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Abstract Introduction Due to increasing use of disease modifying antirheumatic drugs (DMARDs) as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX) on osteoblasts as essential part of bone remodelling cells. Methods Primary bovine osteoblasts (OBs) were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. Results All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01nM and concentrations below had no inhibitory effects anymore. Conclusion Even low dose methotrexate acts as a potent inhibitor of osteoblast’s proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism, suggests possible negative effects of DMARD therapy concerning oral and cranio-maxillofacial bone surgery as could be seen in a similar way in bisphosphonate related osteonecrosis of the jaw.

Abstract Background Hyperbaric oxygen (HBO) therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum concentrations of bFGF and VEGF was not verified in the present study. Additional application of exogenous growth factors in conjunction with HBO was not obviously linked by a coherent cause-and-effect chain as far as wound healing is concerned.

Abstract Background Current approaches in bone regeneration combine osteoconductive scaffolds with bioactive cytokines like BMP or VEGF. The idea of our in-vitro trial was to apply VEGF165 in gradient concentrations to an equine collagen carrier and to study pharmacological and morphological characteristics of the complex in a circulation model. Methods Release kinetics of VEGF165 complexed in different quantities in a collagen matrix were determined in a circulation model by quantifying protein concentration with ELISA over a period of 5 days. The structural changes of the collagen matrix were assessed with light microscopy, native scanning electron microscopy (SEM) as well as with immuno-gold-labelling technique in scanning and transmission electron microscopy (TEM). Results We established a biological half-life for VEGF165 of 90 minutes. In a half-logarithmic presentation the VEGF165 release showed a linear declining gradient; the release kinetics were not depending on VEGF165 concentrations. After 12 hours VEGF release reached a plateau, after 48 hours VEGF165 was no longer detectable in the complexes charged with lower doses, but still measurable in the 80 μg sample. At the beginning of the study a smear layer was visible on the surface of the complex. After the wash out of the protein in the first days the natural structure of the collagen appeared and did not change over the test period. Conclusions By defining the pharmacological and morphological profile of a cytokine collagen complex in a circulation model our data paves the way for further in-vivo studies where additional biological side effects will have to be considered. VEGF165 linked to collagen fibrils shows its improved stability in direct electron microscopic imaging as well as in prolonged release from the matrix. Our in-vitro trial substantiates the position of cytokine collagen complexes as innovative and effective treatment tools in regenerative medicine and and may initiate further clinical research.

Introduction: This study analyzed oncologic patient management from initial tumor diagnosis to tumor follow-up in oral and maxillofacial surgery (OMFS) in Germany., Material and Methods: A dynamic online questionnaire with a total of 44 questions was used to generate general and specific data regarding oncologic patient management with head and neck malignancies, supportive care, and (pre-) rehabilitation from initial tumor diagnosis to tumor follow-up and head and neck cancer center (HNCC) structures in OMFS in Germany. The questionnaire was sent to 81 OMFS departments affiliated with the German-Austrian-Swiss Working Group for Tumors of the Jaw and Facial Region (DÖSAK) and the German Association of Oral and Maxillofacial Surgery (DGMKG). Data analysis was conducted descriptively., Results: Forty-eight OMFS departments participated (response rate 59.26%), of which 36/48 (75%) were certified HNCC. 28/34 (82.4%) reported subjective improvements in oncologic care, most often interdisciplinary collaboration (21/33, 63.64%) and clinic structure changes (21/34, 61.76%). Nearly all OMFS departments present patients in multidisciplinary tumor boards (45/46, 97.83%) and aim for osseous reconstruction post-tumor resection (43/44, 97.73%). Significant discrepancies regarding the frequency of masticatory-functional dental rehabilitation following osseous reconstruction were observed. Before oncologic therapy, patients are offered various supportive services, mostly psychotherapy and psycho-oncological support (24/26, 92.31%). Post-therapy, speech therapy (43/43, 100%), physiotherapy (40/43, 93.02%), lymphatic drainage, and follow-up rehabilitation (39/43, 90.7%, respectively) are most often offered. 17/43 (39.53%) have oncological nursing staff. 36/40 (90%) manage patients and side effects during adjuvant therapy, while 5/41 (12.2%) provide proprietary palliative care. 36/41 (87.8%) offer counseling to patients and families., Conclusion: Oncologic patient care in OMFS is highly standardized and potentially attributable to many certified HNCCs in Germany. Certain treatment aspects are handled differently, possibly due to institution-specific reasons., Clinical Relevance: The high homogeneity in treatment protocols reflects the widespread high and comparable treatment quality of head and neck malignancies in OMFS in Germany., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Metastasis suppressor protein 1 (MTSS1) is a prognostic tumour marker in different malignant epithelial tumour entities and previously mainly the MTSS1 expression was analysed. This study evaluated the best analysis method as a prognosis and aggressiveness tumour marker in head and neck squamous cell carcinoma (HNSCC)., Study Design: MTSS1 expression, MTSS1 intensity, interpretation MTSS1 score and MTSS1 edging score were analysed in formalin-fixed paraffin-embedded tissue slices of 60 patients with proven HNSCC and correlated with clinical and pathological outcome parameters., Results: A lack of MTSS1 expression showed tumour aggressiveness, but surprisingly, mainly MTSS1 intensity was correlated with a worse patient outcome. There was a significant correlation between higher MTSS1 intensity and an increased risk for lymph node metastasis (P = .027) and a significant increased risk for extracapsular growth (P = .016). Furthermore, disease-specific survival was worse in cases with higher MTSS1 intensity (P = .001)., Conclusion: MTSS1 intensity has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Tumor budding (TB) is a histomorphological characteristic of the tumor invasion front and it has an impact on the tumor outcome prediction for head and neck squamous cell carcinoma (HNSCC) aetiopathology., Patients and Methods: The average TB score (TB rel) of all tumor-positive marginal sections (n = 443) in the primary tumor was analyzed in the FFPE-fixed tumor slices of 66 patients with HNSCC, and they were compared with cryo-fixed sections., Results: TB rel correlates with tumor aggressiveness (i.e., lymph node metastasis quantity, lymph node ratio, extra capsular growth, Pn1, pV1, grading). The TB scores often vary between the different tumor margins of FFPE sections in the same patient, and in many cases, they differ depending on the fixation method., Conclusion: Our data show that a randomly selected marginal cut cannot reliably mirror the TB score, and thus, they cannot predict the prognostic outcome. However, TB rel could be a tool that compensates for differences in TB score analysis. TB score determination in cryo sections seems to be inaccurate compared with TB determination in FFPE.

The objective of this study was to analyze, in a randomized controlled multicenter trial, whether a xenogeneic collagen matrix (XCM) could be used to cover skin defects. Patients with the need for skin excisions were recruited and randomized to treatment with a skin graft after a period of granulation or to treatment with an XCM. The results were evaluated by two independent observers on the Patient and Observer Scar Assessment Scale. On this scale, scars are ranked from 1 to 10 in six different categories. Results range from 6 to 60, with lower scores representing scars closer to normal skin. The results 6 months after reconstruction were used as primary endpoint and compared in a non-inferiority approach. A total of 39 wounds in the head and neck region were analyzed. The mean results were 16.55 (standard deviation 6.8) for XCM and 16.83 (standard deviation 8.21) in the control group. The result of the XCM was not significantly inferior to the result of the skin graft (p = 0.91). Within the limitations of the study, it seems that the use of xenogeneic collagen matrices is a viable alternative to other approaches in small skin defects, and therefore should be taken into account whenever the reduction of patient morbidity to a minimum is the priority. TRIAL REGISTRATION: This trial was registered in the German Clinical Trials Register under registration identification number DRKS00010930 and can be found under the following URLs: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00010930. https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00010930., 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 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley-VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: High IMP3 expression is correlated with a worse outcome. Until now, there have been no data about IMP3 expression and clinical outcome for high-risk localisation of squamous cell carcinoma of the skin (cSCC)., Methods: One-hundred twenty-two patients with cSCC of the lip and ear were included, and IMP3 expression in the tumours was immunohistochemically assessed in different evaluation approaches. Subsequently, subgroups were analysed in a matched pair approach and correlated with clinical pathologic parameters. In the following, different IMP3 analysis methods were tested for clinical suitability., Results: We found a significant correlation between IMP3 expression and risk for lymph node metastasis, local relapse, and progression-free survival., Conclusions: On basis of our data, we suggest a prognostic benefit cutoff value for high (>50%) and low (<50%) IMP3 expression. Thus, IMP3 expression has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations., (© 2020 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators., (© 2020 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Cutaneous squamous cell carcinoma (cSCC) and its precursors, actinic keratoses (AK), are common. Physicians of multiple specialties are confronted with their treatment., Methods: This review is based on publications retrieved by a selective search in PubMed, as well as on the German guidelines on AK and cSCC, skin cancer prevention, and surgery with histologic guidance., Results: Local treatments for AK include lesional cryotherapy, curettage, and laser ablation as well as field-directed treatments with topical agents, e.g., diclofenac plus hyaluronic acid, imiquimod, 5-fluorouracil, ingenol mebutate, and photodynamic therapy. These treatments can be administered in various sequences or combinations, depending on individual factors and the stage of the disease. The gold standard of treatment for cSCC is histologically confirmed complete resection; radiotherapy is an alternative. Locally uncontrollable or metastatic disease is treated with systemic drugs. The use of various chemotherapeutic agents, EGFR-directed therapies, and the PD-I inhibitor cemiplimab, either singly or in combination, has been described in uncontrolled trials and case series. Cemiplimab has a reported response rate of 47% and was recently approved for the treatment of advanced cSCC., Conclusion: There are many options for the treatment of AK and cSCC that must be considered in the interdisciplinary care of these entities.

Introduction: Head and neck mucosal melanoma (HNMM) is a rare tumor with a poor outcome. The objective of this study was to assess outcome and prognostic factors for a cohort of patients treated in a head and neck cancer center. In addition, a case series on sentinel lymph node biopsy (SLNB) was included to evaluate it as a method for staging the node-negative neck., Methods: A retrospective study design was chosen, and 50 patients who were treated from 1973 to 2015 in our institution for primary HNMM were included. The Kaplan-Meier method was used to estimate survival rates. Uni- and multivariate analyses were used to study the influence of possible risk factors on the patients' outcome. These risk factors included patient demographics, tumor characteristics, and treatment modalities., Results: All patients were treated surgically and 50% received adjuvant treatment. The median disease specific survival (DSS) was 38 months, with a 5-year survival rate of 44%. Positive surgical margin (p = 0.004) and distant failure (p = 0.005) were associated with a worse DSS. The median disease-free survival (DFS) was 27 months, with a 5-year disease-free rate of 12%. Only tumor depth >5 mm (p = 0.002) was associated with a worse DFS. Five clinically node-negative patients received SLNB and only the two SLN-positive individuals suffered from distant failure. Radiotherapy, chemotherapy, and AJCC/UICC stage had no influence on any outcome measure., Conclusions: Positive surgical margin and distant failure are the only independent prognostic factors for DSS. Tumor depth can predict distant failure. SLNB may be a valuable staging tool for the node-negative neck., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Purpose: Patients with cleft lip, alveolus and palate (CLAP) may suffer from marked asymmetry with an impact on attractiveness and psychosocial aspects. The aim of this study was to assess symmetry in CLAP patients compared to non-cleft controls of similar age with regard to cleft type and treatment concept., Materials and Methods: In CLAP patients with different cleft forms and in healthy non-cleft subjects (control group) a three-dimensional stereophotogrammetric face scan was performed and an objective 3D asymmetry index (AI) was calculated for the whole face, the midface, the upper lip and the nose., Results: In total, 305 patients were included: 140 CLAP patients (90 male, 50 female, mean age 9.9 ± 3.6 years) and 165 controls (87 male, 78 female, mean age 8.7 ± 2.1 years). In general, CLAP patients showed significantly higher asymmetry than controls, with the most severe asymmetry found in unilateral complete CLAP. Patients treated according to an actual concept considering reconstruction of all affected muscular systems had a significant lower and more favourable AI than patients not treated according to this concept (p < 0.05)., Conclusion: An adequate treatment concept is essential to achieve better results concerning symmetry in CLAP, but symmetry values of healthy non-cleft controls are not reached., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: After orbital exenteration a facial prosthesis is a viable option for rehabilitation. The aim of this study was to evaluate implant loss and peri-implantitis of solitary orbital implants with regard to risk factors., Patients and Methods: Implant loss (primary outcome) and periimplantitis (secondary outcome) were reviewed retrospectively in patients who received orbital implants between 2006 and 2015 with a minimum follow-up time of 12 months. Potential risk factors were analyzed using univariate and multivariate statistics., Results: 94 patients were included with 371 inserted implants and 326 implants remaining for final analysis. At the time of last follow-up 18.1% (59/326) of the implants were lost and 3.4% showed signs of periimplantitis but were still stable in situ. Daily smoking (p = 0.016, OR = 2.1), irradiation (p < 0.001, OR = 2.8) and daily alcohol abuse (p = 0.028, OR = 3.1) had a significant effect on periimplantitis and implant loss. Combining smoking and irradiation, implant failure was 46.9% versus 15.0% in patients without these risk factors (p < 0.001, OR = 5.0). Age, tumor entity, ASA Score, anticoagulation, chemotherapy, diabetes and implant position did not show a significant correlation for implant loss or - except for age - periimplantitis. Younger patients showed a higher risk of developing periimplantitis (p = 0.011)., Conclusion: Orbital prostheses retained by solitary implants provide a solid option to reconstruct facial defects. Whereas in general high implant survival can be expected, they should be carefully considered in patients with the risk factors irradiation, smoking and alcohol abuse., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate whether a method of designing digital models of facial prostheses was suitable for patients with orbital defects. 32 patients were included in a retrospective study. 23 of them already had a facial prosthesis. 3D-data of the faces were acquired optically using fringe projection technique without and with (if available) the facial prosthesis in place. The healthy side of the surface models was mirrored to reconstruct the defect area. By generating a NURBS-model, the edges of the virtual prostheses were adapted to the defect region. The CAD models were stored in STL format as templates for facial prostheses. Using an automatically calculated asymmetry index (AI), four situations of the digitized facial surface were analysed for symmetry: 1. with defect area excluded, 2. with mirrored healthy surface, 3. with digital CAD template, and 4. with manually produced facial prosthesis inserted (if available). Mean AI values were 6.05 ± 3.26 (situation 1), 4.79 ± 2.51 (situation 2), 5.12 ± 2.61 (situation), and 6.74 ± 2.77 (situation 4). Additionally, the CAD templates were rated by three anaplastologists. Ratings did not differ significantly. They partially agreed with the three statements "The CAD prosthesis fits harmoniously within the face", "The CAD prosthesis could be used for a wax pattern during conventional fabrication" and "The CAD prosthesis and the wax pattern reduce workload". The results indicate that the presented technique has the potential to increase facial symmetry and facilitate the technical procedure. However, symmetry alone is not a sufficient criterion for design of a facial prosthesis., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)