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The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease.

To the Editor: The study by Taves et al. (1) provides evidence that tumor-derived glucocorticoids suppress local antitumor immunity, thereby promoting tumor growth in mice. In one of the pilot [...]

A possible association between Bell’s palsy and COVID-19 vaccination has been suggested. While it is likely that COVID-19 vaccine recipients from the general population do have a slightly increased risk of developing Bell’s palsy, there are little data regarding this risk in individuals with a history of disease. Gaining a better understanding of this association is particularly important for informing evidence-based recommendations regarding future booster shots in subjects who developed Bell’s palsy as a side effect of vaccination, or as a result of SARS-CoV-2 infection. We previously described the first case of COVID-19 vaccine-related Bell’s palsy; here we report an 18-month clinical and electromyographic follow-up and discuss the implications of receiving further vaccine doses in patients with positive disease history.

Early detection of cancer is considered a cornerstone of preventive medicine and is widely perceived as the gateway to reducing cancer deaths. Based on this assumption, large trials are currently underway to evaluate the accuracy of early detection tests. It is imperative, therefore, to set meaningful "success criteria" in early detection that reflect true improvements in health outcomes. This article discusses the pitfalls of measuring the success of early detection tests for cancer, particularly in the context of screening programs, and provides illustrative examples that demonstrate how commonly used metrics can be deceptive. Early detection can result in downstaging (favourable stage shift) when more early-stage cancers are diagnosed, even without reducing late-stage disease, potentially leading to overdiagnosis and overtreatment. Survival statistics, primarily cancer-specific survival, can be misleading due to lead time, where early detection simply extends the known duration of the disease without prolonging actual lifespan or improving overall survival. Additionally, the misuse of relative measures, such as proportions, ratios, and percentages, often make it impossible to ascertain the true benefit of a procedure and can distort the impact of screening as they are influenced by diagnostic practices, misleadingly improving perceived mortality reductions. Understanding these biases is crucial for accurately assessing the effectiveness of cancer detection methods and ensuring appropriate patient care. [ABSTRACT FROM AUTHOR]

This manuscript critically examines the current classification of oral potentially malignant disorders, questioning the practicality and implications of labeling such a large population as precancerous, given that the actual progression to oral cancer is significantly low for most disorders. The paper advocates for a revised classification system that accurately reflects the varying malignancy risks associated with different disorders. It suggests a reassessment of the diagnostic and management approaches to mitigate overdiagnosis and alleviate patient burdens. We propose categorizing diseases with oral malignant potential as follows: Oral Precancerous Diseases, encompassing high‐risk lesions and conditions like erythroplakia, non‐homogeneous leukoplakia, proliferative leukoplakia, and actinic keratosis; Oral Potentially Premalignant Diseases, covering lesions, conditions, and systemic diseases with distinct oral manifestations harboring a limited or undefined risk of transformation, such as homogeneous leukoplakia, oral submucous fibrosis, oral lichenoid diseases, chronic hyperplastic candidosis, keratosis of known aetiology (smokeless tobacco, khat), palatal lesions in reverse smokers, and dyskeratosis congenita; and Systemic Conditions with Oral Malignant Potential including Fanconi's anemia, xeroderma pigmentosum, and chronic immunosuppression (including patients post‐bone marrow transplantation), which are associated with an increased risk of oral cancer without preceding precursor lesions. We provide illustrative examples to demonstrate how this framework offers practical guidance for research, policy‐making, and clinical practice. [ABSTRACT FROM AUTHOR]

Oral health has witnessed a significant transformation with the integration of biomarkers in early-diagnostic processes. This article briefly reviews the types of biomarkers used in the screening and early detection of oral diseases, particularly oral cancer, periodontal diseases, and dental caries, with an emphasis on molecular biomarkers. While the advent of these biomarkers may represent a leap forward in oral healthcare, it also opens the door to potential overtesting, overdiagnosis, and overtreatment. To inform the selection of novel biomarkers and ensure their rational use in screening tests, it is imperative to consider some key characteristics, which are specific to the biomarker (e.g., surrogate biomarkers should reliably reflect the primary health outcome), to the test (e.g., sensitivity and specificity must be balanced based on the disease of interest), and to the disease (e.g., the efficacy of treatment should improve when the condition is diagnosed earlier). For systemic conditions associated with oral diseases, researchers should be extremely cautious when determining who is "at risk", particularly when such risk is small, non-existent, or inconsequent. This framework aims to ensure that advancements in oral health diagnostics translate into genuine improvements in patient care and well-being. [ABSTRACT FROM AUTHOR]

Objectives: Head and neck squamous cell carcinoma (HNSCC) poses a diagnostic and therapeutic challenge worldwide and is associated with a poor survival rate. Due to the variability in the efficacy of treatments for HNSCC, new predictive biomarkers of therapy outcomes are needed. Recently, we developed an algorithm that employs the mutational profile of TP53 as an independent prognostic factor in HNSCC. In this study, we investigated its role as a predictive biomarker of treatment outcomes in HNSCC patients. We also tested the usefulness of two classification systems for TP53 mutational landscapes. Materials and Methods: Clinical and genomic data were retrieved from The Cancer Genome Atlas database. We built a multivariate stepwise backward binary regression model to assess the role of TP53 mutations in predicting therapeutic outcomes. Results: Cases harbouring high‐risk‐of‐death mutations reported an odds ratio of 3.301 for stable or progressive disease compared to wild‐type cases, while no significant difference in treatment outcomes was found between cases with low‐risk‐of‐death mutations and wild‐type TP53. Our analysis found that older patients with a history of alcohol consumption had a higher risk of stable/progressive disease. Conclusions: This study improves current evidence on the role of TP53 mutations in treatment response in HNSCC patients. [ABSTRACT FROM AUTHOR]

Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: This article discusses a common approach to the early detection of oral cancer, which focuses on identifying and monitoring certain mouth conditions, known as oral potentially malignant disorders (OPMDs). However, despite this strategy, the death rates from cancers of the lip and mouth have not improved in 30 years. Surprisingly, only around 10% of oral cancers actually start as premalignant, and most OPMDs rarely turn into cancer. The article suggests that only a few specific types of these disorders, which have a higher risk of becoming cancerous and/or are prevalent in populations, really need intervention. It also questions the effectiveness of regarding OPMDs as heralding malignancy and calls for a different approach to reduce deaths for oral cancer. Despite the profession placing great emphasis on oral potentially malignant disorders (OPMDs) as a gateway for early recognition and consequently better outcomes for oral cancer, the death rates for lip and oral cavity cancer have remained stagnant for three decades. Evidence shows that only a small fraction of oral cancers are in fact preceded by OPMDs, and that most OPMDs have an annual transformation rate of less than 1%. As OPMDs encompass a very heterogeneous group of oral conditions, it could be argued that only patients with oral mucosal diseases bearing a substantial risk of malignant transformation warrant close surveillance and treatment, these include proliferative leukoplakia, erythroplakia, non-homogeneous leukoplakia, as well as diseases presenting with severe dysplasia at biopsy. In this narrative review, I discuss the intricate epidemiology of the malignancies that we colloquially refer to as oral cancer, explore the limitations of focusing on OPMDs to reduce the incidence and mortality of oral cavity cancer, and argue that a may-be cancer label represents overdiagnosis for most OPMDs. [ABSTRACT FROM AUTHOR]

We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC. [ABSTRACT FROM AUTHOR]

Cluster of differentiation 44 (CD44), a cell surface adhesion molecule overexpressed in cancer stem cells, has been implicated in chemoresistance. This scoping review, following PRISMA-ScR guidelines, systematically identified and evaluated clinical studies on the impact of CD44 expression on chemotherapy treatment outcomes across various cancer types. The search encompassed PubMed (1985–2023) and SCOPUS (1936–2023) databases, yielding a total of 12,659 articles, of which 40 met the inclusion criteria and were included in the qualitative synthesis using a predefined data extraction table. Data collected included the cancer type, sample size, interventions, control, treatment outcome, study type, expression of CD44 variants and isoforms, and effect of CD44 on chemotherapy outcome. Most of the studies demonstrated an association between increased CD44 expression and negative chemotherapeutic outcomes such as shorter overall survival, increased tumor recurrence, and resistance to chemotherapy, indicating a potential role of CD44 upregulation in chemoresistance in cancer patients. However, a subset of studies also reported non-significant relationships or conflicting results. In summary, this scoping review highlighted the breadth of the available literature investigating the clinical association between CD44 and chemotherapeutic outcomes. Further research is required to elucidate this relationship to aid clinicians in managing CD44-positive cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: The most effective means for reducing oral cancer (OC) mortality is by preventing late‐stage disease. Early diagnosis can be improved by increasing awareness among healthcare providers, specifically general dental practitioners (GDP). Therefore, our study aimed to assess GDPs' knowledge of OC risk factors and perceived competence in performing conventional oral examination (COE) in routine dental practice. Material and Methods: This was a cross‐sectional study conducted in five provinces of Indonesia, namely: Aceh, Banda Aceh (BA); Bandung, West Java (WJ); special district Jakarta (JKT), JKT; Pontianak, West Kalimantan (WK); and Sorong, West Papua (WP). The local Dental Association or Faculty of Dentistry invited the GDPs to attend an education program and complete the survey. Results: One hundred seventy‐seven GDPs completed the survey (WJ, n = 63; BA, n = 44, JKT, n = 27; WP, n = 23; and WP, n = 20). A large proportion (164 out of 177, 92.66%) of GDPs felt they had received insufficient training to equip them to diagnose OC and as many as 22.6% (n = 40) did not refer to specialists when they found suspicious mucosal lesions. Notwithstanding the significant regional variations, the majority of Indonesian GDPs self‐reported inadequate knowledge and awareness of OC and scarce confidence in performing COE. Conclusion: GDP knowledge of OC risk factors and COE is key to improving early diagnosis of OC at a community level. Therefore, it is suggested that the lack of knowledge and confidence of GDPs reported here should be addressed through the national dental curriculum in Indonesia. [ABSTRACT FROM AUTHOR]

The article discusses the term "rampant caries" and its historical perspective, epidemiology, diagnosis, and treatment. The term was first used in the 1920s to describe severe tooth decay in children from poor families. It later expanded to include tooth decay in children and adults with various medical conditions and special needs. The prevalence of rampant caries varies depending on the diagnostic criteria used. Treatment typically involves restorative dentistry and preventive care, and a Rampant Caries Control Program is recommended for managing high-risk patients. The article also mentions that there is no agreed-upon consensus for the definition of rampant caries, but it suggests a definition based on the number and type of affected teeth. [Extracted from the article]

A betel quid (BQ) chewing habit has been strongly associated with the development of several oral mucosal diseases. In order to investigate whether individual components of BQ mixtures have distinct physio-pathological effects on oral mucosal cells, we examined the impact of areca nut (AN), Piper betle leaf (Leaf), Piper betle stem inflorescence (SI), areca husk (Husk) and the complete BQ mixture on the growth of oral keratinocytes (OKF-6) and primary oral fibroblasts (MMF-1). Based on their known chemical properties, we selected BQ samples from Banda Aceh (BA) and West Papua (WP) regions for our in vitro study. We used a fluorescein diacetate assay (FDA) to assess the cell viability of BQ components on OKF-6 and MMF-1 cells. The cytotoxic effect of WP-AN on the OKF-6 cell line was observed at a concentration of 100 μg/mL, resulting in a 50% reduction in cell viability (IC50) after a 2-day incubation. Similarly, BA-AN exhibited cytotoxic effect, although at a higher concentration (500 μg/mL). WP-SI also displayed cytotoxic effects at a concentration of 500 μg/mL following 2 days of incubation. In contrast, Leaf, BQ mixture and husk extracts did not show any cytotoxic effects even after 3 days of incubation. No cytotoxic effects were observed at any concentration of BQ components when exposed to MMF-1 cells. Regarding cell proliferation, MMF-1 cells exposed to BA-AN and WP-AN showed increased growth on day 1, followed by decreased growth on day 2, in a dose- and time-dependent manner. Overall, our study indicates that BQ components induce distinctive cytotoxic effects on stromal and epithelial cells from the oral cavity. [ABSTRACT FROM AUTHOR]

The predilection for women in systemic autoimmune diseases is well established. However, this sex bias in oral autoimmune diseases has been classically reported from an epidemiological perspective without any elaborate attempts to unveil the underlying mechanisms. The unique nature of the oral environment is likely to impose a combination of systemic and local factors that ultimately result in the sex bias in autoimmune diseases of the oral cavity. Variations of immune responses, target organ vulnerability, endocrine and genetic factors, sex chromosomes and modes of parental inheritance are potential systemic factors, while the oral microbiome, oral tolerance, saliva, and oral epithelial stem cells may account for local contributing factors. This review will discuss the preponderance of women in oral immune‐mediated diseases, the potential systemic and local mechanisms underlying this predominance and highlight the crucial need for further research in this area. [ABSTRACT FROM AUTHOR]

Simple Summary: The cells of the immune system can exert a dual effect on cancer development and growth. On the one hand, the immune system can be activated by tumor antigens and can elicit an antitumor response. On the other, the inflammatory milieu in the tumor microenvironment can trigger immune effector mechanisms that promote tumor growth. In the oral cavity, the balance between protumor and antitumor immunity can influence the progression from premalignancy to carcinoma. In this article, we review the cells and mechanisms that are thought to be the most important immune determinants of oral cancer development and progression. A still unresolved issue surrounding tumor formation concerns the role that the immune system plays in preventing the formation and progression of neoplasia, including oral squamous cell carcinoma (OSCC). Antitumor immunity has historically been seen as a critical barrier for cancer cells to develop, grow and spread, and this can be modulated using immunotherapies to achieve antitumor clinical responses. However, it has recently become clear that tumor-associated immunity, particularly the inflammatory microenvironment, has the paradoxical effect of enhancing tumorigenesis and progression. In this review, we discuss the multifaceted function of infiltrating immune cells in suppressing or promoting premalignancy and cancer. In particular, we report on the evidence supporting a role for T lymphocytes, dendritic cells, macrophages, and neutrophils in the development and progression of oral potentially malignant disorders (OPMD) and OSCC. We also draw attention to the clinical relevance of immune cell phenotypes and associated molecules for use as biomarkers and to the translatability of current research findings to improve classification systems and precision medicine in patients with OSCC. [ABSTRACT FROM AUTHOR]