Background and Objectives: Antiresorptive drugs are widely used in osteology and oncology. An important adverse effect of these drugs is medication-induced osteonecrosis of the jaw (MRONJ). There is scientific uncertainty about the underlying pathomechanism of MRONJ. A promising theory suspects infectious stimuli and local acidification with adverse effects on osteoclastic activity as crucial steps of MRONJ etiology. Clinical evidence showing a direct association between MRONJ and oral infections, such as periodontitis, without preceding surgical interventions is limited. Large animal models investigating the relationship between periodontitis and MRONJ have not been implemented. It is unclear whether the presence of infectious processes without surgical manipulation can trigger MRONJ. The following research question was formulated: is there a link between chronic oral infectious processes (periodontitis) and the occurrence of MRONJ in the absence of oral surgical procedures? Materials and Methods: A minipig large animal model for bisphosphonate-related ONJ (BRONJ) using 16 Göttingen minipigs divided into 2 groups (intervention/control) was designed and implemented. The intervention group included animals receiving i.v. bisphosphonates (zoledronate, n = 8, 0.05 mg/kg/week: ZOL group). The control group received no antiresorptive drug (n = 8: NON-ZOL group). Periodontitis lesions were induced by established procedures after 3 months of pretreatment (for the maxilla: the creation of an artificial gingival crevice and placement of a periodontal silk suture; for the mandible: the placement of a periodontal silk suture only). The outcomes were evaluated clinically and radiologically for 3 months postoperatively. After euthanasia a detailed histological evaluation was performed. Results: Periodontitis lesions could be induced successfully in all animals (both ZOL and NON-ZOL animals). MRONJ lesions of various stages developed around all periodontitis induction sites in the ZOL animals. The presence of MRONJ and periodontitis was proven clinically, radiologically and histologically. Conclusions: The results of this study provide further evidence that the infectious processes without prior dentoalveolar surgical interventions can trigger MRONJ. Therefore, iatrogenic disruption of the oral mucosa cannot be the decisive step in the pathogenesis of MRONJ.

A broad spectrum of complications following COVID-19 has been documented in adults, including the new onset of autoimmune-related manifestations and rheumatic diseases. Numerous case studies, reviews, and clinical trials have been published regarding the relationship between COVID-19 and the generation of autoantibodies that may cause rheumatic and autoimmune diseases. The currently suggested pathophysiology that leads to the new onset of such disorders may include well-established mechanisms, such as molecular mimicry and hyperstimulation of the immune system. The prevailing conditions documented following COVID-19 include, yet are not limited to, rheumatoid arthritis, myositis, antiphospholipid antibodies, ITP, and thyroid dysfunction. This chapter will summarize the current documentation of the broad-spectrum rheumatic diseases and autoimmune manifestations mediated by a SARS-CoV-2 infection.

Oral lichen ruber planus (OLP) is a poorly understood chronically inflammatory disease of the oral mucosa. Malignant transformation into oral squamous cell carcinoma (OSCC) is reported in between 1-2% of cases in the literature. After malignant transformation, surgical treatment-meaning tumor resection combined with neck dissection-is recommended. The recommended extent of treatment is controversial in the literature because this kind of OSCC is often a highly differentiated tumor with a lower risk for lymph nodal spreading. This study aims to overview 103 patients treated in our department due to OLP. The primary outcome parameter was the development of metastases in OLP patients compared to a group of OSCC patients without OLP and the comparison of survival in between both groups. Statistical analysis showed a significantly lower risk for patients with OSCC and with OLP for lymph nodal spreading (p = 0.013). Patients with OSCC and without OLP had a 4.76-higher risk for lymph nodal spreading. On the other hand, second metachronous tumor occurred more often in patients with OSCC and OLP. Overall, OSCC based on OLP occurs more often in female patients, is more highly differentiated and comes with a lower risk for metastases but has a higher risk for second metachronous tumors. Therefore, special attention should be paid to patients with OSCC based on OLP when planning adjuvant therapy and clinical follow-up. The indication for postoperative radiation should be made cautiously in this case, and clinical controls should be performed more closely due to the risk of recurrent disease or tumors at different locations.

In mandibular reconstruction, computer-assisted procedures, including virtual surgical planning (VSP) and additive manufacturing (AM), have become an integral part of routine clinical practice. Especially complex cases with extensive defects after ablative tumor surgery benefit from a computer-assisted approach. Various CAD/CAM-manufactured tools such as surgical guides (guides for osteotomy, resection and predrilling) support the transition from virtual planning to surgery. Patient-specific implants (PSIs) are of particular value as they facilitate both osteosynthesis and the positioning of bone elements. Computer-based approaches may be associated with higher accuracy, efficiency, and superior patient outcomes. However, certain limitations should be considered, such as additional costs or restricted availability. In the future, automation of the planning process and augmented reality techniques, as well as MRI as a non-ionizing imaging modality, have the potential to further improve the digital workflow.

Many women with silicone breast implants (SBIs) report non-specific complaints, including hearing impairments. Hearing impairment appears to be associated with a number of autoimmune conditions. The current study aimed to evaluate the prevalence and severity of hearing impairments among women with SBIs and to explore potential improvements in their hearing capability following implant removal. Symptomatic women with SBIs (n = 160) underwent an initial anamnestic interview, and women who reported hearing impairments were selected for the study. These women completed self-report telephone questionnaires regarding their hearing difficulties. Some of these women underwent subjective and objective hearing tests. Out of 159 (50.3%) symptomatic women with SBIs, 80 reported hearing impairments, including hearing loss (44/80; 55%) and tinnitus (45/80; 56.2%). Five out of seven (71.4%) women who underwent an audiologic evaluation exhibited hearing loss. Of women who underwent silicone implant removal, 27 out of 47 (57.4%) reported the improvement or resolution of their hearing complaints. In conclusion, hearing impairment is a frequent complaint among symptomatic women with SBIs, and tinnitus was found to be the most common complaint. A significant reduction in hearing difficulties was observed following silicone implant removal. Further studies using larger populations are needed to verify the occurrence of hearing impairments in these women.

The purpose of this study was to determine the expression patterns of specific desmosomal cadherins (desmogleins [DSG] 1/2/3) in oral squamous cell carcinoma (OSCC), and to examine possible associations with clinicopathological parameters and recurrence rates. Changes in desmosomal cadherin assembly may promote tumor metastasis formation. Patients with surgically treated OSCC with 36-60 months of follow-up (median 46 months) qualified for inclusion in this retrospective cohort study. Demographic, clinical and pathohistological data were collected. DSG-1/2/3 expression patterns were determined by an immunohistochemical approach on tissue microarrays. Descriptive and inferential statistics and survival analyses were computed (p < 0.05). The study sample consisted of 88 patients (female: 38; male: 50; average age: 63.02 +/- 17.5 years). DSG-3 overexpression was detected in 45 of 88 specimens. The expression rates for DSG-1 (28/88) and DSG-2 (14/88) were low and inconspicuous. DSG-3 overexpression was significantly associated with poor histologic differentiation (G3, p = 0.001), the presence of cervical node metastasis at primary diagnosis (N+ status, p = 0.001) and early recurrence (p = 0.001). Due to its possible relevance for lymph node metastasis formation and early OSCC recurrence, determination of DSG-3 expression in OSCC specimens may be a valuable tool for treatment planning and post-therapeutic risk assessment. (c) 2021 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.

Medication-related osteonecrosis of the jaw (MRONJ) has become a well-known side effect of antiresorptive, and antiangiogenic drugs commonly used in cancer management. Despite a considerable amount of literature addressing MRONJ, it is still widely accepted that the underlying pathomechanism of MRONJ is unclear. However, several clinical and preclinical studies indicate that infection seems to have a major role in the pathogenesis of MRONJ. Although there is no conclusive evidence for the infection hypothesis yet, available data have shown a robust association between local infection and MRONJ development. This observation is very critical in order to implement policies to reduce the risk of MRONJ in patients under antiresorptive drugs. This critical review was conducted to collect the most reliable evidence regarding the link between local infection and MRONJ pathogenesis.

Objective The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has created hitherto unknown challenges for healthcare systems and patient care. This study aimed to analyze its influence on patient care and healthcare management in oral and maxillofacial surgery (OMFS) in Germany. Materials and methods A nationwide survey of the German Association of Oral and Maxillofacial Surgery was performed. Individual questionnaires containing 10 questions for university as well as non-university hospitals and 15 questions for private practices (PPs) for OMFS were created to collect data for patient numbers and surgical procedures conducted, usage of personal protection equipment (PPE), SARS-CoV-2 tests, and economic aspects. Results Fifty-four hospitals and 240 PPs participated in the study. The reduction in ward capacities and number of surgical procedures ranged from 17 to 78%. PPE consisted of standard surgical masks (58% hospitals, 64% PPs) and FFP2/N95/KN95 respirators (45% hospitals, 48% PPs). Preoperative SARS-CoV-2 tests were more frequently performed in hospitals (34% vs 2%). At PPs, turnover for medical and dental procedures billed to the public insurance had reduced to 58.81% and 62.43%, respectively, of the corresponding values for 2019, and 58.75% of the PPs had applied for short-time allowances. Conclusion With the exception of some elective procedures, primary patient care in OMFS has been assured during the pandemic. However, the immense economic burden on hospitals and PPs cannot be conclusively assessed at this point. Clinical relevance For OMFS, the German healthcare system has shown the ability to adapt to emergency situations such as the SARS-CoV-2 pandemic. Adequate surgical capacities in OMFS are necessary even during pandemics.

The aim of this study was to analyze the current situation of trainees in OMFS in a nationwide survey at German universities and teaching hospitals. A questionnaire about their training in OMFS and discrimination, gender (in-)equality, and reconcilability of work and family life was sent to many OMFS residents in Germany. Seventy-five questionnaires were included. The average age of the participants was 32.15 years (+/- 0.75 years); 47 participants were male, 22 female, and 3 "diverse". The participants' overall satisfaction rate was good. Training concepts existed in most of the teaching hospitals (54.67%). 8.11% of the participants stated discrimination existed against men while, 24.32% agreed that discrimination existed against women. Stating that discrimination against women exists, it was associated with female gender (p < 0.001), being married (p = 0.042), and not aiming for further academic degrees (p = 0.009). Overall, the training situation in Germany seems structured in most teaching hospitals. Apart from the residents' general satisfaction with the training concepts, there seems to be a matter of concern regarding discrimination especially against women and the reconcilability of work and family life in OMFS training. Furthering the establishment of structured training concepts might be useful to overcome these issues in the course of training in OMFS. (C) 2020 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.

Objective. Medication-related osteonecrosis of the jaw (MRONJ) has become a serious concern for patients under antiresorptive treatment, especially in the oncological setting. Different approaches have been described in the management of MRONJ, including innovative autofluorescence-guided surgery. However, until now, there has been a lack of data regarding the outcome. In this study, we evaluated the efficacy of minimally invasive autofluorescence-guided resection in MRONJ. Study Design. Seventy-five patients with 82 lesions were included in this retrospective, single-center study. All included patients were diagnosed with MRONJ according to the American Association of Oral and Maxillofacial Surgeons guidelines and underwent autofluorescence-guided surgery with a minimum follow-up of 3 months. The primary outcome was complete integrity of the mucosa and absence of bone exposure. Results. The MRONJ stages were stage 0 (3.7%), stage 1 (3.7%), stage 2 (75.6%), and stage 3 (17%). Overall, complete mucosal healing of all lesions after the first surgery was 81.7% (67 of 82), whereas it was 90.2% (74 of 82) after revision surgery. Conclusions. The study showed that autofluorescence-guided surgery is a safe and successful treatment option that can be considered for all stages of MRONJ.

Though the exact etiology of autoimmune diseases still remains unknown, there are various factors which are believed to contribute to the emergence of an autoimmune disease in a host including the genetic predisposition, the environmental triggers such as bacterial infections, including the gut microbiota, viral fungal and parasitic infections, as well as physical and environmental agents, hormonal factors and the hosts immune system dysregulation. All these factors interplay was coined by Shoenfeld et al., many years ago “The Mosaic of Autoimmunity” [[1], [2], [3], [4]]. The most prominent pathogenic viruses which have been proposed in the triggering and initiation of autoimmune diseases include: Parvovirus B19, Epstein-Barr-virus (EBV), Cytomegalovirus (CMV), Herpes virus-6, HTLV-1, Hepatitis A and C virus, and Rubella virus [[5], [6], [7], [8], [9], [10], [11]]. These viruses have been implicated in the initiation of chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, primary billiary cholangitis, multiple sclerosis, polymoysitis, uveitis, Henoch Schonlein Puprpura, Systemic Juvenile Idiopathic arthritis, systemic sclerosis, Hashimoto thyroiditis and autoimmune hepatitis [12,13]. Suggested mechanisms of induction of the autoimmunity include both molecular mimicry [14] as well as “bystander activation” whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T-cells, thus leading to the production of pro-inflammatory mediators, which in turn may lead to tissue damage [15]. Alternative suggested mechanisms include epitope spreading as well as presentation of cryptic antigens [16]. Corona viruses represent a major group of viruses mostly affecting human beings through zoonotic transmission. In the past two decades, this is the third instance of the emergence of a novel coronavirus, after the severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 [17,18]. In December 2019 a novel outbreak of a new strain of coronavirus infection emerged in Wuhan, China the SARS-CoV-2 or the Covid-19. The disease which was declared as a pandemic in early March 2020, is characterized by fever, dry cough, myalgia and or extreme fatigue, may be asymptomatic or with minimal flu-like constitutional symptoms leading to a favorable outcome in many instances. However, some of the patients encounter a severe pneumonia with sepsis leading to an acute respiratory distress syndrome (ARDS) with respiratory failure requiring mechanical ventilation, and at times accompanied by hyperferritinemia and multiple organ involvement including hematological, gastrointestinal, neurological and cardiovascular complications leading to death [[19], [20], [21], [22], [23]]. The ARDS described in up to 20% of Covid-19 cases, is reminiscent of the cytokine release syndrome-induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. These cases with Covid-19 are those who develop through the excessive cytokine release and the uncontrolled immune activation, the multiorgan failure with a grave prognosis [24,25].

Background: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptives, evidences suggest that BPs have positive effect on bone formation. The aims of this study were to investigate the effect of zoledronic acid (ZA) and geranylgeraniol (GGOH) on human mesenchymal stem cells (hMSCs) being a part of the bone microenvironment and evaluate whether low dose of bisphosphonate has enhanced osteogenic differentiation of hMSCs. Materials and methods: The effect of ZA and GGOH on MSCs was investigated in addition to the effect of low doses of ZA on osteogenic differentiation of MSCs and analysed by WST-1, Live/Dead staining and coefficient of drug index (CDI). The osteogenic differentiation of the cells was confirmed by ALP activity, xylenol orange and alizarin red staining, microarray and PCR with levels of statistical significance indicated at *P < 0.05, **P < 0.01 and ***P < 0.0001. Main findings: Although, high concentration of ZA had significantly decreased the cell viability in MSCs, GGOH reversed the action of ZA on the cells while at very high concentration; it caused severe reduction in the cell viability. CDI showed antagonism or synergism depending on the concentrations of ZA and GGOH. Conclusion: The treatment of cells with ZA has increased the mineralization and osteogenic differentiation of MSCs. Our study supported the hypothesis that zoledronic acid plays a bifunctional role depending on the concentration. (c) 2020 Elsevier Masson SAS. All rights reserved.

INTRODUCTION:In recent years, considerable progress has been achieved in understanding the interaction between malignant cells and immune cells. The immune system continually seeks out and destroys mutated cells, but in some cases, mutations may occur and give some malignant cells the advantage to neutralize and evade the immune system. One of the regulatory mechanisms that allows these cells to abrogate immune responses is based on Immune Checkpoints. These checkpoints include the Cytotoxic-T lymphocyte antigen-4 (CTLA-4), Programmed cell death protein-1 (PD-1) and its ligand Programmed death-ligand-1 (PD-L1). Tasuku Honjo and James Allison, 2018 Nobel Prize laureates, investigated various components of these mechanisms. They found that in some cases malignant cells may overexpress binding sites that interact with CTLA-4 or PD-1, like the PD-L1 molecule, thus managing to maneuver the immune system. They paved the way for a new class of cancer drugs by showing different strategies to disrupt these checkpoints. This understanding has prompted a paradigm shift in oncology and a breakthrough in the development of new generation immunotherapy drugs: Immune Checkpoint Inhibitors (ICPi). By unbalancing the immune system, these treatments also generated dysimmune toxicities, called Immune Related Adverse Events (irAEs). The study of irAEs is in its infancy; there are very few prospective studies. Where possible, the estimates of irAE incidence were drawn from meta-analyses of randomized controlled trials. In this article, we discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; the impact of autoimmune manifestations on cancer outcome and management of irAEs.

Objective In severe congenital or acquired orofacial anomalies, both dental esthetics and function are usually compromised. In particular, the esthetic ideas of the final desired appearance may differ from patient to patient, as the human esthetic sensibility differs significantly. Especially in complex cases, digital technology today offers outstanding improvements and simplifications in craniomaxillofacial surgical and prosthetic treatments, leading to a wide range of planning and pretreatment options. Clinical Considerations This case report describes a patient-oriented interdisciplinary craniomaxillofacial surgical and prosthetic treatment with noninvasive tooth-colored splints, a Le Fort I osteotomy, and a full-mouth rehabilitation to meet the patient's demand for better function as well as orofacial esthetics and harmony. Conclusions By means of the digitally planned Le Fort I intervention and completion of the prosthetic rehabilitation, it was possible to optimize esthetics and facial harmony. Clinical Significance In complex cases, digital technology today offers outstanding improvements and simplifications in craniomaxillofacial surgery and prosthetic treatments, leading to a wide range of planning and pretreatment options. Computer-aided design/computer-aided manufacturing technology enables the fabrication of tooth-colored flexible polycarbonate splints that offer a noninvasive, removable, functional, and esthetic solution. In intricate cases involving craniomaxillofacial anomalies, often together with necessary orofacial surgeries or prosthetic treatments due to moderate to severe tooth wear, such digital preprosthetic treatment and planning options represent an important enhancement with more predictable results.