Impaired intratumoral dendritic cell function and potential predictive value of dendritic cell markers for metastasis in malignant salivary gland tumors.

BACKGROUND: The differentiation between primary and metastatic salivary gland neoplasms (SGNs) helps in determining appropriate management strategies, including the need for additional diagnostic tests, surveillance, or aggressive treatment. The purpose of this study was to identify and quantify the immature and mature dendritic cells (DCs) in metastatic and no metastatic SGNs and determine its association with clinicopathological findings. MATERIAL AND METHODS: Cross-sectional, observational, and descriptive study that includes 33 malignant salivary gland neoplasms [MSGN (6, 18.1% metastatic)], and 22 pleomorphic adenomas (PA), as a control group. Clinical and histopathological characteristics were obtained. Immunohistochemistry for human leukocyte antigen D-related (HLA-DR), CD1a, CD83, and Ki-67 proteins was done. Positive intra- and peritumoral DCs were counted. RESULTS: Individuals with MSGN had a lower density of intratumoral HLA-DR+ cells than those with PA (p=0.001), Ki-67 immunostaining was significantly higher in MSGN than in PA (6% vs. 1.4%, p<0.001). Metastatic MSGN showed less intratumoral CD1a+ than non-metastatic (3.2 vs. 165.1, p=0.001). No differences in intra- and peritumoral CD83+ cells were found between benign and malignant SGN. CONCLUSIONS: These results suggest that the immune-protective function of intratumoral DCs is compromised in MSGNs. DCs markers may represent useful prediction tools for metastases in salivary gland malignancies, with crucial implications in the implementation of appropriate disease management strategies.

Primary oral and sinonasal mucosal melanomas in Latin America: a systematic review.

Primary oral and sinonasal mucosal melanomas (POSNMMs) are aggressive neoplasms with limited therapeutic alternatives. The aim of this review was to characterize the demographic, clinical, immunohistochemical, and molecular information regarding these tumors in the Latin American population. Articles published in English, Spanish, or Portuguese (1990-2022) retrieved from the PubMed/MEDLINE, Scopus, CAS, Web of Science, EBSCO, and Google Academic databases were included. Thirty-three studies, with a total of 1212 cases, were identified. Clinicopathological data were available for 870 cases and immunohistochemical and/or molecular information for 342. Nineteen studies (57.6%) reported cases of oral melanoma, three (9.1%) sinonasal melanoma, and 11 (33.3%) oral and sinonasal melanoma. Fifteen studies (45.5%) provided only clinicopathological data, 12 (36.4%) reported only immunohistochemical data, two (6.1%) shared clinicopathological and immunohistochemical data, one (3.0%) offered clinicopathological, immunohistochemical, and molecular data, one (3.0%) provided immunohistochemical and molecular data, one (3.0%) clinicopathological and molecular data, and one (3.0%) only molecular data. The mean age of individuals with POSNMMs was 58 years, and slightly more were male (male 51.3%, female 48.7%). In Latin America, POSNMMs are a rare but aggressive malignancy with a poor prognosis and limited treatment options. Although molecular data and targeted therapy are still being researched, data from Latin America indicate the need for multicenter collaborative clinical trials to unite individual and isolated efforts.

Human papillomavirus load in benign HPV-associated oral lesions from HIV/AIDS individuals.

BACKGROUND: Although HPV emerged as a crucial carcinogenic and prognostic biomarker in head and neck cancer, and considering the increase in HPV-associated oral lesions (HPV-OLs) in HIV individuals, molecular information about HPV-OLs is scarce; thus, our aim was to determine viral loads in HPV-OLs from HIV/AIDS individuals. METHODS: HIV/AIDS subjects with HPV-OL were included in this cross-sectional study. Following informed consent, biopsies were obtained. HPV detection and typing were carried out by PCR and sequencing (MY09/11, GP5+/6+). HPV-13 and HPV-32 loads were determined by a high-resolution melting assay. For statistical analysis, X2 , Fisher's exact, and Mann-Whitney U tests were applied, using SPSS software (v.23). RESULTS: Twenty-nine HIV subjects (median age 38 years, 93% males) were included. Most were AIDS individuals (72.4%) under HAART (89.7%). Twenty-two (75.9%) participants had more than one HPV-OL (four with florid presentations), mostly multifocal epithelial hyperplasia (62%), being HPV-13 (26%) and HPV-32 (31%) the most frequent types. HPV load was higher in individuals with multiple HPV-OLs than in solitary lesions (4.9 vs. 3.2 Log10 copies/ml, p = .090) and in HPV-32+ than in HPV-13+ (8.3 vs. 6.4 Log10 copies/ml, p = .014). CONCLUSIONS: Multiple HPV-OLs showed high HPV loads, possibly indicating transcriptional activity of the virus; however, in the HIV setting, the individual and local immunological response could be the key process.

Double-blind placebo-controlled randomized clinical trial evaluating doxycycline effects on chemotherapy-induced oral mucositis.

WHAT IS KNOWN AND OBJECTIVE: Chemotherapy (CT)-associated oral mucositis (OM) is one of the most debilitating and painful side effects in oncology patients, with limited effective management options. During CT, matrix metalloproteinases (MMPs) are upregulated, causing damage in mucosal and submucosal tissues, and playing a key role in OM; therefore, the use of subantimicrobial doxycycline as a MMP inhibitor may represent a potential approach for OM management. The aim of this clinical trial was to evaluate the efficacy and safety of low doses of doxycycline in OM development in individuals with acute leukaemia (AL) during CT. METHODS: Randomized controlled clinical trial (Registration No. NCT01087476) performed in adult AL patients scheduled to receive CT (September 2010-October 2014). Individuals were stratified by leukaemia type and assigned randomly to receive doxycycline hyclate (50 mg/d) (doxycycline group: DG) or placebo (placebo group: PG) before and during CT. Included subjects had a baseline oral examination and thereafter 3 times a week during 21 days. The primary outcome was OM development. RESULTS AND DISCUSSION: One hundred and forty-seven AL subjects were enrolled: 74 in DG and 73 in PG; baseline characteristics between groups were comparable. During follow-up, 15 (10.2%) individuals developed OM; no differences between treatment groups were found (DG:8.1%, PG:12.3%; P = .59). The mean OM Assessment Scale score was 2.51, without differences between groups (DG:2.7, PG:2.4; P = .65). Low baseline blood albumin levels in the OM-affected individuals were identified, revealing the effect of systemic deterioration as a predisposing factor for OM development. No adverse effects were observed. WHAT IS NEW AND CONCLUSION: Subantimicrobial doses of doxycycline did not reduce the incidence, onset, duration or severity of OM.

TNF as marker of oral candidiasis, HSV infection, and mucositis onset during chemotherapy in leukemia patients.

OBJECTIVE: To assess changes in the salivary expression of IL-1α, IL-1ß, IL-2, IL-6, IL-10, IL-17, and TNF in acute leukemia (AL) patients before and during chemotherapy, and its association with HSV infection, oral candidiasis (OC), and oral mucositis (OM) onset. METHODS: Cohort study in AL patients >15 years starting induction chemotherapy at a Mexican oncological center (2013-2014). Onset of oral lesions (OLs) was assessed during follow-up, and saliva was obtained at baseline, at visit 2 (days 4-12), and at visit 3 (days 13-21) after chemotherapy, treated with a protease inhibitor and stored at -70°C. An enzyme-linked immunosorbent assay was performed. Cox proportional hazards regression models were constructed to estimate hazard ratios and its 95% CI (HR, 95% CI) for OL development. RESULTS: Forty-one patients were followed up, and 17 (41.5%) developed OLs. OL patients had higher baseline salivary IL-1α than those without lesions (p = 0.040). During visit 2, OL patients had higher levels of IL-1α (p = 0.033), IL-1ß (p = 0.016), IL-6 (p = 0.035), and TNF (p = 0.019) than those who did not develop OLs. Patients with HSV infection, OC, and OM showed higher salivary TNF levels during follow-up (HR: 3.52, 95% CI: 1.35-9.14, p = 0.010). CONCLUSION: AL patients undergoing chemotherapy with high salivary TNF levels were more likely to develop HSV infection, OC, and OM.

Viral infections associated with oral cancers and diseases in the context of HIV: a workshop report.

Human herpesviruses (HHVs) and human papillomavirus (HPV) are common in the general population and, in immunocompetent people, are mostly carried asymptomatically. However, once an individual becomes immunocompromised by age, illness or HIV infection these dormant viruses can manifest and produce disease. In HIV-positive patients, there is an increased risk of disease caused by HHVs and HPV infections and cancers caused by the oncoviruses Epstein-Barr Virus, HHV-8 and HPV. This workshop examined four questions regarding the viruses associated with oral cancers and disease in the HIV-positive and -negative populations, the immune response, and biomarkers useful for accurate diagnostics of these infections and their sequalae. Each presenter identified a number of key areas where further research is required.

The global burden of oral diseases in pediatric HIV-infected populations: a workshop report.

OBJECTIVES: To achieve a comprehensive understanding about the global burden of oral diseases in HIV-infected children and to identify research needs. MATERIALS AND METHODS: A literature search was conducted in PubMed (2009-2014) to address five questions: (i) prevalence of oral diseases in HIV-infected compared with uninfected children, (ii) impact of oral diseases on quality of life, (iii) effect of antiretroviral exposure in utero on craniofacial and dental development, (iv) important co-infections and antiretroviral complications, and (v) value of atraumatic restorative treatment. RESULTS: Studies showed a high prevalence of dental caries in HIV-infected children but the relationship between HIV infection and dental caries remains unclear. Also quality of life needs further investigation supported by better study designs and improvement of the instruments used. Up-to-date evidence suggested long-term harms associated with in utero antiretroviral exposure were minor but would require long-term follow-up through National Registries. The reviews also revealed the wide spectrum of metabolic disease due to antiretroviral therapy and co-infections such as tuberculosis. Finally, atraumatic restorative technique appears to be a simple and safe technique to treat dental caries but outcomes need further evaluation. CONCLUSIONS: The impact of antiretroviral therapy in HIV-infected children has raised novel challenging questions in the field of oral health warranting future research.

Clinicopathological characterization of primary oral and sinonasal melanoma in a referral centre in Mexico City: 2000-2012.

In Mexico, there have been few studies on primary oral and sinonasal melanoma, an aggressive neoplasm with a low survival rate and few therapeutic alternatives. Further, there is limited information about its clinical and histopathological characteristics. The aim of this retrospective study was to describe the clinicopathological profile of these tumours in patients attending a major oncology reference centre in Mexico City over a 12-year period. Demographic and clinical data were obtained from the clinical charts, and histopathological features were evaluated. χ(2), Fisher's exact, and Mann-Whitney U-tests were used for analysis; significance was set at P<0.05. Thirty-three cases were studied (73% sinonasal melanoma (SNM) and 27% oral melanoma (OM)); 58% were female and the median age was 66 (Q1-Q3 55.5-75) years. Compared with OM patients, SNM patients had a shorter time to diagnosis (16.7 vs. 11.7 months, P=0.022), were identified at earlier stages (33.3% vs. 58.3%, P=0.010), and all presented symptoms (66.7% vs. 100%, P=0.015). All samples showed vertical growth and 96.9% exhibited pleomorphism. A higher proportion of cases with pleomorphism developed metastases at follow-up than those without (60% vs. 12.5%, P=0.026). The present study provides valuable information that could form the basis of future studies in the search for advanced therapy modalities.

Urban legends series: oral manifestations of HIV infection.

Human immunodeficiency virus-related oral lesions (HIV-OLs), such as oral candidiasis (OC) and oral hairy leukoplakia (OHL), have been recognized as indicators of immune suppression since the beginning of the global HIV epidemic. The diagnosis and management of HIV disease and spectrum of opportunistic infection has changed over the past 30 years as our understanding of the infection has evolved. We investigated the following controversial topics: (i) Are oral manifestations of HIV still relevant after the introduction of highly active antiretroviral therapy (HAART)? (ii) Can we nowadays still diagnose HIV infection through oral lesions? (iii) Is the actual classification of oral manifestations of HIV adequate or does it need to be reviewed and updated? (iv) Is there any novelty in the treatment of oral manifestations of HIV infection? Results from extensive literature review suggested the following: (i) While HAART has resulted in significant reductions in HIV-OLs, many are still seen in patients with HIV infection, with OC remaining the most common lesion. While the relationship between oral warts and the immune reconstitution inflammatory syndrome is less clear, the malignant potential of oral human papillomavirus infection is gaining increasing attention. (ii) Effective antiretroviral therapy has transformed HIV from a fatal illness to a chronic manageable condition and as a result expanded screening policies for HIV are being advocated both in developed and in developing countries. Affordable, reliable, and easy-to-use diagnostic techniques have been recently introduced likely restricting the importance of HIV-OLs in diagnosis. (iii) The 1993 EC-Clearinghouse classification of HIV-OLs is still globally used despite controversy on the relevance of periodontal diseases today. HIV-OL case definitions were updated in 2009 to facilitate the accuracy of HIV-OL diagnoses by non-dental healthcare workers in large-scale epidemiologic studies and clinical trials. (iv) Research over the last 6 years on novel modalities for the treatment of HIV-OLs has been reported for OC and OHL.

Association between age and high-risk human papilloma virus in Mexican oral cancer patients.

OBJECTIVE: Studies reporting low prevalence of HPV in OSCC with declining age at presentation are increasing. The aim of this study was to determine the prevalence of HPV in a group of OSCC cases and controls in a Mexican population. METHODS: The matched case-control study included 80 OSCC cases and 320 controls. HPV/DNA presence was evaluated through PCR amplification using three sets of consensus primers for the L1 gene. A conditional logistic regression analysis was carried out for the matched OSCC cases and controls. Interactions between risk factors and OCSS were tested in the construction process of the models. RESULTS: HPV prevalence was 5% in OSCC cases and 2.5% in controls. HPV-detected types were 16, 18 and 56. According to conditional logistics regression model, an association was detected between HR-HPV and OSCC. All HR-HPV-positive OSCC cases corresponded to young patients (<45 years), non-smokers and non-alcohol drinkers. CONCLUSIONS: The HR-HPV can be a contributing factor to oral carcinogenesis, especially in younger individuals without known risk factors such as tobacco and alcohol.

Clinical markers of immunodeficiency and mechanism of immune reconstitution inflammatory syndrome and highly active antiretroviral therapy on HIV: workshop 3A.

Antiretroviral therapy (ART) has improved survival and changed the disease pattern of HIV infection. However, ART may cause serious side effects, such as metabolic and cardiovascular complications. In addition, immune reconstitution inflammatory syndrome (IRIS) is being increasingly reported in relation to ART. The article presents the consensus of a workshop around 4 key issues: (1) the differences in the response of adults and children to highly active antiretroviral therapy, (2) the mechanism of the new HIV entry inhibitors and its effect on oral markers, (3) the pathogenesis of IRIS and the contradictory findings of the possible oral lesions related with IRIS, (4) and the benefits and barriers associated with using ART in the developing and developed world. The consensus of the workshop was that there is a need for future studies on the oral manifestations of HIV in individuals treated with new ARTs-especially, children. IRIS was considered a promising field for future research; as such, workshop attendees recommended formulating an IRIS-oral lesions case definition and following strict criteria for its diagnosis.

hMLH1 promoter methylation is an early event in oral cancer.

Promoter methylation is believed to inactivate the expression of hMLH1. This process has been implicated in the tumorigenesis of oral squamous cell carcinoma (OSCC). Thus, the aim of this study was to determine the profile of hMLH1 methylation and protein expression in OSCC. The matched case-control study included 50 OSCC cases and 200 controls, with a median of age 64 (Q1-Q3 54-71) years. Protein expression was determined by immunohistochemical staining, and hMLH1 gene promoter methylation was analyzed by methylation-specific polymerase chain reaction (MSP). A conditional logistic regression model for risk factors was built for OSCC cases and matched controls. Promoter methylation of hMLH1 was detected in 38 (76%) OSCC cases, but in none of the control samples. Of the 38 OSCC samples with promoter methylation, 12 (32%) were negative for hMLH1 protein, and corresponded to early clinical stages (10 in stage II and 2 in stage I). All 12 unmethylated samples showed positive stain for hMLH1. Multiple logistic regression analysis showed an OR of 16.54 (IC 95%: 1.69-161.68, p=0.016) for methylation of the hMLH1 gene and early stages of OSCC, adjusting by gender and tobacco use. This study showed a high frequency of hMLH1 promoter methylation that occurred in most of the early stage cases and in about half of the late stage cases. It is proposed that hMLH1 promoter methylation is an early event that is maintained during tumor progression.

Identification of oral candidosis, hairy leukoplakia and recurrent oral ulcers as distinct cases of immune reconstitution inflammatory syndrome.

Oral lesions such as candidosis, hairy leukoplakia (HL) and oral ulcers are strikingly absent in the numerous reports of immune reconstitution inflammatory syndrome (IRIS). To document oral manifestations attributable to immune reconstitution, we conducted a longitudinal follow-up of a cohort of HIV+ individuals starting highly active antiretroviral therapy (HAART) and completing oral pathology follow-up up to 12 weeks after treatment initiation. HIV-infected patients had oral examinations, CD4+ T-cell count and viral load determinations performed at baseline, and at weeks 4, 8 and 12 after HAART initiation. Among individuals with satisfactory viral response and recovery of > or =50 CD4+ T-cell/microL, eight patients complied with strict IRIS criteria: two developed clinical signs of oral candidosis (OC), two oral ulcers, three HL and one Kaposi's sarcoma. CD4+ T-cell counts at symptom onset suggested no remaining immune suppression. Our findings show that cases of OC, HL and recurrent ulcers can be instances of IRIS.

Clinical, histological and immunohistochemical findings in oral Kaposi's sarcoma in a series of Mexican AIDS patients. Comparative study.

BACKGROUND: The origin of spindle cells (SC) in oral Kaposi's sarcoma (OKS) is still an intriguing aspect. Thus the aim of the present study was to compare the clinical, histological and immunohistochemical characteristics of OKS and oral pyogenic granuloma (OPG), in order to contribute to the knowledge of the cells involved in Kaposi's sarcoma pathogenesis. METHODS: In this retrospective, observational and comparative study, 39 OKS and 30 OPG cases were included. Immunohistochemical studies were performed for vimentin, alpha SMA, desmin, C-kit, CD34, D2-40 and LANA-1 [human herpesvirus-8(HHV-8)]. Statistical comparisons were done using the chi-square and Wilcoxon-Mann-Whitney rank sum tests. RESULTS: Fourteen (35.9%) OKS cases also affected the skin, and 83.8% involved the palate. All OKS and OPG were positive for vimentin and CD34. OKS samples were positive for alpha SMA, and 25.6% expressed C-kit. All OKS cases were positive for HHV-8, and the number of positive cells increased significantly from early / intermediate to late histological stage. D2-40 was expressed in the cellular component and vascular walls of all OKS cases, but it was negative in OPG. HHV-8 expression was increased in late histological stages of OKS lesions. CONCLUSIONS: The expression of D2-40 marker in the vascular walls and SC supports the view of a lymphatic differentiation in neoplastic cells of OKS. Desmin, alpha SMA, D2-40, C-kit and HHV-8 were the main markers differently expressed in OKS and OPG.

(A3) HIV Phenotypes, oral lesions, and management of HIV-related disease.

Workshop participants discussed: the role of HIV subtypes in disease; the treatment of oral candidiasis; the relationship between and among viral load, CD4+ counts, oral candidiasis and oral hairy leukoplakia, pigmentation; and the development of a reliable oral index to predict disease progression. Regarding HIV, the literature revealed that Type I (HIV-I), in particular group M, is involved in the majority (90%) of documented infections, and groups N and O to a lesser extent. Viral envelope diversity led to the subclassification of the virus into nine subtypes, or clades-A-D, F-H, J, and K-each dominating in different geographical areas. HIV-2, currently occurring mostly in West Africa, appears to be less virulent. No evidence could be produced of any direct impact of type, subtype, or clade on oral lesions, and participants believed that further research is not feasible. Oral candidiasis in patients from resource-poor countries should be prevented. When the condition does occur, it should be treated until all clinical symptoms disappear. Oral rinsing with an antimicrobial agent was suggested to prevent recurrence of the condition, to reduce cost, and to prevent the development of antifungal resistance. Lawsone methyl ether, isolated from a plant (Rhinacanthus nasutus leaves) in Thailand, is a cost-effective mouthrinse with potent antifungal activity. Evidence from a carefully designed prospective longitudinal study on a Mexican cohort of HIV/AIDS patients, not receiving anti-retroviral treatment, revealed that the onset of oral candidiasis and oral hairy leukoplakia was heralded by a sustained reduction of CD4+, with an associated sharp increase in viral load. Analysis of the data obtained from a large cohort of HIV/AIDS patients in India could not establish a systemic or local cause of oral melanin pigmentation. A possible explanation was a dysfunctional immune system that increased melanin production. However, longitudinal studies may contribute to a better understanding of this phenomenon. Finally, a development plan was presented that could provide a reliable prediction of disease progression. To be useful in developing countries, the index should be independent of costly blood counts and viral load.

Mechanical deformation inhibits IL-10 and stimulates IL-12 production by mouse calvarial osteoblasts in vitro.

The skeleton is continuously remodelled throughout life, a process that is orchestrated by cells of the osteoblast lineage. Remodelling involves a complex network of cell-cell signalling involving systemic hormones, locally produced cytokines, growth factors and the mechanical environment of the cells. Here, we report on the effect of mechanically-induced strain on the synthesis by mouse calvarial osteoblasts in monolayer culture of IL-10 and IL-12, two cytokines that inhibit osteoclast formation in bone marrow cultures; IL-10 also suppresses osteoblast differentiation suggesting a role for both cytokines in bone physiology. A tensile strain was applied to the cells intermittently for 6s, every 90s, for 2-96h. After 2-h culture, supernatants from deformed cells contained significantly less IL-10 than control cultures. In contrast, mechanical deformation had a stimulatory effect on IL-12 synthesis; however, by 48h both had returned to control levels. These data suggest that IL-10 and IL-12 can be added to the growing list of mechanical stress-responsive genes. The down-regulation of IL-10 and stimulation of IL-12 further suggests that the initial response of the cells to mechanical deformation was an osteogenic one.

Host pathogen interaction and the development of oral lesions.

The aetiologies of oral ulceration, disseminated interstitial lymphocytosis syndrome and oral lymphomas have been reviewed, with emphasis on the role of HIV infection in the primary causation or modification of the presentation of these entities. There is a paucity of evidence to explain why oral ulceration is so severe in HIV infection, and why major ulceration affects the oropharynx. A number of mechanisms have been proposed to account for the development of lymphomas in patients with HIV infection, including a genetic predisposition, decreased immunosurveillance due to HIV infection, alteration of endothelial cell function and dysregulation of cytokine networks. From this review, it was concluded that there is a need for a prospective multicentre study, to elucidate the aetiological mechanisms involved in lymphomas of the oral regions in this patient group. It was concluded that, although there is anecdotal evidence implicating tobacco use in the aetiology of the lesions reviewed, this is insufficient to allow definitive statements to be made and further systematic evaluation is indicated.

Intralesional vinblastine vs. 3% sodium tetradecyl sulfate for the treatment of oral Kaposi's sarcoma. A double blind, randomized clinical trial.

In this double-blind, randomized trial, we compared the clinical efficacy of intralesional vinblastine (VNB) and 3% sodium tetradecyl sulfate (STS) in the treatment of oral Kaposi's sarcoma (OKS). Subjects with OKS were randomly assigned to receive a single intralesional injection of either VNB or STS, at a standard dose (0.2 mg/cm(2)). Differences were evaluated by the Mann-Whitney U and Fisher's exact tests. Sixteen HIV-infected patients were included, eight received VNB and eight received STS; clinical response was evaluated at days 7, 14, and 28 following treatment. Tumor size reduction was 0.68 and 0.61 cm in the VNB and STS groups, respectively (P=0.80). Two VNB patients had complete or partial response whereas four STS subjects had partial responses (P=0.61). Patients in both groups experienced minimal toxicity. We conclude that intralesional vinblastine or STS are adequate for the management of OKS. The benefits of STS are its low cost and ease of use.