Tumour Genetic Heterogeneity in Relation to Oral Squamous Cell Carcinoma and Anti-Cancer Treatment.

Oral squamous cell carcinoma (SCC) represents more than 90% of all oral cancers and is the most frequent SCC of the head and neck region. It may affect any oral mucosal subsite but most frequently the tongue, followed by the floor of the mouth. The use of tobacco and betel nut, either smoked or chewed, and abuse of alcohol are the main risk factors for oral SCC. Oral SCC is characterized by considerable genetic heterogeneity and diversity, which together have a significant impact on the biological behaviour, clinical course, and response to treatment and on the generally poor prognosis of this carcinoma. Characterization of spatial and temporal tumour-specific molecular profiles and of person-specific resource availability and environmental and biological selective pressures could assist in personalizing anti-cancer treatment for individual patients, with the aim of improving treatment outcomes. In this narrative review, we discuss some of the events in cancer evolution and the functional significance of driver-mutations in carcinoma-related genes in general and elaborate on mechanisms mediating resistance to anti-cancer treatment.

Burnout phenomenon: neurophysiological factors, clinical features, and aspects of management.

Burnout syndrome is a distinct "occupational phenomenon" rather than a medical condition, comprising emotional exhaustion, physical fatigue, and cognitive weariness. Both exogenous work-related and endogenous personal factors determine the extent and the severity of symptoms in burnout syndrome. Persistent burnout is a cause of reduced quality of life and is associated with increased risk of sleep impairment and with several medical disorders including mild cognitive impairment, diabetes, and cardiovascular disease.Active coping strategies promoting mental resilience and adaptive behavior, stress-reducing activities, improving work conditions, and reducing exposure to work stressors together may alleviate the distress of burnout and should be introduced early in the clinical course of burnout syndrome. The purpose of this review was to explain this complex and puzzling phenomenon and to describe burnout management.

Noma staging: a review.

Noma is a bacterial, non-communicable, grossly destructive and disfiguring necrotising oro-facial disease. It is rare, but occurs most commonly in chronically malnourished children with other debilitating illnesses, in remote, poverty-stricken communities, mainly in sub-Saharan Africa, and much more rarely in central Latin America and in parts of Asia. In South Africa and in Zimbabwe, noma is observed, again rarely, in immunosuppressed HIV-seropositive subjects. The World Health Organization (WHO) has classified noma into five sequential stages: stage 1, acute necrotising ulcerative gingivitis; stage 2, oedema; stage 3, gangrene; stage 4, scarring; stage 5, sequela. In the opinion of the authors, this WHO classification requires fundamental re-appraisal. The purpose of this viewpoint article is to highlight the weaknesses of this classification, and to propose a simpler, more logical and practical evidence-based staging of noma, which if used should improve the quality and value of future epidemiological data about noma.

The burnout construct with reference to healthcare providers: A narrative review.

Burnout syndrome is a psychological response to long-term exposure to occupational stressors. It is characterized by emotional exhaustion, cognitive weariness and physical fatigue, and it may occur in association with any occupation, but is most frequently observed among professionals who work directly with people, particularly in institutional settings. Healthcare professionals who work directly with patients and are frequently exposed to work overload and excessive clinical demands, to ethical dilemmas, to pressing occupational schedules and to managerial challenges; who have to make complex judgements and difficult decisions; and who have relatively little autonomy over their job-related tasks are at risk of developing clinical burnout. In turn, clinical burnout among clinicians has a negative impact on the quality and safety of treatment, and on the overall professional performance of healthcare systems. Healthcare workers with burnout are more likely to make mistakes and to be subjected to medical malpractice claims, than do those who are burnout-naïve. Experiencing the emotional values of autonomy, competence and relatedness are essential work-related psychological needs, which have to be satisfied to promote feelings of self-realization and meaningfulness in relation to work activities, thus reducing burnout risk. Importantly, an autonomy-supportive rather than a controlling style of management decreases burnout risk and promotes self-actualization, self-esteem and a general feeling of well-being in both those in charge and in their subordinates. The purpose of this article is to discuss some of the elements constituting the burnout construct with the view of gaining a better understanding of the complex multifactorial nature of burnout. This may facilitate the development and implementation of both personal, behavioural and organizational interventions to deal with the burnout syndrome and its ramifications.

Is noma a neglected/overlooked tropical disease?

Noma is a debilitating orofacial necrotizing bacterial disease that disproportionately affects impoverished malnourished persons, particularly young children, the vast majority of whom live in tropical and subtropical areas in sub-Saharan Africa. It has a very high mortality rate; causes significant physical and psychological morbidity, stigmatization and social discrimination; could be prevented, controlled and indeed eliminated by common public health interventions; and is overlooked with regard to public health awareness, in-depth scientific research activities and allocation of funding for prevention, treatment and research. According to the WHO, noma comprises five sequential 'stages': (1) necrotizing gingivitis, (2) edema, (3) gangrene, (4) scarring and (5) sequelae. This WHO staging of noma is contentious, leading to diagnostic confusion with misestimation of the number of noma cases reported in epidemiological studies. We therefore suggest a simpler, more practical and scientifically valid two-stage classification comprising only (1) acute noma and (2) arrested noma. Noma meets all the WHO criteria for classification as a neglected tropical disease (NTD). Most survivors of noma live with gross physical disfigurement and disability, and with impaired psychosocial functioning, so they are very often stigmatized and unjustifiably discriminated against. Owing to the paucity of evidence-based epidemiological data on noma, the relatively low number of people affected worldwide, and its apparently limited geographic distribution, noma does not yet feature on the WHO's list of NTDs, or on any global health agenda, and thus has not become a health priority for global action. We strongly support the inclusion of noma within the WHO list of NTDs. Without doubt this will increase the awareness of noma among healthcare providers and promote the systematic international accumulation and recording of data about noma.

Judgment and decision-making in clinical dentistry.

The development of clinical judgment and decision-making skills is complex, requiring clinicians-whether students, novices, or experienced practitioners-to correlate information from their own experience; from discussions with colleagues; from attending professional meetings, conferences and congresses; and from studying the current literature. Feedback from treated cases will consolidate retention in memory of the complexities and management of past cases, and the conversion of this knowledge base into daily clinical practice. The purpose of this narrative review is to discuss factors related to clinical judgment and decision-making in clinical dentistry and how both narrative, intuitive, evidence-based data-driven information and statistical approaches contribute to the global process of gaining clinical expertise.

Interrelations between pain, stress and executive functioning.

AIM: The purpose of this narrative review is to discuss the interrelations between pain, stress and executive functions. IMPLICATIONS FOR PRACTICE: Self-regulation, through executive functioning, exerts control over cognition, emotion and behaviour. The reciprocal neural functional connectivity between the prefrontal cortex and the limbic system allows for the integration of cognitive and emotional neural pathways and then for higher-order psychological processes (reasoning, judgement etc.) to generate goal-directed adaptive behaviours and to regulate responses to psychosocial stressors and pain signals. Impairment in cognitive executive functioning may result in poor regulation of stress-, pain- and emotion-related processing of information. Conversely, adverse emotion, pain and stress impair executive functioning. The characteristic of the feedback and feedforward neural connections (quantity and quality) between the prefrontal cortex and the limbic system determine adaptive behaviour, stress response and pain experience.

Selected pathobiological features and principles of pharmacological pain management.

Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term elevation of the sensitivity and responsiveness of spinal cord neurons. Inflammatory pain typically resolves following resolution of inflammation; however, nerve injury-either peripheral or central-may cause persistent neuropathic pain, which frequently manifests as hyperalgesia or allodynia. Neuralgias, malignant metastatic bone disease, and diabetic neuropathy are some of the conditions associated with severe, often unremitting chronic pain that is both physically and psychologically debilitating or disabling. Therefore, optimal pain management for patients with chronic neuropathic pain requires a multimodal approach that comprises pharmacological and psychological interventions. Non-opioid analgesics (e.g., paracetamol, aspirin, or other non-steroidal anti-inflammatory drugs) are first-line agents used in the treatment of mild-to-moderate acute pain, while opioids of increasing potency are indicated for the treatment of persistent, moderate-to-severe inflammatory pain. N-methyl D-aspartate receptor antagonists, antidepressants, anticonvulsants, or a combination of these should be considered for the treatment of chronic neuropathic pain. This review discusses the various neural signals that mediate acute and chronic pain, as well as the general principles of pain management.

Noma (cancrum oris): An unresolved global challenge.

Noma (canrum oris) is a mutilating necrotizing disease of uncertain etiology, but it is accepted that it is caused primarily by a polybacterial infection with secondary ischemia. The consequent necrotizing fasciitis, myonecrosis, and osteonecrosis results in destruction of facial structures with severe functional impairment and disfigurement. It most frequently affects children, particularly in sub-Saharan Africa, who are malnourished or debilitated by systemic conditions including but not limited to malaria, measles, and tuberculosis; and less frequently debilitated HIV-seropositive subjects. In the vast majority of cases, in susceptible subjects, noma is preceded by necrotizing stomatitis. However, it has been reported, albeit rarely, that noma can arise without any preceding oral lesions being observed. Noma is not recurrent and is not transmissible.

Pain: Persistent postsurgery and bone cancer-related pain.

The generation of neuropathic pain is a complex dynamic process. Factors involved include one or more dysregulated sensory neural pathways; dysregulated activity of specific neurotransmitters, synapses, receptors and cognitive and emotional neural circuits; and the balance between degenerative and regenerative neural events. Risk factors include age, sex, cognition, emotions, genetic polymorphism, previous or ongoing chronic pain conditions and the use of certain drugs. Intense pain experienced before, during and after surgery is a risk factor for the development of central sensitization with consequent persistent postsurgery neuropathic pain. Blockade of N-methyl-D-aspartate receptors with appropriate drugs during and immediately after surgery may prevent persistent postsurgical pain. Most cancers, but particularly malignant metastases in bone, can induce persistent pain. Local factors including direct damage to sensory nerve fibres, infiltration of nerve roots by cancer cells and algogenic biological agents within the microenvironment of the tumour bring about central sensitization of dorsal horn neurons, characterized by neurochemical reorganization with persistent cancer pain. In this article, the clinical features, pathogenesis and principles of management of persistent postsurgery pain and cancer pain are briefly discussed.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma.

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown.

Review: allergic contact stomatitis.

Allergic contact stomatitis (ACS) is an oral mucosal immunoinflammatory disorder variably characterized clinically by erythematous plaques, vesiculation, ulceration, and/or hyperkeratosis and by pain, burning sensation, or itchiness. ACS is brought about by a T cell-mediated, delayed hypersensitivity immune reaction generated by a second or subsequent contact exposure of an allergen with the oral mucosa, in a genetically susceptible, sensitized subject. Lichenoid contact reaction is a variant of ACS brought about by direct contact with the oral mucosa of certain metals in dental restorations. The features of ACS are neither clinically nor histopathologically specific, so the diagnosis is usually presumptive and can only be confirmed by resolution of the inflammation after withdrawal or removal of the suspected causative allergen. When ACS is suspected but an allergen cannot be identified, patch testing is necessary. In persistent cases, topical corticosteroids are the treatment of choice, but for severe and extensive lesions, systemic corticosteroid and systemic antihistamines may be indicated. In this short review, we highlight the clinical, immunologic, and histopathological features of ACS, and provide some guidelines for diagnosis and management.

Immunopathogenic Oral Diseases: An Overview Focusing on Pemphigus Vulgaris and Mucous Membrane Pemphigoid.

Pemphigus vulgaris, mucosal pemphigoid (mucous membrane pemphigoid), lichen planus, discoid lupus erythematosus and erythema multiforme are a group of immune-mediated mucocutaneous disorders characterised clinically by the formation of blisters, erosions or ulcers. The oral mucosa is often affected, and sometimes the disease is limited to the mouth. The target antigens, autoreactive immune responses, microscopic features, treatment and prognosis vary from one disease to the other. Treatment aims to eliminate exogenous risk factors, suppress the pathogenic immuno-inflammatory reactions, promote healing and prevent infection. The aim of this article is to provide the general dental practitioner with a succinct overview of the diagnostic, clinical, aetiopathogenic features and characteristics of, as well as treatment guidelines for oral pemphigus vulgaris and oral mucosal pemphigoid. Early diagnosis and treatment could prevent severe consequences of the disease in their full-blown forms.

Physiological oral melanin pigmentation in a South African sample: A clinical study.

AIM: Physiological oral melanin pigmentation is genetically determined, more frequently affecting people with darker skin. It can involve any oral mucosal site, but predominantly the gingiva. The aim of the present study was to determine the prevalence and to characterize the clinical features of physiological oral melanin pigmentation in a South African population sample. METHODS: A trainee in the discipline of periodontology and oral medicine interviewed all participants and examined the oral soft tissues. The diagnosis of physiological oral melanin pigmentation was based on clinical findings and on the history reported by the patient. A predetermined list of exclusion criteria was applied. RESULTS: The study population comprised 430 participants, of whom 319 (74%) were black, 55 (13%) Indian, 54 (12.5%) white, and two (0.5%) were mixed race. A total of 182 participants were diagnosed with physiological oral melanin pigmentation. The overall prevalence of physiological oral melanin pigmentation in the ethnically-mixed study population was 42%: 54% of blacks were affected, 16% of Indians, and 21% of whites. The female (101): male (81) ratio was 1.2:1; the gingiva was the site most frequently affected (73%). The total number of oral mucosal sites with physiological oral melanin pigmentation in the study population was 263; 68% of participants had one, 22% had two, 7% had three, and 3% had four sites affected. There was no significant association between the number of sites affected and sex or age. CONCLUSIONS: In this study of a South African population sample, the prevalence of physiological oral melanin pigmentation was higher in blacks than in Indians or whites, and the gingiva was the oral mucosal site most frequently affected.

Is chronic ulcerative stomatitis a variant of lichen planus, or a distinct disease?

Chronic ulcerative stomatitis is an immune-mediated mucocutaneous disorder characterized clinically by erosions or ulcers. Most cases are limited to the mouth. The histopathological features are non-specific or mimic those of oral lichen planus, and studies by immunofluorescent microscopy are essential for definitive diagnosis. The defining immunopathogenic mechanism is the binding of IgG to the nuclear protein deltaNp63alpha of keratinocytes in the basal and parabasal cell layers of the oral stratified epithelium. DeltaNp63alpha functions as a regulator of epithelial stem cell activity and as an antiapoptotic agent and regulates the expression of cell-to-cell and cell-to-basement membrane adhesion molecules. The autoimmune IgG-deltaNp63alpha interaction is thought to result in damage to the structural attachment of keratinocytes to one another and to the epithelial basement membrane zone and in dysregulation of the cell cycle and apoptosis of basal keratinocytes with the development of erosions or ulcers. The aims of treatment are to suppress the pathogenic immunoinflammatory responses, to prevent local infection and to promote healing. The purpose of this article is to provide a succinct review of the diagnostic, clinical and etiopathogenic features of, and treatment guidelines for chronic ulcerative stomatitis, and to argue that this disease should be regarded as a variant of oral lichen planus, rather than as a distinct entity.

Biomechanical cell regulatory networks as complex adaptive systems in relation to cancer.

Physiological structure and function of cells are maintained by ongoing complex dynamic adaptive processes in the intracellular molecular pathways controlling the overall profile of gene expression, and by genes in cellular gene regulatory circuits. Cytogenetic mutations and non-genetic factors such as chronic inflammation or repetitive trauma, intrinsic mechanical stresses within extracellular matrix may induce redirection of gene regulatory circuits with abnormal reactivation of embryonic developmental programmes which can now drive cell transformation and cancer initiation, and later cancer progression and metastasis. Some of the non-genetic factors that may also favour cancerization are dysregulation in epithelial-mesenchymal interactions, in cell-to-cell communication, in extracellular matrix turnover, in extracellular matrix-to-cell interactions and in mechanotransduction pathways. Persistent increase in extracellular matrix stiffness, for whatever reason, has been shown to play an important role in cell transformation, and later in cancer cell invasion. In this article we review certain cell regulatory networks driving carcinogenesis, focussing on the role of mechanical stresses modulating structure and function of cells and their extracellular matrices.

Epstein-Barr Virus and Its Association with Oral Hairy Leukoplakia: A Short Review.

In immunocompromised subjects, Epstein-Barr virus (EBV) infection of terminally differentiated oral keratinocytes may result in subclinical productive infection of the virus in the stratum spinosum and in the stratum granulosum with shedding of infectious virions into the oral fluid in the desquamating cells. In a minority of cases this productive infection with dysregulation of the cell cycle of terminally differentiated epithelial cells may manifest as oral hairy leukoplakia. This is a white, hyperkeratotic, benign lesion of low morbidity, affecting primarily the lateral border of the tongue. Factors that determine whether productive EBV replication within the oral epithelium will cause oral hairy leukoplakia include the fitness of local immune responses, the profile of EBV gene expression, and local environmental factors.

Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events.

Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption.