Perineural Invasion Is a Significant Prognostic Factor in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

(1) Objectives: This systematic review and meta-analysis aimed to summarize current evidence regarding the prognostic role of perineural invasion (PNI) in patients with oral squamous cell carcinoma (OSCC). (2) Methods: We searched Cochrane Central, ProQuest, PubMed, Scopus, Science Direct, and Web of Science, using relevant keywords to identify eligible articles. Two independent reviewers conducted two-stage screening, data extraction, and quality assessment. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) criteria. All analyses were performed using comprehensive meta-analysis (CMA; version 3.3.070) software. (3) Results: The study included 101 published articles encompassing 26,062 patients. The pooled analyses showed that PNI was associated with significantly worse overall survival (OS; HR = 1.45, 95% CI: 1.32-1.58; p < 0.001), worse disease-specific survival (DSS; HR = 1.87, 95% CI: 1.65-2.12; p < 0.001), and worse disease-free survival (DFS; HR = 1.87, 95% CI: 1.65-2.12; p < 0.001). Similarly, both local recurrence-free survival (LRFS) and regional recurrence-free survival (RRFS) were worse in patients with PNI (HR = 2.31, 95% CI: 1.72-3.10, p < 0.001; and HR = 2.04, 95% CI: 1.51-2.74, p < 0.001), respectively. The random-effect estimate of three studies demonstrated that the presence of PNI was associated with worse failure-free survival (FFS; HR = 2.59, 95% CI: 1.12-5.98, p < 0.001). (4) Conclusions: The current evidence suggests that PNI can be used as an independent predictor of the prognosis for patients with OSCC. The presence of PNI was associated with worse OS, DFS, DSS, FFS, and with recurrence. Asian patients and patients with extra-tumoral or peripheral PNI invasion were associated with worse prognosis.

Awareness, perceptions and attitudes toward medication-related osteonecrosis of the jaw among physicians who treat osteoporosis.

Osteoporosis is the most common indication for antiresorptive drugs (ARDs). Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of ARDs. Multiple risk factors can increase the risk of MRONJ, one of which is the duration of ARD intake, which is usually prolonged for osteoporosis cases. Prevention of MRONJ relies on collaborative care between treating physicians and dental practitioners. Therefore, knowledge about MRONJ and its prevention strategies is crucial for both teams. Aim: This study aimed to assess the knowledge and attitudes of physicians toward MRONJ in osteoporosis patients. Another aim was to develop recommendations for the prevention of MRONJ. Materials and methods: Through an online survey, basic information such as the practice location, training, knowledge, perceptions, and attitudes of physicians regarding ARDs and MRONJ in osteoporosis patients was collected. Statistical analysis was performed for all variables, and their correlations were explored. Results: A total of 221 physicians participated in the survey: 34.8% were rheumatologists, 25.3% were endocrinologists, 8.6% were family medicine physicians, 5.9% were orthopedists, and 5.9% were internal medicine physicians. Of them, 58.0% reported more than 6 years of experience. Only 78.7% were aware of MRONJ and recognized that bisphosphonates (BPs) can contribute to MRONJ. In contrast, 56.0% recognized denosumab as a causative factor for MRONJ. Duration of ARD therapy and pre- and post-ARD dental care were known to influence the risk of MRONJ by 62% and 65.6% of the participants, respectively. Only 41.6% and 31.2% of participants informed patients about MRONJ prior to BP and denosumab therapy, respectively. Only 25.3% and 20.8% referred patients to dentists before BP and denosumab therapy, respectively. Overall, 65.6% of the participants had a negative attitude toward MRONJ, and 34.4% had a positive attitude. A positive attitude was mostly observed among rheumatologists (55.8%) compared to other specialists (p <0.001). More years of experience were associated with a higher level of knowledge and positive attitude. Conclusion: The findings of this study identified a notable gap in the awareness, knowledge and attitudes of physicians regarding MRONJ in osteoporosis patients. Continuing education programs about ARDs and MRONJ risk are highly recommended.

Oral manifestations in hospital-admitted COVID-19 patients: a case control study.

The oral cavity can present early manifestations of several systemic diseases. Since the emergence of the COVID-19 pandemic, there have been many published studies reporting the direct effect of the virus on orofacial structures. In the present study, oral signs and symptoms of 22 hospital-admitted COVID-19 patients were examined and compared to a matching control group. Loss of taste and smell was the most prevalent symptom (65%), followed by oral dryness (45%) and halitosis (30%). The most common oral lesions were candidal infections (68%). Other less common manifestations were oral ulcerations (36%) followed by the appearance of white patches (27.3%). There was a statistically significant association between candidal infection and age in the study group, where the p-value was 0.008. In the present study, 80% of those who had candida infections were aged 60 years or above. There was no significant association with comorbidities such as diabetes mellitus and hypertension.

Salivary Oxidative Stress and Antioxidant Capacity in Smokeless Tobacco (Naswar) Users.

Background: Naswar, a smokeless tobacco product, commonly consumed in Pakistan, is associated with a 10-fold increase in the risk of oral cancer. However, little is known about Naswar's underlying toxicity mechanisms. Objective: The current study aimed to investigate the effects of Naswar use on oral health and salivary parameters. Methods: A case-control study was conducted among Naswar users (n=42) and age-matched healthy controls (n=42) in Pakistan in 2019. Participant data were collected using questionnaires. Decayed, missing, and filled teeth (DMFT) scores were computed during clinical examinations. Unstimulated whole saliva was collected to assess salivary flow rate, pH, and salivary total oxidative stress (TOS)/total antioxidant capacity (TAC) using commercially available kits. Participants' oral health parameters were compared between cases and controls using ANOVA. Results: No significant differences were observed between the two groups in terms of age, oral health, and hygiene practices and mean DMFT score. Mean salivary pH and the salivary flow rate was significantly (p<0.001) higher in Naswar users (7.7 and 0.71 mL/minute, respectively) than in non-users (6.95 and 0.52 mL/minute, respectively). Although TOS and TAC were not significantly different between the groups, Naswar users generally had a higher TOS (51.6±42 µmol/L) and lower TAC (0.55±0.18 mmol/L) than non-users (TOS 45.5±38.2 µmol/L and TAC 0.57±0.17 mmol/L). Correlational analysis also revealed a significant positive correlation between DMFT score and Naswar use duration (r=0.796, p<0.001) and the number of dips/units consumed each day (r=0.515; p<0.001). Conclusion: Habitual Naswar use is associated with increased salivary flow rate, pH, and TOS, and reduced TAC levels in Pakistani adults compared to non-users. The pro-oxidant changes may contribute toward deleterious effects of Naswar use including oral cancer.

Tear Cytokine Levels in Sicca Syndrome-Related Dry Eye: A Meta-Analysis.

Sjogren's syndrome (SS) is an autoimmune disease that affects exocrine glands, mainly salivary and lacrimal glands. Several studies have investigated cytokine profiles in tears in order to understand the pathogenesis of SS and find additional diagnostic markers. This systematic review and meta-analysis aimed to analyze cytokines in tears of SS patients. A systematic literature search of the Cochrane, Medline via PubMed, Scopus, and Web of Science databases was conducted using key terms related to "Sjögren's syndrome" and "tears" combined with "biomarker", "cytokines", "interleukin", and "chemokines", following PRISMA guidelines. Article selection was subjected to certain eligibility criteria. A total of 17 articles (from 1998 and 2022) were selected for the quantitative and qualitative analysis. When compared to controls, concentrations of IFN-γ, TNF-α, IL-1α, IL-1 Ra, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21 and IL-22 were consistently higher; however, IL-23 was significantly lower in patients with SS compared to the controls. Tear levels of some cytokines were significantly elevated among SS groups compared to control groups. Therefore, these cytokines could be potential biomarkers of SS. However, standardization of sample collection and analytical methods is necessary in order to translate these findings into clinical practice.

Clinical and Radiographic Outcomes of Dental Implants in Patients Treated With Antiresorptive Drugs: A Consecutive Case Series.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious concern for dentists as well as maxillofacial surgeons. Therefore, the safety of dental implant placement in patient receiving antiresorptive drugs (ARDs) has been the subject of controversial debate for several years and remains a source of uncertainty for surgeons and patients. This consecutive case series assessed the clinical and radiographic outcomes of dental implants placed in patients under antiresorptive therapy. Patients who received at least one dental implant at the Department of Oral and Maxillofacial Surgery, Ludwig Maximilian University (LMU), Munich, Germany, between 2010 and 2019 with a history of current or past antiresorptive medication were included the study. The main outcomes were occurrence of MRONJ, implant success, and survival rate. A total of 16 patients were treated with 39 implants. No implant loss or MRONJ occurred in the respective patients. The reasons for antiresorptive intake were osteoporosis, malignancy, edema of bone marrow, or diffuse sclerosing osteomyelitis (DSO). MRONJ occurred neither around implants nor in other locations. Cumulative implant success was 92.6% (25 of 27). No subjective complaints or postoperative complications were documented. Mean bone loss was 0.60 ± 0.98 mm. The prevalence of peri-implantitis was 30% on patient level and 29.6% on implant level. None of the patients had failed implants. No major complications after implant placement under antiresorptives could be detected. As long as implant surgery follows a specific protocol, implant placement in patients treated with antiresorptive therapy seems to be safe and predictable.

Oral Manifestations of COVID-19: A Cross-Sectional Study of Their Prevalence and Association with Disease Severity.

BACKGROUND: COVID-19, caused by SARS-CoV-2, has impacted the world in an unprecedented way since December 2019. SARS-CoV-2 was found in the saliva of patients, and entry points for the virus may have been through the numerous angiotensin-converting enzyme 2 receptors in the oral cavity. Oral manifestations of COVID-19 could contribute to the burden of oral disease. OBJECTIVE: To determine the prevalence of oral manifestations of COVID-19 in patients and their association with disease severity. METHODS: Interviews were conducted with adult participants diagnosed with COVID-19 between October 2021 and March 2022 to document their demographic and health status data, symptoms, and the presence of oral manifestations of COVID-19. Chi-square and the Fisher's exact test were used to compare data on the presence or absence of oral manifestations of COVID-19. RESULTS: Of 195 participants interviewed, 33% were 18 to 24 years old, 33% were 25 to 34 years old, and 75% were female. A total of 57 (29%) had oral manifestations; the most common were taste disorders (60%), xerostomia (42%), and oral ulcers (11%). There was no relationship between the severity of COVID-19 and the presence of the oral manifestations. CONCLUSION: Oral manifestations of COVID-19 were common among female patients and linked to certain general COVID-19 symptoms regarding frequency and extent.

Fluorescence-guided surgery for osteoradionecrosis of the jaw: a retrospective study.

OBJECTIVE: Osteoradionecrosis of the jaw (ORNJ) is one of the most severe head and neck complications in patients treated with radiotherapy. The goal of treatment is to suppress ORNJ progression. Currently, surgical removal of necrotic bone is an effective management approach for advanced stages. In this study, we present our experience in managing ORNJ using fluorescence-guided surgery. METHODS: Nineteen ORNJ lesions in 15 hospitalized patients were treated with fluorescence-guided surgery. We retrospectively reviewed patients' demographic data, comorbidities, local preceding event, location, ORNJ stage, and treatment outcomes with a median follow-up of 12 months. RESULTS: Twelve lesions (63%) were treated surgically under tetracycline fluorescence, and seven lesions (37%) were surgically treated under auto-fluorescence. Overall, four lesions (21%) achieved complete mucosal healing, eight lesions (42%) showed partial mucosal healing with bone exposure and no signs or symptoms of inflammation, and seven lesions (37%) were progressive. The results showed that either healing or ORNJ stabilization was achieved in 63% of lesions (n = 12). CONCLUSION: Fluorescence-guided surgery can be beneficial in curing or stabilizing ORNJ. However, randomized clinical trials are needed to confirm these findings.

Oral lesions associated with smokeless tobacco users in Saudi Arabia: Single center cross-sectional study.

INTRODUCTION: Smokeless tobacco (SLT) causes significant harm to the oral cavity and is considered a risk factor for oral cancer. Various forms, products, and patterns of SLT are used across different populations. Many products, such as nicotine and betel nut, have addictive and carcinogenic properties. SLT use is associated with benign, premalignant, or malignant lesions. This study aimed to identify the characteristics of these oral lesions and their association with SLT exposure. MATERIALS AND METHODS: This cross-sectional study, performed at our institution's Faculty of Dentistry, included all the patients with a history of using SLT within a 5-year period at the oral medicine clinic. The patients' demographic details were collected, and information regarding habit, duration, frequency, site of placement, and history of habit discontinuity were recorded. If a biopsy was performed, the diagnoses were also reported. RESULTS: Of the 59 patients included, 89.8% were male and 10.2% were female. SLT lesions in the oral cavity were usually focal lesions (76.3%). The most preferred placement site by SLT users was the mandibular posterior vestibule. Follow-up of SLT patients after quitting or clinical changes in the placement site showed a 92.8% regression or complete healing of the lesions. Of the 59 patients who underwent SLT, 18.6% were diagnosed with oral squamous cell carcinoma. CONCLUSION: This study demonstrated a high percentage of remarkable regression or complete healing of SLT lesions related to early diagnosis and habit change. In contrast, 18.6% of the lesions progressed to SCC.

Infection as an Important Factor in Medication-Related Osteonecrosis of the Jaw (MRONJ).

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.

Autofluorescence-guided surgery for the treatment of medication-related osteonecrosis of the jaw (MRONJ): a retrospective single-center study.

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.

Surgical treatment of medication-related osteonecrosis of the upper jaw: Case series.

PURPOSE: The management of maxillary medication-related osteonecrosis of the jaw (MRONJ) is challenging. Therefore, identifying the proper treatment is important. This study aimed to evaluate the surgical treatment of maxillary MRONJ using single-layer closure with mucoperiosteal flap and double-layer closure with buccal fat pad flap (BFPF) and mucoperiosteal flap and to find the outcomes after rehabilitation with obturators. METHODS: A retrospective analysis was conducted and included all surgically treated and followed-up maxillary MRONJ cases in a single center. Demographics and clinical data, stage of MRONJ, surgical treatment, and treatment outcome were collected. RESULTS: Seventy-nine lesions were included. Removal of necrotic bone was followed by coverage with mucoperiosteal flap in 60 lesions and BFPF in 14 lesions. Seven lesions (five primarily and two following unsuccessful treatment with BFPF) underwent necrectomy and were reconstructed with obturators. Complete mucosal healing was achieved in 76.7% of the lesions covered with mucoperiosteal flap. BFPF led to complete mucosal healing in 85.7% of the lesions. No complications were observed in the defects rehabilitated with obturators. CONCLUSION: Removal of necrotic bone followed by closure with mucoperiosteal flap is reliable for MRONJ treatment. BFPF is effective for closure of MRONJ-related oroantral communications (OACs).

Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series.

PURPOSE: Osteonecrosis of the jaw has been recently reported in patients receiving denosumab for the treatment of metastatic bone disease and osteoporosis. It is essential to investigate this disease as a new osteonecrosis entity in order to recognize its optimal management strategies. MATERIALS AND METHODS: A total of 63 cases of denosumab-related osteonecrosis of the jaw (DRONJ) diagnosed at two clinical centres were retrospectively reviewed. Demographics, comorbidities, antiresorptive medication use, local preceding event, location, DRONJ stage, treatment and treatment outcomes were analyzed. RESULTS: In all, 69 MRONJ lesions in 63 patients were diagnosed. The mean patient age was 70 ± 9 years. Denosumab was the only received antiresorptive medication in 50.8% of the patients. Discontinuation of denosumab prior to treatment was recorded for 66.7% of the patients, with a mean period of 6 ± 3.4 months. Stage 2 was the most common stage of the disease (71%). The lesions were predominantly located in the mandible (63.5%). The most common preceding local event was extraction (55.6%). Surgical treatment was performed in 95.7% of the cases, while purely conservative treatment was performed in 4.3%. DRONJ healed after surgical treatment in 71.7% of the treated lesions. Complete mucosal healing was achieved in 77.2% of the lesions treated with fluorescence-guided surgery (17/22). Clinical characteristics and treatment outcomes were not significantly different between patients with and without previous intake of bisphosphonates. CONCLUSION: DRONJ is more prevalent at extraction and local infection sites in cancer patients. Within the limitation of this study, surgical treatment, particularly fluorescence-guided surgery, appears to be effective for the management of DRONJ. The prior use of bisphosphonates does not seem to affect severity nor the treatment success rate of DRONJ.

DFT investigation of the interaction between single-walled carbon nanotubes and fluorene-based conjugated oligomers.

π-Conjugated oligomers with relatively short molecular backbones can be used effectively in dispersion of carbon nanotubes (CNTs). In this paper, we present a systematic study on interactions between diphenylene-fluorene oligomers (DPFs) and single-walled CNTs (SWCNTs) using density functional theory (DFT) calculations. Four DFT methods are used in this work: the long range (LR)-corrected CAM-B3LYP, the dispersion (D)-corrected B97D, the LR- and D-corrected wB97XD, and the hybrid B3LYP. The DPFs examined in this study contain different functional groups attached to the π-conjugated backbone, including two different end groups, carboxaldehyde (ALD) and dithiafulvenyl (DTF), and three different side chains (SCs), C8H17, OC10H21, and SC10H21. The computational results disclose the effects of end groups, SCs, and DFT methods on structures, dipole moments, and energetics of isolated DPFs and DPF/SWCNT combinations. Consistent with our previous study (involving oligo(p-phenylene ethynylene)s (OPEs)) [Aljohani et al., J. Phys. Chem. C, 2017, 121, 4692-4702], our results herein demonstrate that the type of end group plays a key role in determining the strength of interactions between SWNTs and conjugated oligomers. In particular, DTF-endcapped oligomers have a stronger electrostatic interaction with SWCNT than ALD-endcapped oligomers do. As a result, DTF-endcapped conjugated oligomers become more polarized than ALD-endcapped oligomers after complexing with SWCNTs. The magnitude of binding energy, on the other hand, shows dependence on the orientation of the backbone and side chains of these oligomers relative to the SWCNT which in the case of fluorene-based oligomers is not always favourable for optimal binding. This study indicates that fluorene-based oligomers might not be as good dispersants of SWCNTs as OPEs.

What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review.

PURPOSE: To conduct a systematic review of the literature to detect the effect of anti-resorptive drugs (ARDs) and their administration characteristics in the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients. METHODS: Systematic search in PubMed, Web of Sciences and Cochrane Library was performed for relevant studies to July 2016. Population variables (age, gender, comorbidities, medications, preceding events, number of patients with MRONJ), ARDs and clinical variables were abstracted independently from these articles. RESULTS: The 44 eligible studies described 680 MRONJ cases in osteoporotic patients. The mean age of MRONJ patients was 69.7 ± 5.2 years. It was more common in females. Mandible was the most common site. Alendronate was the most frequently administered ARD. Oral route of administration was noted in 86.7% of the patients. The mean duration of BPs intake was 50.4 ± 19 months. Extraction was the most frequently preceding event followed by dentoalveolar surgery. Corticosteroids or immunosuppressants were the most common concomitant medications in MRONJ. CONCLUSION: A long duration of ARDs administration seems to be an important risk factor in MRONJ development. Patients under treatment with corticosteroids or immunosuppressants might be at a higher risk even if the BPs duration is less than 4 years.

Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series.

PURPOSE: To report a case series of patients with the nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw-a form of jaw osteonecrosis that does not manifest with necrotic bone exposure/mucosal fenestration. METHODS: Among 332 individuals referred to 5 clinical centers in Europe because of development of jawbone abnormalities after or during exposure to bisphosphonates, we identified a total of 96 patients who presented with the nonexposed variant of osteonecrosis. Relevant data were obtained via clinical notes; radiological investigations; patients' history, and referral letters. RESULTS: The most common clinical feature of nonexposed osteonecrosis was jaw bone pain (88/96; 91.6%); followed by sinus tract (51%), bone enlargement (36.4%); and gingival swelling (17.7%). No radiological abnormalities were identified in 29.1% (28/96) of patients. In 53.1% (51/96) of the patients; nonexposed osteonecrosis subsequently evolved into frank bone exposure within 4.6 months (mean; 95% confidence interval; 3.6-5.6). CONCLUSIONS: Clinicians should be highly vigilant to identify individuals with nonexposed osteonecrosis, as the impact on epidemiological data and clinical trial design could be potentially significant. Although the present case series represents approximately 30% of all patients with bisphosphonates-associated osteonecrosis observed at the study centers, further population-based prospective studies are needed to obtain robust epidemiological figures.