Serum and salivary Cu/Zn ratio as a diagnostic biomarker for oral submucosal fibrosis: an analysis of trace metals and LOX gene variants.

This study aimed to analyze the serum and salivary levels of copper (Cu), zinc (Zn), iron (Fe), chromium (Cr), manganese (Mn) and the Cu/Zn ratio and investigate the association between LOX gene variants (rs18800449 and rs2288393) and oral submucosal fibrosis (OSMF). A total of 250 subjects were included in the study: OSMF patients (n = 50), areca nut chewers without OSMF (n = 100) and controls (n = 100). Trace metals were measured using an atomic absorption spectrophotometer, while LOX gene variants were genotyped using the tetra primer amplification refractory mutation system (tetra ARMS) polymerase chain reaction (PCR) method. The results showed significant variations in serum and salivary Cu, Zn, Fe and Cr levels and serum Mn concentrations among the three groups (p < 0.0001). Serum Cu levels were significantly higher in OSMF patients, while serum Zn levels were significantly lower. Both serum and salivary Cu/Zn ratios demonstrated a statistically significant difference (p < 0.0001) and diagnostic potential to differentiate OSMF from chewers and controls. However, LOX gene variants did not show an association between OSMF and chewers, except for rs1800449 genotypes, which showed a significant and increased risk with the AA genotype in OSMF patients compared to controls (OR = 7.58; 95%CI 2.30-24.97). The study suggests that trace elements and genetic variants may impact the etiology of OSMF. The findings may aid in early diagnosis, suitable treatment, and as a prognostic indicator for disease progression.

[Oral squamous cell carcinoma in the background of oral submucous fibrosis - a systematic review]. / Skvamozno-kletochnaya kartsinoma polosti rta na fone podslizistogo fibroza polosti rta - sistematicheskii obzor.

Oral squamous cell carcinoma (OSCC) in the background of oral submucous fibrosis (OSMF) is one of the most common presentations of oral cancer among Asian population. OSCC arising in the background of OSMF (OSCC with OSMF) has been a topic of interest among researchers recently and a few studies have considered this to be a distinct clinicopathological entity. This systematic review analyses the demographic and clinicopathological variations of OSCC with OSMF from conventional OSCC to evaluate the distinctiveness of OSCC with OSMF. A comprehensive search from PubMed, Google scholar and manual search were carried out and 4 articles were retrieved and analysed systematically. Out of the total 377 OSCC with OSMF cases and 542 conventional OSCC, males were found to be predominantly affected (82.7% and 73.6%). 47% of the OSCC with OSMF cases were well differentiated squamous cell carcinomas as against 33.4% in conventional OSCC. Lymph node metastases were seen predominantly in conventional OSCC (49.1%) than OSCC with OSMF cases (40.7%). OSCC with OSMF were more prevalent in males and showed better tumour differentiation and lesser lymph node metastasis. Even though the present results inculpate OSCC with OSMF as a distinct clinicopathological entity, there is a dire need for thorough investigation.

Left colonic localization, non-granular morphology, and pit pattern independently predict submucosal fibrosis of naïve colorectal neoplasms before endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) represents the method of choice for removal of large colorectal neoplasms with suspected submucosal invasion. Presence and degree of submucosal fibrosis increases ESD duration and technical complexity, reduces the rate of curative resection and reduces safety profile. The aim of the study was to identify pre-procedural predictive factors of submucosal fibrosis in naïve colorectal neoplasms and to assess the impact of fibrosis on technical and clinical ESD outcomes. METHODS: All consecutive ESD performed between 2014 and 2021 were retrieved from a prospectively collected database. For each patient, pre-procedural, procedural, and post-procedural data were recorded. Logistic regression was used to identify pre-procedural predictive factors for submucosal fibrosis. The study was approved by Institutional Reviewer Board and registered on ClinicalTrials.gov (NCT04780256). RESULTS: One hundred-74 neoplasms (46.6% rectum, 21.8% left colon, 31.6% right colon; size 34.9 ± 17.5 mm) from 169 patients (55.0% male; 69.5 ± 10.4-year-old) were included. 106 (60.9%) neoplasms were granular type laterally spreading tumor (LST-G), 42 (24.1%) non-granular (LST-NG), and 26 (14.9%) sessile; invasive pit pattern was observed in 90 (51.7%) lesions. No fibrosis (F0) mild (F1) and severe (F2) were observed in 62 (35.6%), 92 (52.9%), and 20 (11.5%), respectively. Left colonic localization [OR 3.23 (1.1-9.31)], LST-NG morphology [OR 5.84 (2.03-16.77)] and invasive pit pattern [OR 7.11 (3.11-16.23)] were independently correlated to submucosal fibrosis. Lower curative resection rate (59.8% vs. 93.5%, P < 0.001) was observed in case of fibrosis; the incidence of adverse events was higher in case of severe fibrosis (35.5%) compared to no (3.2%) and mild fibrosis (3.3%; P < 0.001). Procedure time was significantly impacted by presence and degree of fibrosis (P < 0.001). CONCLUSIONS: Left colonic localization, LST-NG morphology, and invasive pit pattern are independent predictors of fibrosis, affecting technical and clinical ESD outcomes. Pre-procedural stratification is pivotal to estimate procedure time, required operator's experience and advanced dissection techniques. Cecinato P et al. Left colonic localization, non-granular morphology, and pit pattern independently predict submucosal fibrosis of colorectal neoplasms before endoscopic submucosal dissection. Surg Endosc. 2023.

Factors for conversion risk of colorectal endoscopic submucosal dissection: a multicenter study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become a widely accepted treatment method for colorectal tumors; however, there are some persistent problems. This multi-center study aimed to characterize the risk factors for incomplete resection and perforation in standardized colorectal ESD procedures. METHODS: This study included 2423 consecutive patients who underwent ESD for 2592 colorectal tumors between August 2013 and December 2018 at 11 institutions (1 academic hospital and 10 affiliated hospitals) from the Hiroshima GI Endoscopy Research Group. We evaluated the risk factors for interruption, piecemeal resection, and perforation of standardized colorectal ESD in relation to clinicopathologic and endoscopic characteristics. RESULTS: The incidences of interruption, piecemeal resection, and perforation were 0.7%, 2.9%, and 3.0%, respectively. Multivariate analysis identified the following risk factors for interruption: perforation during the procedure, deep submucosal invasion (> 1000 µm), poor scope operability, and severe submucosal fibrosis. The risk factors for piecemeal resection included poor scope operability, severe submucosal fibrosis, and procedure time (≥ 85 min). The risk factors for perforation during the procedure were severe submucosal fibrosis, poor scope operability, procedure time (≥ 85 min), and tumor size (≥ 40 mm). Independent risk factors for severe submucosal fibrosis included a history of biopsy and lesions located on the fold or flexure. CONCLUSIONS: Severe submucosal fibrosis and poor scope operability are the common risk factors for interruption, piecemeal resection, and perforation in standardized colorectal ESD.

Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics.

Oral submucous fibrosis (OSF) belongs to a group of potentially malignant disorders that are characterized by the progressive fibrosis of the lining mucosa as well as an increasing loss of tissue mobility [...].

Clinicopathological Evaluation of Tobacco-related Oral Mucosal Lesions.

AIM: To clinically evaluate the nature of precancerous and cancerous lesions associated with tobacco consumption habit and to correlate clinical profile with the histopathological findings of clinically suspected precancerous and cancerous lesions. MATERIALS AND METHODS: These included the examination of patients who visited the outpatient department (OPD) of the institute that includes 1,500 patients who had tobacco chewing habits were classified into the following two groups according to their characteristics. The study group comprised 270 patients, of which 170 gave consent for biopsy and 100 patients who not gave consent were counseled for tobacco cessation. RESULTS: Among 270 patients, the highest number of patients, 146 (54.07%) patients, were found to be smokeless tobacco consumers followed by 65 (24.07%) patients who were smoked tobacco consumers while 59 (21.85%) patients were found to have both the habits. Wide variation was noted in duration and frequency of habit. Most prevalent site was the buccal mucosa affected in 138 (51.11%) patients who consumed both smoked as well as smokeless tobacco. And on clinical examination, 138 (51%) patients had leukoplakia followed by 54 (20%) patients with oral squamous cell carcinoma and 40 (15%) patients with oral submucous fibrosis (OSMF). Other patients were tobacco pouch keratosis 17 (6%), smoker's melanosis 8 (3%), smoker's palate 7 (3%), and erythroplakia 6 (2%). The patients who gave consent (170 patients) were evaluated histopathologically to correlate with clinical findings. CONCLUSION: Tobacco-related oral lesions are also high, which brings an alarming signal toward the development of cancer. Our contribution as healthcare providers can be made by conducting more oral health education programs and educating the general population about the adverse effects of tobacco. The appropriate clinical assessment and categorization of all these lesions aided us in motivating patients to undergo necessary treatments and also to discontinue their habits in order to prevent deterioration of their conditions. CLINICAL SIGNIFICANCE: Set up de-addiction centers in dental colleges and help tobacco users in discontinuing their habits. Interestingly, this study also served as a mirror for those patients who were unaware of the lesions they were giving abode to in their oral cavities.

Oral submucous fibrosis presenting with histopathological lichenoid changes as predominant feature: Report of five cases and review of the literature.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity associated with habitual chewing of quid, with a high incidence among populations of the Indian subcontinent and Southeast Asia. Clinically, its initial manifestation may mimic oral lichen planus or lichen sclerosus. If the habit is not halted, the mucosa gets leathery and thickened, and fibrous bands form causing significant morbidity. Microscopically, it is characterized by atrophic epithelium, loss of rete ridges, and hyalinization of lamina propria. Of note, these hallmark histopathological features may be overlooked in the unusual presence of lichenoid interface changes, which may lead to the wrong diagnosis. We present herein five cases in which the rare joint appearance of OSF and lichenoid reaction features posed a diagnostic challenge. Due to its progressive nature and malignant potential, the presence of oral lichenoid changes overlying submucous hyalinization, in the right clinical and demographic setting, should raise suspicion of OSF and prompt actions directed at quid-chewing discontinuation.

Oral microbiota alteration associated with oral cancer and areca chewing.

Oral cancer is among most common neoplasm of oral cavity; in many cases, it develops at the site of premalignant lesion. Areca nut has been identified as a carcinogen, which was proved to promote the inflammation level and contributes to oral malignancy. Chewing areca nut is the main cause of the premalignant disease oral submucous fibrosis (OSF). Bacterial alterations were suggested to be assonated with oral cancer progression. Therefore, the present study was carried out to determine the changes of microbiota in the mucosa along stage of development of oral cancer with areca nut chewing. 162 participants, reporting to department of oral medical center, were enrolled into the study which includes 45 patients each of OSF, 42 of oral cancer, 29 healthy controls (HC) with areca nut chewing, and 46 healthy controls (HC) never chewing areca nut. Oral swabbing of tongue dorsum, buccal mucosa, and gingiva was evaluated by MiSeq platform of the V3-V4 region of the 16S rRNA gene. These data revealed microbial changes that may mirror oral cancer progression and reflect clinical preconditions such as areca nut chewing. Consequently, revealing microbial changes in patients with oral squamous cell carcinomas and the premalignant disease oral submucous fibrosis (OSF) with areca nut chewing might improve our understanding of the pathobiology of the disease and help in the design of novel diagnostic and treatment strategies.

Malignant transformation of oral submucous fibrosis: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to determine the proportion of patients who develop oral carcinomas following a diagnosis of oral submucous fibrosis (OSF) in reported longitudinal studies. We also aimed to evaluate the demographic and clinicopathological factors contributing to the progression of OSF to cancer. METHODS: Individual search strategies were applied for the following bibliographic databases: MEDLINE by PubMed, Scopus, Embase, Web of Science, and Grey literature databases until August 30, 2020. Methodological assessment of the risk of bias of the included studies was undertaken using the modified Newcastle-Ottawa scale. Meta-analyses were conducted using a random-effects (DerSimonian and Liard) method to calculate the pooled proportion of the malignant transformation (MT) in OSF patients. RESULTS: Out of 585 records screened, a total of 9 observational studies were included with a total number of 6,337 patients; of these, 292 OSF cases developed carcinomas. The pooled proportion of the MT was 4.2% (95% CI: 2.7%-5.6%) with an annual transformation rate of 0.73%. Subgroup analysis revealed that the pooled MT proportion was significantly higher among population-based studies in comparison with hospital-based ones (p < .005). Most of the studies showed a high risk of bias. In several studies, there was a lack of information about the demographic and clinicopathological characteristics of OSF patients and associated risk indicators; this insufficiency in details hindered the ability to conduct further subgroup analyses. CONCLUSIONS: Despite the poorly reported and the limited number of studies, our analysis confirms that close to 4% of patients diagnosed with OSF may develop oral cancer. Cases with oral epithelial dysplasia had a higher potential for malignant transformation.

Why do Only Certain Cases of Oral Submucous Fibrosis Undergo Malignant Transformation?

Oral submucous fibrosis (OSMF) causes desmoplasia and rigidity of submucosa of the oral cavity, resulting in reduced mouth opening, and in advanced stage causes difficulty in swallowing. OSMF has poor morbidity in terms of oral function as well as general health due to loss of oral function, such as eating. In severe conditions, it can cause dysphagia and hearing loss. Various clinicians have tried the different treatment modalities to reverse the disease process, but with limited success and that too in alleviating the associated symptoms.

Genetic Susceptibility and Protein Expression of Extracellular Matrix Turnover-Related Genes in Oral Submucous Fibrosis.

Betel quid (BQ) chewing increased the risk of oral cancer and oral submucous fibrosis (OSMF), an oral premalignant disorder (OPMD) with malignant transformation potential. BQ components such as areca nut (AN), trauma by coarse AN fiber, catechin, copper, alkaloids, stimulated reactive oxygen species (ROS), inflammation and cytotoxicity are suggested to be the contributing factors. They may induce tissue inflammation, proliferation of fibroblasts and collagen deposition, myofibroblast differentiation and contraction, collagen cross-links and inhibit collagen phagocytosis, finally leading to the development of OSMF and oral cancer. These events are mediated by BQ components-induced changes of extracellular matrix (ECM) turnover via regulation of TGF-ß1, plasminogen activator inhibitor-1 (PAI-1), cystatin, lysyl oxidase (LOX) and tissue inhibitors of metalloproteinases (TIMPs) and metalloproteinases (MMPs). Genetic susceptibility is also involved in these disease processes. Further understanding the molecular mechanisms of BQ-induced OSMF and oral cancer can be helpful for future disease prevention and treatment.

LINC00312/YBX1 Axis Regulates Myofibroblast Activities in Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) has been recognized as a precancerous disorder in the oral cavity. Great effort has been made to inhibit the malignant progression of OSF over the past decades, but the cure of this fibrosis disease has not been discovered. In the present study, we found that a long noncoding RNA, LINC00312, was upregulated in OSF tissues, and positively associated with several fibrosis factors, such as α-SMA, type I collagen, and fibronectin. As such, we sought to investigate the role of LINC00312 in OSF progression and identify its interacting factor that mediated oral fibrogenesis. Our results showed that the inhibition of LINC00312 downregulated the myofibroblast activities, including collagen gel contractility, transwell migration, and wound healing, as well as the gene expression of myofibroblast markers. We verified that YBX1 was a downstream factor of LINC00312 and revealed that the downregulation of YBX1 repressed the gene expression of α-SMA and p-Smad2 along with the reduced myofibroblast phenotypes. Most importantly, we demonstrated that the LINC00312-induced myofibroblast activities were reverted by the knockdown of YBX1, suggesting that the LINC00312-mediated myofibroblast transdifferentiation was through YBX1. Collectively, our findings revealed that the LINC00312/ YBX1 axis may serve as a target for the development of therapies against OSF.

Recognition of oral potentially malignant disorders and transformation to oral cancer.

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

Insight on the relationship of ABO blood grouping associated with oral premalignant lesions, conditions and inherited oral cancer syndromes.

BACKGROUND: Risk factors such as chronic use of tobacco, smoking and alcohol consumption of individual's lifestyle may possibly influence the significant role in the etiopathogenesis of precancerous lesions (PL) and Conditions (PC) and lead to oral cancer. Previous studies have revealed that genetic factors have contributed to a remarkable extent in the development of this chronic disease. Limited studies have confirmed that ABO blood groups remain reportedly possible genetic factor to the specific disease such as oral malignant. In this context, we have reported that individuals in a particular blood group are more prone to develop lesions and certain types of cancer. This has thrown a light to take up an effort to conduct this present study. MATERIALS AND METHODS: The present study covering 105 patients and grouped into three subjects with 35 participants in each. a) oral squamous cell carcinoma b) oral leukoplakia and c) submucous fibrosis. Gender and age group impact was also made to understand the interaction between the focused sample groups. A separate control was gathered from a same geographical population composed of gender-matched healthy volunteers. Slide agglutination was employed for blood grouping and results were tabulated for statistical analysis. RESULTS: Blood group "A" exhibited a significant relationship between oral squamous cell carcinoma patient and odd ratio shown 1.74 times higher risk of developing oral cancer. Gender different and habit stimulation have increased the risk. A significant relationship was observed between ABO blood group and oral leukoplakia and oral submucous fibrosis. CONCLUSION: Study inferred that blood group "A" is found to be at the high risk in developing oral malignant syndrome due to its susceptibility, whereas oral pre-cancer is hypothesized that individual habits are the host risk factor and transformed to carcinoma by interacting genetic factors to act upon ABO blood group.

LncRNA LINC00974 activates TGF-ß/Smad signaling to promote oral fibrogenesis.

BACKGROUND: Oral submucous fibrosis (OSF) is a progressive scarring disease and has been considered as a premalignant condition of the oral cavity. However, the detailed molecular mechanisms underlying the pathogenesis of OSF are still unclear. METHOD: Here, we examined the expression of a novel long non-coding RNA LINC00974 in OSF and investigated its function role in myofibroblast transdifferentiation. Phenotypic analyses, including collagen gel contraction, migration, invasion and wound healing assays, were used to assess the myofibroblast activities following overexpression or inhibition of LINC00974. RESULTS: We found that the expression of LINC00974 in OSF tissues or myofibroblasts was aberrantly upregulated, and there was a positive correlation between LINC00974 and myofibroblast markers. Our results showed that inhibition of LINC00974 suppressed the myofibroblast activities, while overexpression of LINC00974 increased the activation. We demonstrated that the expression levels of α-SMA, α-1 type I collagen, fibronectin were downregulated in the LINC00974-inhibited myofibroblasts. Additionally, the TGF-ß secretion and phosphorylated Smad2 expression were also repressed in the LINC00974-inhibited myofibroblasts. We further demonstrated that silence of LINC00974 prevented the arecoline-induced myofibroblast activation, and LINC00974-increased myofibroblast activities were via TGF-ß pathway. CONCLUSION: Altogether, these findings suggested that arecoline-increased myofibroblast transdifferentiation was via LINC00974-mediated activation of TGF-ß signaling.

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy.

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5-15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

Oral submucous fibrosis: an etiological dilemma.

OBJECTIVE: Oral Submucous Fibrosis (OSF), is a well-recognized, oral potentially malignant disorder predominantly affecting the South- Asian countries. OSF causes unique generalized fibrosis of the submucosal oral soft tissues, resulting in marked rigidity of the oral mucosa leading to progressive inability to open the mouth, rigidity of lips and difficulty in protruding the tongue. In this review we have discussed the multifactorial etiology of this potentially malignant disorder, including Chillies, Nutritional Deficiencies, Inducible nitric oxide synthsis (iNOS), genetic and immunological predisposition; and most importantly the role of areca nut and the effect of copper content in it.

Oral submucous fibrosis: An update on current theories of pathogenesis.

Over the last 40 years, many theories linking oral submucous fibrosis (OSMF) to various risk factors have been proposed. Spicy, pungent foods and irritants such as supari (areca nut), paan (betel leaves), tobacco (through chewing or smoking)-the common Asian habits of chewing the aforementioned agents-have all been incriminated as causative agents. Systemic factors such as nutritional deficiency, genetic predisposition and autoimmunity have also been proposed in the pathogenesis of OSMF. However, the precise aetiology of OSMF is still unknown, and no conclusive evidence has been found despite many extensive investigations on implicated factors. Most of the ideas proposed have been derived from the existing clinical and epidemiological data. We present a comprehensive review of the various theories regarding the pathogenesis of the condition, but have not concentrated on malignant transformation in this article.

Rebamipide to Manage Stomatopyrosis in Oral Submucous Fibrosis.

INTRODUCTION: Oral submucous fibrosis (OSF) causes progressive debilitating symptoms, such as oral burning sensation (stomatopyrosis) and limited mouth opening. The standard of care (SOC) protocol includes habit cessation, intralesional steroid and hyaluronidase injections, and mouth opening exercises. The objective of the study was to evaluate efficacy of rebamipide in alleviating burning sensation of the oral mucosa in OSF in comparison with SOC intralesional steroid injections. MATERIALS AND METHODS: Twenty OSF patients were divided into two groups [rebamipide (100 mg TID for 21 days) and betamethasone (4 mg/mL biweekly for 4 weeks)] of 10 each by random sampling. Burning sensation was assessed every week for 1 month. Burning sensation scores were analyzed using repeated measures analysis of variance (ANOVA) and paired t-test. RESULTS: Change in burning sensation score was significant (p < 0.05) in the first four visits. However, score between the 4th and 5th visit was not statistically significant (p > 0.05). CONCLUSION: Our study has shown that rebamipide can be considered as an effective modality to manage burning sensation in patients suffering from OSF. CLINICAL SIGNIFICANCE: Considering stomatopyrosis and trismus as a major cause for inability to eat in OSF, use of newer adjunctive modalities, such as rebamipide will ease patients suffering and also encourage them to consume food.