Orofacial complications from immune checkpoint inhibitors: A retrospective analysis from two academic medical centers.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are FDA-approved for various cancers, yet their orofacial immune-related adverse events (irAEs) remain poorly understood. Our two-center retrospective study aims to better understand the prevalence and nature of these orofacial irAEs. METHODS: We retrospectively collected demographics, ICI details, and onset of orofacial irAEs in ICI-treated patients at University of California San Francisco and City of Hope (2013-2021). Orofacial irAEs were identified by ICD-10 codes and data categorized as dry mouth/xerostomia, oral mucosal lesions, and orofacial neuropathies. Patients with pre-existing orofacial conditions resembling the reported irAEs were excluded. RESULTS: Among 3768 ICI-treated patients, 408 (10.8%) developed 467 orofacial irAEs: oral mucosal diseases (41.4%), dry mouth/xerostomia (41.0%), and orofacial neuropathies (17.6%). Notably, head and neck cancers had the highest incidence of orofacial irAEs. CONCLUSIONS: Orofacial irAEs are relatively common in patients receiving ICIs, necessitating careful monitoring and management of these complications during and after the treatment.

Efficacy of alpha-lipoic acid in patients with burning mouth syndrome compared to that of placebo or other interventions: a systematic review with meta-analyses.

Burning mouth syndrome (BMS) is a chronic oral disorder of unknown etiology which presents therapeutic challenges. Alpha-lipoic acid (ALA) has been studied as a potential treatment for BMS. The objective of this systematic review and meta-analysis was to evaluate the effectiveness of ALA compared to that of placebo or other interventions in individuals with BMS. Randomized controlled trials (RCT) using ALA to treat BMS were identified from MEDLINE, Cochrane Library, EMBASE, and Web of Science up to February 3, 2021. The assessment of the risk of bias in the included studies was based on the Cochrane guidelines. The primary outcome evaluated was the visual analog scale (VAS) pain intensity. ALA was compared with placebo, clonazepam, gabapentin, pregabalin, ALA plus gabapentin, capsaicin, Biotène®, and laser therapy. Altogether, 137 records were scanned for inclusion/exclusion, and nine RCTs (two unclear and seven at high risk of bias) were included in the qualitative and quantitative analyses, with a total of 594 patients with BMS included in this review. All studies reported an improvement in VAS pain scores ranging from -0.72 to -2.77. Meta-analysis results showed a non-significant reduction in pain intensity for ALA (P = 0.616) compared to that of placebo on a VAS of 0-10. Patients taking ALA were 1.923 times more likely to show an improvement in self-reported BMS symptoms (P = 0.031) than those in the placebo group. Clonazepam and pregabalin showed a significant VAS pain reduction of 4.08 and 4.68 (P < 0.001), respectively, compared to that with ALA. Although ALA intervention provided a non-significant improvement in the pain score and was more likely to produce a reduction in BMS symptoms, the evidence was of low quality. Further research is needed to establish clear guidelines for the use of ALA for BMS treatment.

Efficacy of oral and topical antioxidants in the prevention and management of oral mucositis in head and neck cancer patients: a systematic review and meta-analyses.

PURPOSE: To evaluate the effectiveness of antioxidants in the prevention and management of oral mucositis in adults undergoing radiotherapy and/or chemotherapy with diagnosed head and neck cancer (HNC) compared to placebo intervention. METHODS: Cochrane, EMBASE, PubMed, and Web of Science databases were used to search for randomized controlled trials (RCTs) comparing oral or topical antioxidants with placebo in clinically diagnosed HNC adult patients receiving radiotherapy with/without chemotherapy. The primary outcome was to assess the efficacy of the antioxidant to prevent and decrease the incidence/prevalence and severity of oral/oropharyngeal mucositis. The risk of bias was assessed following Cochrane's guidelines. RESULTS: The database search resulted in 203 records up to February 19, 2021. Thirteen RCTs were included with 650 HNC-diagnosed patients. Included studies showed a statistically significant improvement in mucositis severity score for all antioxidants except melatonin. However, further studies are needed as only one study reported outcomes for zinc, propolis, curcumin, and silymarin. Patients receiving vitamin E were 60% less likely to develop severe mucositis grade 2 or higher than those receiving placebo in one study (P = 0.040). Patients receiving zinc were 95% less likely to develop severe mucositis (grades 3-4) in one study compared to placebo (P = 0.031). One meta-analysis showed no statistical difference in the risk of having severe mucositis (grades 3-4) with 199 patients compared to placebo for honey (n = 2 studies, P = 0.403). Meta-analyses could not be conducted for zinc, propolis, curcumin, melatonin, silymarin, and selenium due to the lack of studies reporting similar outcomes for the same intervention. CONCLUSION: Though oral and topical antioxidants significantly improved mucositis severity scores in HNC patients receiving radiotherapy with/without chemotherapy in individual studies, the quality of the evidence was low due to the small number of studies and unclear/high-risk bias. Additionally, large RCTs are needed to confirm these results.

Regeneration of temporomandibular joint using in vitro human stem cells: A review.

Temporomandibular joint disorders (TMDs) range from gross anatomic deformities of the disc and hard tissue to functional disturbances. Traditional treatment of TMDs includes physical therapy, use of appliances, pharmacological, surgical and psychological interventions. However, during the late stage of TMDs, conventional management often results in inadequate relief of symptoms. Stem cell-based tissue regeneration has been studied extensively in joint regeneration, including the Temporomandibular Joint (TMJ). This study aims to review the potential of various human stem cells (HSC) for the regeneration of the TMJ. In vitro studies using human mesenchymal stem cells cultured under different conditions to evaluate regeneration of TMJ related structures were searched on PubMed, EMBASE, Cochrane, and Web of Science up to March 2020. In vitro studies utilized several different types of stem cells under varying conditions. Increased osteogenesis and/or chondrogenesis were noted with stem cell interventions compared to control groups on Alkaline Phosphatase (ALP) activity, Col-I, Col-II, Col-X, RUNX2, LPL, and Aggrecan mRNA expression. This review emphasizes the potential of stem cell therapies in the regeneration of TMJ-related structures. However, further in vivo studies are required to evaluate the efficacy and safety of these therapies in humans.

Efficacy of ketamine in the treatment of migraines and other unspecified primary headache disorders compared to placebo and other interventions: a systematic review.

BACKGROUND: Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of productivity on a global scale. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine. METHODS: An electronic search of databases published up to February 2021, including Medline via PubMed, EMBASE, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search was conducted to identify randomized controlled trials (RCTs) investigating ketamine in the treatment of migraine/headache disorders compared to the placebo. The authors assessed the risk of bias according to the Cochrane Handbook guidelines. RESULTS: The initial search strategy yielded 398 unduplicated references, which were independently assessed by three review authors. After evaluation, this number was reduced to five RCTs (two unclear risk of bias and three high risk of bias). The total number of patients in all the studies was 193. Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low. One RCT reported that intranasal ketamine was superior to intranasal midazolam in improving the aura attack severity, but not duration, while another reported that intranasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity. In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, intravenous (I.V.) ketamine was inferior to I.V. prochlorperazine and diphenhydramine in another study. CONCLUSION: Further double-blind controlled studies are needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches using intranasal and subcutaneous routes. These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.

Local Anesthetic Injections for the Short-Term Treatment of Head and Neck Myofascial Pain Syndrome: A Systematic Review with Meta-Analysis.

AIMS: To evaluate the effectiveness of local anesthetic trigger point injections in adults with myofascial pain syndrome (MPS) in the head, neck, and shoulder regions compared to dry needling, placebo, and other interventions. METHODS: Randomized controlled trials using local anesthetic injections in adults diagnosed with MPS were included. The Cochrane Library, MEDLINE via PubMed, Web of Science, and EMBASE libraries were searched. The primary outcome was pain measured with a 0 to 10 visual analog scale (VAS). Secondary outcomes included pain threshold, range of cervical motion, depression scale, and pressure pain intensity (PPI) score. Risk of bias was analyzed based on Cochrane's handbook. RESULTS: The initial search strategy yielded 324 unduplicated references up to April 1, 2018. A total of 15 RCTs were included, with 884 adult patients diagnosed with MPS. Meta-analysis showed a significant improvement in VAS pain scale of 1.585 units at 1 to 4 weeks in the local anesthetic group compared to the dry needling group (95% confidence interval -2.926 to -.245; P = .020). However, when only including double-blinded studies, the effect was not statistically significant (P = .331). There was also a significant improvement in pain of 0.767 units with local anesthetic at 2 to 8 weeks compared to placebo (95% confidence interval -1.324 to -0.210; P = .007). No statistically significant differences were found in other secondary outcomes between local anesthetic and all other interventions. CONCLUSION: Though local anesthetics provided a significant improvement in pain compared to dry needling, evidence was of low quality, and sensitivity analyses including only double-blinded studies provided no statistically significant difference. Additional studies are needed to confirm these results.

Lack of Utility of Cytokeratins in Differentiating Pseudocarcinomatous Hyperplasia of Granular Cell Tumors from Oral Squamous Cell Carcinoma.

Granular cell tumor (GCT) of the oral cavity is a benign lesion. Half of oral GCTs demonstrate pseudocarcinomatous hyperplasia (PCH) of the mucosa which can mimic invasive islands of oral squamous cell carcinoma (SCC). Such similarity can be confusing when diagnosing or evaluating the two conditions, potentially leading to misdiagnosis or misclassification. Indeed, several misdiagnosed cases of oral GCT have been reported in the literature as OSCC or malignant oral GCT that resulted in unnecessary aggressive treatment for the affected patients. The aim of this study was to investigate if the cytokeratin pattern of the PCH can help in differentiating GCT from oral SCC. To distinguish between these two entities, we examined 12 patient specimens of oral GCT-PCH and oral SCC histologically and via immunohistochemistry (IHC) for CK13, CK17 and P75. The results suggest that the cytokeratin profile of PCH is similar to that of oral SCC. Therefore, consideration of IHC findings for epithelial markers alone may lead to erroneous diagnosis; thus, the presence of the granular tumor underneath the PCH and its immunopositivity for P75 or other neural definition markers can be essential to identify the underlying tumor and exclude oral SCC. Finally we recommend more studies on the molecular biology of PCH to understand how it can mimic oral SCC histologically without harboring its malignant phenotype clinically, which could have significant translational potential for understanding invasive oral SCC.

Modified protocol including topical minocycline in orabase to manage medication-related osteonecrosis of the jaw cases.

OBJECTIVE: Management of medication-related osteone-crosis of the jaw (MRONJ) with active infection can be a serious challenge for clinicians. Based on Association of Oral and Maxillofacial Surgeons (AAOMS) recommendations, we have tested a modified treatment protocol using topical minocycline. STUDY DESIGN: Five patients diagnosed with stage II or III MRONJ lesions were willing to consent to our protocol. In addition to conventional treatment as suggested by the AAOMS, such as, surgical debridement, chlorhexidine irrigation, and systemic antibiotics, we applied 10% minocycline to the lesions once a week for sustained local antibiotic delivery. RESULTS: All five patients reported pain relief after the first minocycline application. Complete healing occurred in three patients; case three healed completely after the third application, one case continues to improve toward resolution and one withdraws due to other non-relevant medical problem. CONCLUSIONS: In this study, we are reporting favorable results using a modified protocol with topical minocycline to treat MRONJ lesions.

Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells.

Based on our previous finding that protease-activated receptor 2 (PAR-2) regulates hemophagocytosis of oral squamous cell carcinoma (SCC) cells, which induces their heme oxygenase 1-dependent keratinization, we have formulated a hypothesis that PAR-2 functions in wider activities of SCC cells. To confirm this hypothesis, we investigated immunohistochemical profiles of PAR-2 in oral SCC tissues and its functional roles in cell proliferation and invasion in SCC cells in culture. The PAR-2 expression modes were determined in 48 surgical tissue specimens of oral SCC. Using oral SCC-derived cell systems, we determined both gene and protein expression levels of PAR-2. SCC cell proliferation and invasive properties were also examined in conditions in which PAR-2 was activated by the synthetic peptide SLIGRL. PAR-2 was immunolocalized in oral SCC and carcinoma in situ cells, especially in those on the periphery of carcinoma cell foci (100% of cases), but not in normal oral epithelia. Its expression at both gene and protein levels was confirmed in 3 oral SCC cell lines including ZK-1. Activation of PAR-2 induced ZK-1 cell proliferation in a dose-dependent manner. PAR-2-activated ZK-1 cells invaded faster than nonactivated ones. The expression of PAR-2 is specific to oral malignancies, and PAR-2 regulates the growth and invasion of oral SCC cells.

Hemophagocytosis-mediated keratinization in oral carcinoma in situ and squamous cell carcinoma: a possible histopathogenesis of keratin pearls.

Although the histopathogenetic process of keratin pearls is still poorly understood, acceleration of keratinization in squamous cell carcinoma (SCC) cells may represent one possible therapeutic avenue. Based on our histopathological observations, we have hypothesized that SCC cells are keratinized by phagocytosis of extravasated erythrocytes. To confirm this hypothesis, we firstly examined immature keratin pearls in oral carcinoma in situ (CIS) and mature ones in SCC by immunohistochemistry. Concentric dyskeratotic cells in CIS keratin pearls became positive for keratin (K) 10, K17, heme oxygenase-1 (HO-1), or protease activated receptor-2 (PAR-2), a candidate regulator for hemophagocytosis. When ZK-1 cells, an SCC cell system, were incubated with human peripheral blood erythrocytes, or with crude and purified hemoglobins (Hbs), their erythro-hemophagocytotic activities were confirmed by immunofluorescence. Immunofluorescence signals for K10, K17, and HO-1 were enhanced due to hemophagocytosis in time-dependent manners. mRNA expression levels for the three molecules were most enhanced by purified Hb, followed by crude Hb and erythrocytes. K17/K10 mRNA expression levels were more elevated when PAR-2 was activated in ZK-1 cells. The results indicated that immature and mature keratin pearls in CIS and SCC were generated by oxidative stresses derived from erythro-hemophagocytosis, which might mediate HO-1 expression and be regulated by PAR-2. Thus, hemorrhage from the rupture of blood vessels can be one of the triggers for keratin pearl formation in oral CIS and SCC.

Intraepithelially entrapped blood vessels in oral carcinoma in-situ.

It can be difficult to make a certain diagnosis in case of an oral borderline malignant lesion on hematoxylin-eosin-stained sections only. Furthermore, assessment of surgical margins of borderline lesions is difficult with the naked eye. We set out to determine the topographical distribution of capillary blood vessels within the epithelial zone and to assess its use as an aid for histopathological diagnosis and a framework for clinical assessment of lesional margins using optical techniques, such as narrow-band imaging (NBI) endoscopy. Capillary blood vessels entrapped in the epithelial compartment, which we have designated as intraepithelially entrapped blood vessels (IEBVs), were examined for their frequency, location, and shape in normal mucosa, dysplasia, and carcinoma in-situ (CIS) of the tongue using immunohistochemistry for CD31 and type IV collagen. When counted per unit length of epithelial surface, IEBVs increased in number significantly in CIS (5.6 ± 2.8), which was two times more than in normal (1.9 ± 1.6) and dysplastic (2.4 ± 1.5) epithelia. In addition, IEBVs in CIS had compressed shapes with occasional obstruction or collapse with hemorrhage and were arranged perpendicular to and extending up to the epithelial surface. These characteristic IEBVs in CIS were considered to be generated by complex expansion of rete ridges due to carcinoma cell proliferation within the limited epithelial space determined by the basement membrane. The recognition of IEBVs was helpful in the differential diagnosis of oral CIS, and the present data provide a valuable frame of reference for detecting oral CIS areas using such NBI-based optical devices.

Acetic acid treatment for wrinkle-free oral mucosal epithelia in paraffin section preparation.

For histopathological assessment of oral borderline malignancies, it is important to carefully detect subtle epithelial changes on fully stretched tissue sections. However, it is not generally easy to obtain wrinkle-free sections when using formalin-fixed paraffin-embedded oral mucosal samples. Since acetic acid treatment is already utilized for large brain tissue sections, we examined whether that treatment was also effective for oral mucosal tissues containing normal to malignant epithelial lesions. Paraffin sections were floated in various concentrations of acetic acid for 10 min after stretching in water for 1 min, then wrinkle formations were examined using hematoxylin and eosin staining, as well as for staining intensity with keratin immunohistochemistry. Wrinkles were formed in both epithelial and connective tissue zones of sections treated with less than a 40-mM (0.25%) concentration of acetic acid. In contrast, treatments with concentrations at 80 mM (0.5%) and higher resulted in cracking between the epithelial layer and lamina propria, as well as poor immunohistochemical results for keratins 13 and 17, even though the wrinkles completely disappeared. These results indicate that 40 mM is the optimal concentration of acetic acid solution to prevent wrinkles in the epithelial layer while maintaining the immunohistochemical qualities of oral mucosa tissue sections, especially those containing borderline malignant epithelial lesions.

High relative frequency of oral squamous cell carcinoma in Yemen: qat and tobacco chewing as its aetiological background.

To study the association of qat chewing with the occurrence of oral cancer, the frequency of oral cancer among whole body cancers and the patients' histories of tobacco consumption and qat chewing were examined in Yemen where qat chewing has been most popular. All primary malignant tumors listed in the surgical pathology files at Al-Thawra Hospital, University of Sana'a, in the year 2004 were analyzed, and the patients' histories of tobacco consumption and qat chewing were examined. A total of 649 cases of primary malignant tumors (348, 53.6% males and 301, 46.4% females) were extracted. Oral cancer was the most frequent body cancer in both males (17.2%) and females (19.6%). Squamous cell carcinoma (SCC) was the most frequent oral cancer (84%), and the tongue (42%), gingiva (23%) and buccal mucosa (20%) were the most common sites. Among the 119 patients with oral cancer, information on chewing habits and smoking was obtained in 92 patients (77.3%). There were 70 tobacco chewers (76.1%), 55 qat chewers (59.8%), and 22 smokers (23.9%). Simultaneous chewing of tobacco and qat was found in 48 cases (52.2%). The present survey has disclosed for the first time that oral SCC is the most frequent cancer in this study area in Yemen, and that the high relative frequency of oral SCC may be related to the habits of chewing tobacco and qat.