Generative Adversarial Networks in Digital Histopathology: Current Applications, Limitations, Ethical Considerations, and Future Directions.

Generative adversarial networks (GANs) have gained significant attention in the field of image synthesis, particularly in computer vision. GANs consist of a generative model and a discriminative model trained in an adversarial setting to generate realistic and novel data. In the context of image synthesis, the generator produces synthetic images, whereas the discriminator determines their authenticity by comparing them with real examples. Through iterative training, the generator allows the creation of images that are indistinguishable from real ones, leading to high-quality image generation. Considering their success in computer vision, GANs hold great potential for medical diagnostic applications. In the medical field, GANs can generate images of rare diseases, aid in learning, and be used as visualization tools. GANs can leverage unlabeled medical images, which are large in size, numerous in quantity, and challenging to annotate manually. GANs have demonstrated remarkable capabilities in image synthesis and have the potential to significantly impact digital histopathology. This review article focuses on the emerging use of GANs in digital histopathology, examining their applications and potential challenges. Histopathology plays a crucial role in disease diagnosis, and GANs can contribute by generating realistic microscopic images. However, ethical considerations arise because of the reliance on synthetic or pseudogenerated images. Therefore, the manuscript also explores the current limitations and highlights the ethical considerations associated with the use of this technology. In conclusion, digital histopathology has seen an emerging use of GANs for image enhancement, such as color (stain) normalization, virtual staining, and ink/marker removal. GANs offer significant potential in transforming digital pathology when applied to specific and narrow tasks (preprocessing enhancements). Evaluating data quality, addressing biases, protecting privacy, ensuring accountability and transparency, and developing regulation are imperative to ensure the ethical application of GANs.

Electronic nicotine delivery systems: Oral health implications and oral cancer risk.

There is a paucity of evidence surrounding the potential detrimental effects of electronic nicotine delivery systems (ENDS) for both systemic and oral health. The effects of conventional cigarettes on the development of oral cancer are well known; however, the role of ENDS in oral carcinogenesis is yet to be elucidated. Furthermore, the exponential rise of the use of ENDS by the general public means that dental healthcare providers are more likely to encounter questions on their safety in the oral cavity, and on their effectiveness as a smoking cessation aid. Herein, we review the most up to date literature on the systemic and oral health complications of ENDS. Moreover, evidence-based recommendations on the use of ENDS as a smoking cessation tool within the dental setting are discussed.

Central mechanisms of pain in orofacial pain patients: Implications for management.

BACKGROUND: Central sensitization (CS) is a form of neuroplasticity characterized by changes in the neural sensitivity, responsiveness, and/or output that are not contingent on peripheral input nor activity-dependent. CS is characterized by activation of unmyelinated C-fibers resulting in a cascade of events at molecular and cellular levels which eventuate into generation of synaptic currents at rest. CS, therefore, contributes to heightened generalized pain sensitivity, further complicates the process of reaching a diagnosis, and increases the possibility of treatment failure. BODY: Trigeminal nerve is the main sensory supplier of the anterior part of the head, including the intraoral structures. Primary afferent nociceptors of the trigeminal nerve and low threshold mechanoreceptors synapse with wide dynamic range (WDR) neurons in the pons. This multifaceted network of nerve interactions which is further complicated by the modulatory circuits that can suppress or heighten the activity of WDR neurons is one of the main contributors to CS. The importance of CS in orofacial pain disorders is emphasized in the context of chronic pain development. As for all chronic pain conditions, it is crucial to consider the biopsychosocial aspects of chronic orofacial pain in managing this diverse group of conditions. This review highlights current understanding of the biopsychosocial model and central mechanisms contributing to the pathogenesis of chronic orofacial pain.

The use of artificial intelligence, machine learning and deep learning in oncologic histopathology.

BACKGROUND: Recently, there has been a momentous drive to apply advanced artificial intelligence (AI) technologies to diagnostic medicine. The introduction of AI has provided vast new opportunities to improve health care and has introduced a new wave of heightened precision in oncologic pathology. The impact of AI on oncologic pathology has now become apparent, and its use with respect to oral oncology is still in the nascent stage. DISCUSSION: A foundational overview of AI classification systems used in medicine and a review of common terminology used in machine learning and computational pathology will be presented. This paper provides a focused review on the recent advances in AI and deep learning in oncologic histopathology and oral oncology. In addition, specific emphasis on recent studies that have applied these technologies to oral cancer prognostication will also be discussed. CONCLUSION: Machine and deep learning methods designed to enhance prognostication of oral cancer have been proposed with much of the work focused on prediction models on patient survival and locoregional recurrences in patients with oral squamous cell carcinomas (OSCC). Few studies have explored machine learning methods on OSCC digital histopathologic images. It is evident that further research at the whole slide image level is needed and future collaborations with computer scientists may progress the field of oral oncology.

Deficient double-strand break repair in oral squamous cell carcinoma cell lines.

BACKGROUND: Approximately 20% of oral squamous cell carcinoma (OSCC) cases arise without any identifiable environmental cause, suggesting involvement of genetic influences in their aetiology. DNA double-strand breaks (DSBs) sever both strands of DNA and pose a potential threat to genomic integrity. A hastened accumulation of somatic mutations consequent to DSB repair is deemed to be a likely event in tumorigenesis of OSCC. METHODS: Two discrete chemical approaches, namely hydrogen peroxide and camptothecin, were used to induce DSB in oral cell lines derived from normal through dysplastic to OSCC tissues. After optimization, gamma histone 2Ax (γH2Ax) foci were counted as an indirect measure of kinetics of DSB and confirmed with Western blot of γH2Ax, Nbs1 and ATM. RESULTS: Maximal number of γH2Ax foci was detected 1 and 2 hours post-exposure to camptothecin and hydrogen peroxide, respectively; when adjusted for the baseline number of γH2Ax, neoplastic cell lines showed the lowest number of maximal DSB and slowest rate of repair compared to other cell lines. γH2 Ax Western blot closely mirrored the trend observed in immunofluorescent staining for γH2 Ax foci. Changes in the expression level of ATM and Nbs1 were minimal; however, ATM expression showed a slight gradual increase in normal cells which reached its peak at 2 hours after exposure to camptothecin. CONCLUSIONS: There is a difference in efficiency of DSB repair pathways in cell lines derived from different stages of oral tumorigenesis with neoplastic cell lines having the most defective DSB repair system.

An Update on the Use of Artificial Intelligence in Digital Pathology for Oral Epithelial Dysplasia Research.

INTRODUCTION: Oral epithelial dysplasia (OED) is a precancerous histopathological finding which is considered the most important prognostic indicator for determining the risk of malignant transformation into oral squamous cell carcinoma (OSCC). The gold standard for diagnosis and grading of OED is through histopathological examination, which is subject to inter- and intra-observer variability, impacting accurate diagnosis and prognosis. The aim of this review article is to examine the current advances in digital pathology for artificial intelligence (AI) applications used for OED diagnosis. MATERIALS AND METHODS: We included studies that used AI for diagnosis, grading, or prognosis of OED on histopathology images or intraoral clinical images. Studies utilizing imaging modalities other than routine light microscopy (e.g., scanning electron microscopy), or immunohistochemistry-stained histology slides, or immunofluorescence were excluded from the study. Studies not focusing on oral dysplasia grading and diagnosis, e.g., to discriminate OSCC from normal epithelial tissue were also excluded. RESULTS: A total of 24 studies were included in this review. Nineteen studies utilized deep learning (DL) convolutional neural networks for histopathological OED analysis, and 4 used machine learning (ML) models. Studies were summarized by AI method, main study outcomes, predictive value for malignant transformation, strengths, and limitations. CONCLUSION: ML/DL studies for OED grading and prediction of malignant transformation are emerging as promising adjunctive tools in the field of digital pathology. These adjunctive objective tools can ultimately aid the pathologist in more accurate diagnosis and prognosis prediction. However, further supportive studies that focus on generalization, explainable decisions, and prognosis prediction are needed.

World Workshop on Oral Medicine VIII: barriers to research in oral medicine: lessons learned from a bibliometric analysis of the oral potentially malignant disorders literature.

OBJECTIVE: This study aimed to assess the impact of oral medicine (OM) practitioners on the literature regarding oral potentially malignant disorders (OPMDs), focusing on oral leukoplakia. STUDY DESIGN: Using a bibliometric approach on the Scopus database until September 1, 2022, the top 100 cited articles were analyzed for article type, subtopic, specialty contributions, author metrics, and keywords. The Bibliometrix package for R and VOSviewer were used to evaluate interactions and generate science maps. RESULTS: OM practitioners, comprising 39% of contributors, played a significant role in studies related to nomenclature and screening of OPMDs. Notably, 4 OM specialists ranked among the most prolific authors, demonstrating denser collaboration with OM co-authors compared to other cancer specialists. However, there was a scarcity of OPMD management studies authored by OM practitioners. CONCLUSIONS: Despite the paucity of OM practitioners, the findings underscored the substantial contribution of OM practitioners in developing OPMD nomenclature and classification, emphasizing the need for increased collaboration with cancer specialists to conduct comprehensive clinical trials for OPMD management. The study highlights the importance of standardized criteria in OPMDs research for better data comparison and encourages further efforts from the OM scientific community.

Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran.

BACKGROUND: Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factors that may contribute to this high incidence have not been thoroughly studied. The aim of this study was to evaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC. METHODS: In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewed and usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeled through unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration), physical activity, and education. RESULTS: ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals, compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increased significantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13], discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intake reduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5 times higher selenium, 5.48 times as much ß-carotene and 1.98 times as much α-tocopherol as the amount ESCC cases consumed. CONCLUSION: This study suggests that high intake of nutrients primarily found in plant-based foods is associated with a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play major roles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophageal cancer in Iran, and perhaps other high-risk regions.

Adherence to dietary recommendations and risk of esophageal squamous cell carcinoma: a case-control study in Iran.

BACKGROUND/AIM: The Dietary Guidelines for Americans Adherence Index (DGAI) 2005 was developed to assess the contribution of dietary patterns to chronic disease risk. The objective of this study was to evaluate the association of dietary patterns as measured by the DGAI 2005 with the esophageal squamous cell carcinoma (ESCC) risk in Iran. METHODS: This case-control study was conducted on 50 ESCC cases and 100 hospital controls aged 40-75 years. Participants were interviewed using validated food frequency questionnaires and the DGAI score was calculated subsequently. RESULTS: Generally, the mean DGAI 2005 score for this population was low (9.54 ± 1.79) and the control group scored significantly higher compared to the ESCC cases (p < 0.001). Being in the highest tertile of DGAI scores reduced the risk of ESCC by 31%. Consumption of salty, peppery, and sour foods in combination increased the ESCC risk by 7.23%, followed by consumption of fried/barbecued meals (OR 3.79; 95% CI 1.10-5.44; p < 0.001) and high-temperature food/beverages (OR 3.68; 95% CI 1.20-8.99; p < 0.001). CONCLUSIONS: Consumption of a diet in accordance with dietary recommendations was associated with a lower risk of ESCC. Preventive strategies to reduce the ESCC risk in high-risk regions of the world should focus on overall dietary patterns and dietary habits in order to be effective.

A qualitative difference. Patients' views of hospital food service in Iran.

Undernutrition and food acceptability in hospitals form a worldwide problem, but existing studies offer a predominantly Western perspective. This research investigated inpatients' satisfaction with meals in five Iranian hospitals, using focus group discussions, interviews and meal observations. The main problem areas included food quality and quantity, nutritional control, meal arrangements and staff attitudes. Iran's hospitals follow a Western model, which may be appropriate for medical systems, but is less so for patient feeding, due to budgetary constraints and cultural factors. Understanding patients' experience makes it possible to improve feeding arrangements, with a positive impact upon patients' nutrition.

Synchronous Multifocal Canalicular Adenomas.

Canalicular adenoma (CAD) is an uncommon benign tumor of minor salivary glands with predilection for the upper labial mucosa. An 80-year-old female presented with nine submucosal nodules of the upper labial mucosa and bilateral buccal mucosa. Histopathologic examination revealed multifocal circumscribed tumor islands with a tubular growth pattern within a loose hypocellular myxoid background stroma. Interconnecting rows of columnar tumor cells imparted a canalicular morphology. In addition to the characteristic histopathologic findings, a comprehensive immunohistochemical panel supported a final diagnosis of multifocal CAD. Synchronous multifocality in CAD is an infrequent finding and this sine qua non clinicopathologic correlation article exemplifies such a case.

Unusual presentation of granular cell tumour of buccal mucosa.

Granular cell tumour (GCT) is a rare soft tissue lesion which many consider to have malignant potential of yet unknown aetiopathogenesis. Oral GCT lesions may occur in an area of leucoplakia and are predominantly present on the tongue. This case study highlights an uncommon presentation of this condition located on the buccal mucosa and illustrates the need for meticulous evaluation of suspicious lesions. Due to the malignant risk associated with GCT lesions, it is important to make the correct diagnosis and ensure complete surgical excision for these cases. Ongoing long-term follow-up is also indicated to monitor for recurrence or malignancy.

Nicotine e-vaping and cardiovascular consequences: a case series and literature review.

BACKGROUND: Cardiovascular toxicity as a consequence of nicotine from conventional tobacco cigarette smoking is well documented. However, little is known about the cardiovascular consequences of nicotine e-vaping. We review the literature and report a case series of three cases of major adverse cardiovascular clinical effects post nicotine e-vaping. CASE SUMMARY: Three patients with known peripheral arterial disease who switched from heavy cigarette smoking consumption to a high-intensity dose of nicotine e-vaping all developed further arterial complications within 6-30 months. DISCUSSION: With the recent epidemic of e-vaping in young individuals and the national outbreak of e-vaping use-associated lung injury (EVALI), the dangers of e-vaping are now coming to light. The pulmonary effects are now well described, and this paper highlights three new cases of cardiovascular toxicity associated with e-vaping. The potential role of nicotine e-vaping and the risk of coronavirus disease-2019 (COVID-19) will also be discussed.

Measuring professionalism in residency training programs in Iran.

BACKGROUND AND AIM: To assess the Farsi (Persian) translated and modified version of the questionnaire of the American Board of Internal Medicine (ABIM) for measuring professionalism, and also, measuring the professional attitudes and behaviors associated with the medical residency training environment in Iran. METHODS: After a pilot study, a 17-item questionnaire was distributed to 282 medical residents of two major universities of Iran, from December 2006 through February 2007. RESULTS: Of the 282 distributed questionnaires, 259 (95.2%) were used in the analysis. Based on the analyses, two items were omitted and 15 items were retained for further analysis. The mean score was 106 (Standard Deviation (SD), 22.4) out of maximum 150, whereas the item mean was 6.12 (SD, 0.37) out of maximum 10. Corrected item-to-total correlations ranged from low to moderate. The internal reliability of the scale, based on Cronbach's alpha, meets Nunnally's minimal requirement. A factor analysis was performed, based on principal components and varimax rotation. The solution identified three factors (subscales) including excellence, honor/integrity and altruism/respect. Together these factors represented 58.8% of the common variance. CONCLUSION: This study showed the content validity and internal reliability of the Farsi version of the ABIM questionnaire. Therefore, it can be considered as an encouraging step toward developing a short, reliable and valid instrument for measuring professionalism in medical environments.

Pathology is Always Around Us: Apophenia in Pathology, a Remarkable Unreported Phenomenon.

People often wonder, "How do pathologists identify the patterns that lead to a diagnosis [...].

Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in malignant transformation.

OBJECTIVES: To map the genomic pathways of patients with oral leukoplakia (OLK) which transformed to cancer (progressive) and those which did not (non-progressive), and to compare their exomic profiles. MATERIALS AND METHODS: Whole exome sequencing was performed on 42 sequential samples from five progressive and eight non-progressive patients. Association of genomic variant frequencies with progression or lesion severity were analysed by non-parametric tests (Kruskal-Wallis and Mann-Whitney-Wilcoxon) and multivariate sparse partial least squares discriminant analysis (sPLS-DA). Enrichment analysis was used to characterise the effect of mutations upon biological pathways. Confirmatory studies used qPCR and immunohistochemistry. RESULTS: Using sPLS-DA, the variant frequency of a small number of genes could be used to classify the samples based on lesion severity or progressive status. Enrichment analysis showed that DNA damage repair gene related pathways were highly impacted in lesions which progressed to cancer. Multivariate analysis of a set of 148 DNA damage repair genes could be used to classify progressive lesions using mutation frequency. BRCA1, BRCA2 and other double strand break (DSB) repair Fanconi anaemia (FA)/BRCA pathway genes were prominent contributors to this classification. CONCLUSION: Patients with progressive and non-progressive OLK can be differentiated using the frequency of exomic variants, particularly in DNA damage repair pathway genes. To our knowledge, this is the first report of FA/BRCA (DSB) pathway involvement in malignant transformation of OLK to oral squamous cell carcinoma (OSCC).

Oral Assessment and Management of the Patient with Head and Neck Cancer.

Patients undergoing treatment of head and neck cancer risk developing significant acute and chronic changes that affect the hard and soft tissue of the oral cavity and the head and neck region. This article discusses considerations and recommendations for patients before, during, and after treatment of head and neck cancer. The objective of these recommendations is to maintain oral health, compensate for treatment- and disease-associated morbidities, and improve quality of life. To achieve this objective, treatment of head and neck cancer must include an oral evaluation and management plan well-integrated within the overall oncologic treatment plan from the initiation of therapy.

hMSH6: a potential diagnostic marker for oral carcinoma in situ.

Oral medicine specialists rely upon accurate assessment of pathology to rationalise lesion management, especially for high-risk oral epithelial dysplasia, carcinoma in situ (CIS) and oral squamous cell carcinoma. Cross-discipline cancer research has highlighted the role of genetic instability in neoplasia. Improved diagnostic stringency from translation of immunostaining for DNA repair defects into current pathology practice has potential to benefit pathologists, clinicians and patients. The focus of this study was the obligatory and non-obligatory components of the MutLα and MutSα mismatch repair heterodimers, namely hMLH1, hMSH2, hPMS2 and hMSH6, which were studied in 274 formalin-fixed paraffin-embedded sections. A readily apparent inverse correlation between oral disease severity and both obligatory and non-obligatory components of MutLα and MutSα was observed (hMLH1, ρ=-0.715; hPMS2, ρ=-0.692; hMSH2, ρ=-0.728; and hMSH6, ρ=-0.702), with particularly conspicuous loss of hMSH6 expression from the stratum basale of CIS.

Next generation sequencing and its application in deciphering head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) are a group of heterogeneous tumours mainly attributable to tobacco use, alcohol consumption and infection with human papillomavirus. Based on the stage of cancer at the time of diagnosis, patients are managed by surgery, radiotherapy, chemotherapy or a combination of these. Early diagnosis usually improves patient prognosis. Since their first commercial application in 2005, next generation sequencing (NGS) platforms are rapidly changing the face of basic science laboratories; however prior to progressing to clinical applications, clinicians should carefully examine currently available data and guidelines for technical and ethical matters concerning NGS. In this review, we compare various commercially available NGS platforms, with special consideration given to their clinical application in the management of HNSCC.

Evaluation of Iranian college athletes' sport nutrition knowledge.

The purpose of this study was to assess the nutrition knowledge and the factors determining this knowledge in Iranian college basketball and football athletes. By highlighting gaps in nutrition knowledge of these athletes, sport nutrition professionals may begin to address these gaps by educating athletes with a view toward minimizing injury and enhancing sport performance. Sixty-six basketball and 141 football players (response rate 78.4%) from 4 medical and 8 nonmedical universities in Tehran agreed to participate in this cross-sectional study. A 2-part questionnaire was used; the first part comprised questions identifying demographic information, and the second part comprised a previously well-validated questionnaire on sport nutrition knowledge. The overall knowledge score was 33.2% (+/- 12.3%). Men scored 28.2% (+/- 12.7%), and women, 38.7% (+/- 14.2%). In both genders, the highest score was obtained for the nutrients subcategory, and the supplements subcategory was the most poorly answered. When compared with their peers, a significantly higher score was obtained by women (p < .001), athletes at medical universities (p < .001), and those obtaining nutrition information from reputable sources (p = .03). The coach was cited by 89.4% of athletes as their main source of nutrition information. This study showed that the sport nutrition knowledge of these athletes is inadequate. Considering that this substandard level of knowledge may contribute to poor dietary behaviors, these athletes would benefit from nutrition-related training and education.