclusion: Our results suggest that DNA-PK promotes cellular senescence, but DFCs may control the induction of cellular senescence via down-regulation of DDR genes. However, we also showed that inhibition of DNA-PK cannot renew senescent DFCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

(1) Background: The radial forearm flap (RFF) has evolved as the flap of choice for intraoral mucosal reconstructions, providing thin and pliable skin with a safe blood supply. Perforator flaps such as the anterolateral thigh (ALT) flap are increasingly being discussed for the same applications. (2) Methods: Patient history, treatment details, and outcome of 12 patents with moderate to extended defects of the lip and/or nose area that were reconstructed by a folded radial forearm flap were retrospectively evaluated for oncologic and functional outcomes. (3) Results: The mean oncologic and functional follow-up were 21.1 (min. 3.8; max. 83.3) and 31.2 (min. 6; max. 96) months, respectively. All flaps survived without revision. In eight cases, major lip defects were reconstructed by an RFF; in six patients, the palmaris longus tendon was included for lip suspension. The functional results in terms of eating, drinking, and mouth opening were good in five cases, while three patients were graded as fair due to moderate drooling. In seven cases, the major parts of the nose were reconstructed with two good and five fair (nostril constriction in three cases) functional results. (4) Conclusions: The folded RFF remains a unique free flap option for complex three-dimensional lip and nose reconstructions in terms of flexibility, versatility, and robustness.

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.

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.

The aim of this study was to analyse the radiological and clinical outcomes of condylar reconstruction by fibula free flap (FFF), comparing conventional freehand and CAD/CAM techniques. Fifteen patients (nine CAD/CAM, six freehand) who underwent condylar reconstruction with a FFF were reviewed retrospectively regarding pre- and postoperative computed tomography/cone beam computed tomography scans and clinical function. After surgery, all patients were free of temporomandibular joint pain. Mean postoperative mouth opening was 30.80 mm, with no significant difference between the freehand and CAD/CAM groups. In all patients, laterotrusion was decreased to the contralateral side (P = 0.002), with no difference between freehand and CAD/CAM, while the axis of mouth opening deviated to the side of surgery (P < 0.001). All patients showed significant radiological deviation of the fibular neocondyle in the laterocaudal direction (lateral: P = 0.015; caudal: P = 0.001), independent of the technique. In conclusion, reconstruction of the mandibular condyle by FFF provided favourable functional results in terms of mouth opening, reduction of pain, and mandibular excursions. Radiological deviation of the neocondyle and deviation of laterotrusion and mouth opening did not impair clinical function. CAD/CAM planning facilitated surgery, decreased the surgery time, and improved the fit of the neocondyle in the fossa., (Copyright © 2022 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Contributions of TGFβ to cancer progression are well documented. However, plasma TGFβ levels often do not correlate with clinicopathological data. We examine the role of TGFβ 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 TGFβ expression levels during oral carcinogenesis. In human HNSCC, TGFβ and Smad3 protein expression levels and TGFB1 gene expression were determined. Soluble TGFβ levels were evaluated by ELISA and TGFβ bioassays. Exosomes were isolated from plasma using size exclusion chromatography, and TGFβ content was quantified using bioassays and bioprinted microarrays., Results: During 4-NQO carcinogenesis, TGFβ levels in tumour tissues and in serum increased as the tumour progressed. The TGFβ content of circulating exosomes also increased. In HNSCC patients, TGFβ, Smad3 and TGFB1 were overexpressed in tumour tissues and correlated with increased soluble TGFβ levels. Neither TGFβ expression in tumours nor levels of soluble TGFβ correlated with clinicopathological data or survival. Only exosome-associated TGFβ reflected tumour progression and correlated with tumour size., Conclusions: Circulating TGFβ + exosomes in the plasma of patients with HNSCC emerge as potential non-invasive biomarkers of disease progression in HNSCC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

(1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55-1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15-0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19-0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years ( p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group.

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 mm 2 , whereas the 3D measurement showed fracture areas with a significantly larger average value of 374.16 mm 2 ( 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.

A 50-year-old patient presented with a two-year history of chronic osteomyelitis of the left mandibular body. It was treated by wide segmental resection of the left hemimandible and reconstruction with a free vascularized fibular graft. Six months after surgery, the patient returned with pain, swelling, and moth-like lesions in the transplant in combination with appositional bone formation surrounding the ossified fibular bone. Radiographic and histological examination led to the diagnosis of a recurrent osteomyelitis with proliferative periostitis affecting the resected and reconstructed mandible. Application of ibandronate led to a significant symptom decrease., (© 2022. The Author(s).)

Background: Evaluating the tumor microenvironment and its influence on clinical management and therapy response is becoming increasingly important. However, only a few studies deal with the spatial distribution of immune cells within the tumor. This study aimed to describe the topology of immune cells in the microenvironment of oral squamous cell carcinoma (OSCC) sectioned by tumor invasion front and tumor center and to test their prognostic relevance regarding patient survival., Methods: A total of 55 OSCC patient specimens were collected retrospectively. The cancer tissue was immunohistochemically stained using an automated tissue stainer Ventana Benchmark Ultra (Roche) and analyzed using discrete expression marker profiles on immune cells. We investigated CD4+ lymphocytes, CD8+ lymphocytes, CD68+ macrophages, CD163+ macrophages, and M1 macrophages regarding their spatial distribution., Results: The statistical analysis revealed that the quantity and distribution of CD4+ ( p = 0.007), CD8+ ( p < 0.001), CD68+ ( p < 0.001), CD163+ cells ( p = 0.004), and M1 ( p < 0.001) macrophages were significantly higher at the invasion front compared to the tumor center in all observed cases. However, high and low immune cell counts in the tumor center and invasion front were not associated with overall survival., Conclusion: Our results show two distinct immune microenvironments of the tumor center compared to the invasion front. Future studies are needed to explore how these results can be leveraged to improve patient therapy and outcome.

Dental Follicle Cells (DFCs) are somatic stem cells with a limited lifespan, but little is known about a possible mechanism of cellular senescence. Previous studies have shown that cellular senescence is associated with increased demand of glycolsis or the "glycolytic metabotype", which can be induced by activation of 5' adenosine monophosphate-activated protein kinase (AMPK), and decreased autophagy. This study examined the role of AMPK in inducing senescence in DFCs. During the induction of cellular senescence, AMPK activity was impaired, suggesting a negative impact on senescence induction. In line with this assumption, cellular senescence was induced upon inhibition of AMPK with a specific siRNA. In addition, after this inhibition, autophagy was also inhibited. Moreover, specific inhibition of autophagy promoted cellular senescence. However, inducers of AMPK such as metformin or AICAR surprisingly increased senescence in DFCs. Interestingly, autophagy was impaired after long-term induction of AMPK with AICAR and metformin. Moreover, activation of AMPK induces the consumption of glucose but decreases NAD/NADH ratio in DFCs that suggest not only "glycolytic metabotype" of DFCs but also Mitochondrial Dysfunction Associated Senescence (MiDAS). Both changes are highly associated with the induction of cellular senescence. Hence, both AMPK activation and inhibition promote the induction of cellular senecence of DFCs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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, 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.

Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. In our experiments, direct 3D co-culture of BMSCs with tumor cells from the head and neck region (HNSCC) results in strong expression and secretion of MMP-9. The observed MMP-9 secretion mainly originates from BMSCs, leading to increased invasiveness. In addition to our in vitro data, we show in vivo data based on the chorioallantoic membrane (CAM) model. Our results demonstrate that MMP-9 induces hemorrhage and increased perfusion in BMSC/HNSCC co-culture. While we had previously outlined that MMP-9 expression and secretion originate from BMSCs, our data showed a strong downregulation of MMP-9 promoter activity in HNSCC cells upon direct contact with BMSCs using the luciferase activity assay. Interestingly, the 2D and 3D models of direct co-culture suggest different drivers for the downregulation of MMP-9 promoter activity. Whereas the 3D model depicts a BMSC-dependent downregulation, the 2D model shows cell density-dependent downregulation. In summary, our data suggest that the direct interaction of HNSCC cells and BMSCs promotes tumor progression by significantly facilitating angiogenesis via MMP-9 expression. On the other hand, data from 3D and 2D co-culture models indicate opposing regulation of the MMP-9 promoter in tumor cells once stromal cells are involved.