Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Are Patients with Syndromic Craniosynostosis at Greater Risk for Epilepsy than Patients with Nonsyndromic Craniosynostosis?

OBJECTIVE: The aim of this study was to determine whether patients with syndromic craniosynostosis (SCS) are at increased risk for epilepsy relative to patients with nonsyndromic craniosynostosis (NSCS). METHODS: A retrospective cohort study was completed using the Kids' Inpatient Database (KID). All patients diagnosed with craniosynostosis (CS) were included. The primary predictor variable was study grouping (SCS vs. NSCS). The primary outcome variable was a diagnosis of epilepsy. Descriptive statistics, univariate analyses and multivariate logistic regression were performed to identify independent risk factors for epilepsy. RESULTS: The final study sample included a total of 10,089 patients (mean age, 1.78 years ± 3.70; 37.7% female). 9278 patients (92.0%) had NSCS, and the remaining 811 patients (8.0%) had SCS. A total of 577 patients (5.7%) had epilepsy. Not controlling for other variables, patients with SCS were at increased risk for epilepsy relative to patients with NSCS (OR 2.1, P < 0.001). After controlling for all significant variables, patients with SCS were no longer at increased risk for epilepsy relative to patients with NSCS (OR 0.73, P = 0.063). Hydrocephalus, Chiari malformation (CM), obstructive sleep apnea (OSA), atrial septal defect (ASD), gastro-esophageal reflux disease (GERD) were all independent risk factors (P < 0.05) for epilepsy. CONCLUSIONS: Syndromic craniosynostosis (SCS) in itself is not a risk factor for epilepsy relative to NSCS. The greater prevalence of hydrocephalus, CM, OSA, ASD, and GERD, all of which were risk factors for epilepsy, in patients with SCS relative to patients with NSCS likely explains the greater prevalence of epilepsy in SCS relative to NSCS.

Implant Survival in Tissue-Engineered Mandibular Reconstruction-Early Experiences.

Study Design: This article is to evaluate the early outcomes of dental implants placed in bone generated with tissueengineering techniques, specifically recombinant human bone morphogenic protein-2 (rhBMP-2), allogeneicbone particulate, and bone marrow aspirate concentrate (BMAC) in patients with resection of benignpathology. Objective: To evaluate the long-term prognosis of dental implants placed in tissue engineered mandibular reconstruction. Methods: We retrospectively evaluated 12 patient records, all of whom underwent segmental mandibular resection of benign pathology and reconstruction with a combination of BMAC, rhBMP-2, and allogeneic bone. Collecteddata points included the patient's age, gender, medical and social histories, implant site and placement date, resection/reconstruction date, final prosthesis, pathology resected, and follow-up dates (average 25 monthsof follow-up). Implant success was defined as clinical osseointegration (immobility), absence of peri-implantradiolucency, and absence of infection. Results: Twelve patients met inclusion criteria with a total of 46 implants. The overall implant survival rate was 91.3%. There were 4 implant failures occurring in two patients: 1 failure in Patient 3 and 3 failures in Patient 8. Neitherpatient had any existing medical comorbidities or social history known to increase the risk for implant failure. The average implant placement occurred 11.6 months after mandibular reconstruction. Conclusions: Preliminary findings of implant placement in bone generated with tissue engineering techniques have shown to be another predictable alternative for orofacial rehabilitation. Practical Implications: Dental rehabilitationusing dental implants is a predictable treatment option for patients that have required reconstruction of largebony defects status post resection of benign pathology using novel tissue engineering techniques.

Case report: golimumab-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw is an uncommon but highly morbid adverse event of certain medical therapies. Although classically induced by bisphosphonates, the recent advent of monoclonal antibodies is contributing to a rise in cases. In this case report, we present a rare case of golimumab-associated medication-related osteonecrosis of the jaw and discuss the possible mechanisms of pathogenesis.

Reconstruction of Critical Sized Maxillofacial Defects Using Composite Allogeneic Tissue Engineering: Systematic Review of Current Literature.

The current review aimed to assess the reliability and efficacy of tissue-engineered composite grafts in the reconstruction of large maxillofacial defects resulting from trauma or a benign pathologic disease. A systematic review of the literature was conducted using PubMed/Medline, Embase, and Scopus up to March 2022. The eligibility criteria included patients who had been treated with composite allogeneic tissue engineering for immediate/delayed reconstruction of large maxillofacial defects with minimum/no bone harvesting site. In the initial search, 2614 papers were obtained, and finally, 13 papers were eligible to be included in the current study. Most included papers were case reports or case series. A total of 144 cases were enrolled in this systematic review. The mean age of the patients was 43.34 (age range: 9-89). Most studies reported a successful outcome. Bone tissue engineering for the reconstruction and regeneration of crucial-sized maxillofacial defects is an evolving science still in its infancy. In conclusion, this review paper and the current literature demonstrate the potential for using large-scale transplantable, vascularized, and customizable bone with the aim of reconstructing the large maxillofacial bony defects in short-term follow-ups.

Repair of complex ovine segmental mandibulectomy utilizing customized tissue engineered bony flaps.

Craniofacial defects require a treatment approach that provides both robust tissues to withstand the forces of mastication and high geometric fidelity that allows restoration of facial architecture. When the surrounding soft tissue is compromised either through lack of quantity (insufficient soft tissue to enclose a graft) or quality (insufficient vascularity or inducible cells), a vascularized construct is needed for reconstruction. Tissue engineering using customized 3D printed bioreactors enables the generation of mechanically robust, vascularized bony tissues of the desired geometry. While this approach has been shown to be effective when utilized for reconstruction of non-load bearing ovine angular defects and partial segmental defects, the two-stage approach to mandibular reconstruction requires testing in a large, load-bearing defect. In this study, 5 sheep underwent bioreactor implantation and the creation of a load-bearing mandibular defect. Two bioreactor geometries were tested: a larger complex bioreactor with a central groove, and a smaller rectangular bioreactor that were filled with a mix of xenograft and autograft (initial bone volume/total volume BV/TV of 31.8 ± 1.6%). At transfer, the tissues generated within large and small bioreactors were composed of a mix of lamellar and woven bone and had BV/TV of 55.3 ± 2.6% and 59.2 ± 6.3%, respectively. After transfer of the large bioreactors to the mandibular defect, the bioreactor tissues continued to remodel, reaching a final BV/TV of 64.5 ± 6.2%. Despite recalcitrant infections, viable osteoblasts were seen within the transferred tissues to the mandibular site at the end of the study, suggesting that a vascularized customized bony flap is a potentially effective reconstructive strategy when combined with an optimal stabilization strategy and local antibiotic delivery prior to development of a deep-seated infection.

Management of MACROGLOSSIA: Case Series and Suggested Algorithm.

PURPOSE: Idiopathic macroglossia is a rare entity of true tongue enlargement without an underlying etiology. There are only a few case reports on the diagnosis and management of idiopathic macroglossia. This study's purpose was to present a series of patients with idiopathic macroglossia and suggest a treatment algorithm. METHODS: This was a retrospective case series of a cohort of patients with macroglossia who were treated by the Oral and Maxillofacial Surgery service at the University of Texas Health Science Center at Houston (UTHealth)and Emory University. The patient's medical comorbidities, history of present illness, clinical presentation, radiographic findings, and disease management were studied. The outcome variables include normalization of the tongue size, dependence on parenteral nutrition, and tolerating tracheostomy decannulation. RESULTS: Five patients with a mean age of 45 years were included in the study. All of the patients (n = 5, 100%) in our cohort developed macroglossia following prolonged oral intubation, with 3.5 weeks being the average length of intubation. All patients presented with difficulty feeding orally and breathing. The average tongue dimension was 12.20 x 6.25 cm. All tongue enlargements were located in the anterior 2/3 of the tongue, and all patients had displaced anterior dentition. In addition, 60% of the patients (n = 3) experienced altered tongue sensation (pain and/or decreased taste). These patients were surgically managed with tracheostomy and percutaneous endoscopic gastrostomy (PEG) tube placement followed by partial glossectomy (n = 5, 100%). We defined successful outcomes as 1) modifying the tongue to a functional, nonprotruding form, 2) tracheostomy decannulation and 3) PEG tube removal. Tracheostomy decannulation and PEG tube removal were achieved in 80% of the patients (n = 4). CONCLUSIONS: In this patient cohort, we were unable to identify the cause of the pathology based on existing clinical data. When the etiology is unclear or irreversible, management should involve tracheostomy and surgical feeding access for the initial stabilization, followed by modified glossectomy to improve form, function, and cosmesis thereby improving the overall quality of life.

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

Current Trends in the Reconstruction and Rehabilitation of Jaw following Ablative Surgery.

The reconstruction and rehabilitation of jaws following ablative surgery have been transformed in recent years by the development of computer-assisted surgery and virtual surgical planning. In this narrative literature review, we aim to discuss the current state-of-the-art jaw reconstruction, and to preview the potential future developments. The application of patient-specific implants and the "jaw-in-a-day technique" have made the fast restoration of jaws' function and aesthetics possible. The improved efficiency of primary reconstructive surgery allows for the rehabilitation of neurosensory function following ablative surgery. Currently, a great deal of research has been conducted on augmented/mixed reality, artificial intelligence, virtual surgical planning for soft tissue reconstruction, and the rehabilitation of the stomatognathic system. This will lead to an even more exciting future for the functional reconstruction and rehabilitation of the jaw following ablative surgery.

COVID-Associated Avascular Necrosis of the Maxilla-A Rare, New Side Effect of COVID-19.

PURPOSE: The purpose of this article is to present an interesting, rare case of a patient who experienced avascular necrosis of the maxilla associated with COVID-19 infection. METHODS AND RESULTS: Our team retrospectively evaluated this patient's chart after completion of surgical management. The patient is a 72-year-old male who presented to the University of Texas Health Science Center at Houston for surgical management of his infarcted maxilla, which developed as a sequela of infection with COVID-19. A literature review was completed using PubMed. Twenty-five articles are reviewed and discussed. CONCLUSIONS: Infection with COVID-19 confers a hypercoagulable state in patients, leading to various complications in the head and neck region. In our case report, we present a patient who developed avascular necrosis of the maxilla secondary to infection with COVID-19. Thromboembolic prophylaxis is imperative in COVID-19 patients due to the high rate of potential systemic complications.

Massive macroglossia, a rare side effect of COVID-19: clinical, histologic, and genomic findings in COVID-19-positive versus COVID-19-negative patients.

PURPOSE: The primary purpose of this study is to identify if there is an underlying genetic predisposition for COVID-related macroglossia and if this susceptibility is higher among individuals of African heritage. Secondary objectives include determining if genetic testing of COVID-infected patients who are intubated and prone could identify patients with higher susceptibility to the development of macroglossia. METHODS: A retrospective chart review was completed for each patient, and prospectively, genetic and histopathologic analyses were completed. Whole-exome sequencing was completed on two patients; immunohistochemistry was completed on the COVID-positive tissue samples. RESULTS: Histopathology of the COVID-positive patient revealed significant peri-lymphocytic infiltrate, which was absent in the COVID-negative patient. Immunohistochemistry confirmed the presence of immune cells. Results from the whole-exome sequencing were inconclusive. CONCLUSION: The findings of this study are consistent with others that have observed a lymphocytic infiltrate in the organs of patients infected with SARS-CoV-2. On histology, IHC highlighted a CD45 + predominance, indicating that a robust immune response is present in the tissues. The pathobiology of this phenomenon and its role in the development and/or persistence of massive macroglossia requires further study.

The Incidence of COVID-19 Patients in Oral and Maxillofacial Surgery.

PURPOSE: The SARS-CoV-2 global pandemic has resulted in widespread changes to healthcare practices across the United States. The purpose of this study is to examine the incidence of COVID-19 patients in the oral-maxillofacial surgery setting in order to help guide perioperative protocols during the pandemic. METHODS: In this retrospective cohort study, predictor variables (presence of preoperative symptoms on presentation, patient age, patient gender, patient race, hospital location, and presence of statewide stay-at-home orders) were examined with outcome variables (SARS-CoV-2 test results) over 10 months between March 2020 and December 2020 for patients undergoing surgical procedures in the operating room by the following Oral-Maxillofacial Surgery Departments: - Louisiana State University Health Sciences Center (Baton Rouge, LA) - University of Illinois at Chicago (Chicago, IL) - University of Texas Health Science Center at Houston (Houston, TX) Data analysis included Fisher exact tests to compare categorical variables across COVID test groups and Wilcoxon rank sum tests to compare continuous covariates. Two-sample tests of proportions were used to compare observed COVID-19 positivity rates to other study results. RESULTS: Out of 684 patients in 3 institutions, 17 patients (2.5%, 95% CI = 1.5 to 4.0%) tested positive for COVID-19 over a 10 month interval (March 1, 2020- December 31, 2020). The majority of patients that tested positive were asymptomatic in the preoperative setting (P-value = .09). They were significantly more likely to be African-American (P-value = .015) and less likely to have a stay-at-home order present at the time of surgery (P-value = .033). Age, gender, and hospital location did not play a statistically significant role. CONCLUSION: Our results demonstrate a 2.5% incidence of COVID-19 infection in the total population of patients undergoing scheduled oral-maxillofacial surgeries in 3 major healthcare systems across the United States. This data may help inform perioperative protocols and infection control measures during the COVID-19 pandemic.

Brush swab as a noninvasive surrogate for tissue biopsies in epigenomic profiling of oral cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. METHODS: Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e., cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. RESULTS: There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation (r = 0.913 for cancer samples and r = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p-value = 0.00021) but not different between tissues and brush swabs (mean p-value = 0.11). CONCLUSIONS: Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

Comprehensive Oromandibular Reconstruction Utilizing an Anterolateral Thigh Free Tissue Transfer Flap and Tissue Engineering: Technical and Timing Considerations.

The present report describes the technical nuances involved in oromandibular reconstruction utilizing a soft tissue free flap and tissue engineering in a step wise fashion for complete oral rehabilitation.

Localized mandibular infection affects remote in vivo bioreactor bone generation.

Mandibular reconstruction requires functional and aesthetic repair and is further complicated by contamination from oral and skin flora. Antibiotic-releasing porous space maintainers have been developed for the local release of vancomycin and to promote soft tissue attachment. In this study, mandibular defects in six sheep were inoculated with 106 colony forming units of Staphylococcus aureus; three sheep were implanted with unloaded porous space maintainers and three sheep were implanted with vancomycin-loaded space maintainers within the defect site. During the same surgery, 3D-printed in vivo bioreactors containing autograft or xenograft were implanted adjacent to rib periosteum. After 9 weeks, animals were euthanized, and tissues were analyzed. Antibiotic-loaded space maintainers were able to prevent dehiscence of soft tissue overlying the space maintainer, reduce local inflammatory cells, eliminate the persistence of pathogens, and prevent the increase in mandibular size compared to unloaded space maintainers in this sheep model. Animals with an untreated mandibular infection formed bony tissues with greater density and maturity within the distal bioreactors. Additionally, tissues grown in autograft-filled bioreactors had higher compressive moduli and higher maximum screw pull-out forces than xenograft-filled bioreactors. In summary, we demonstrated that antibiotic-releasing space maintainers are an innovative approach to preserve a robust soft tissue pocket while clearing infection, and that local infections can increase local and remote bone growth.