Expresión de las moléculas del Complejo Mayor de Histocompatibilidad clase II y moléculas co-estimuladoras en carcinomas orales in vitro

El descubrimiento de que el epitelio escamoso estratificado que cubre la mucosa oral podia expresar moleculas del Complejo Mayor de Histocompatibilidad clase II en varias condiciones patologicas de tipo inflamatorio abrio la posibilidad de que los queratinocitos orales sean celulas inmunologicamente activas, las cuales pueden funcionar con .celulas presentadoras de antigenos'ñ. Para una efectiva activacion de los linfocitos T, las celulas presentadoras de antigenos requieren, ademas de la expresion de moleculas del Complejo Mayor de Histocompatibilidad clase II, senales co-estimuladoras. El proposito del presente estudio fue determinar la expresion de moleculas del Complejo Mayor de Histocompatibilidad clase II y las moleculas co-estimuladoras CD40, CD80 y CD86 en queratinocitos bucales normales y derivados de carcinomas de celulas escamosas. Usando citometria de flujo en queratinocitos cultivados de mucosa oral sana y siete lineas celulares derivadas de carcinomas orales, fue confirmado que los queratinocitos expresan moleculas del Complejo Mayor de Histocompatibilidad clase II despues de estimulacion con IFN'Á in vitro. Todas las lineas celulares expresaron constitutivamente CD40, por el contrario, CD80 y CD86 universalmente fueron negativos. La ausencia de estas ultimas moleculas pudiera ser la causa por la cual los carcinomas orales escapan de la vigilancia inmunologica y pueden crecer, invadir y hacer metastasis pese al sistema inmunologico.Recognition in the 1980Es that keratinocytes can express class II molecules of the Major Histocompatibility Complex (MHC) first raised the possibility that these cells might have an immunological function, and may even act as antigen presenting cells (APC). For effective T lymphocyte activation, APC require, in addition to MHC II, appropriate costimulatory signals. The aim of this study was to determine the expression of MHC class II and the co-stimulatory molecules CD40, CD80 and CD86 in keratinocytes derived from healthy oral mucosa and oral carcinomas. Using flow cytometry, it was confirmed that oral keratinocytes .switch on'ñ expression of MHC class II molecules after stimulation with IFN'Á in vitro. All keratinocyte lines expressed CD40 constitutively; by contrast, CD80 and CD86 were universally absent. Loss of CD80 and CD86 may be one means whereby tumours escape immunological surveillance.

An international survey of speciality training in oral and maxillofacial pathology

BACKGROUND: Speciality training in oral and maxillofacial pathology (OMFP) across the world would be aided by guidance on a generic curriculum and training programme that all countries could use as a template. In order to facilitate this, we require an understanding of the various forms which OMFP training takes across the world. METHODS: We sent a questionnaire to OMF pathologists in the 42 countries represented in the IAOP membership, via their Regional Councillor. The questionnaire included detailed demographics, entry requirements, specialty training program and facilities/ resources. RESULTS: Replies were received from 22/42 countries (52%). OMFP is a dental/dental and medical speciality in 72%, and in 92% of those, this is recognised by a licensing board. Training was undertaken in an academic environment in 85% (with many offering a further academic qualification) and the median length of training was 4 years. General/anatomical pathology training is mandated in 85% of programs and a common core of general sub-specialities was identified. An end of training assessment was conducted in 80% of programs with most including written, practical and oral elements. Training program directors and educational supervisors were in place in 12/16 programs and, in most, Quality Assurance of training was externally monitored. In only one country was the number of trainees linked to workforce planning. CONCLUSIONS: Training in OMFP varies across the world. However, we feel there is sufficient commonality for the development of an agreed indicative framework on education and training in Oral and Maxillofacial Pathology, perhaps under the auspices of the IAOP.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1600-0714hb201

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor induced enterocolitis treated with infliximab

Introduction Immune Checkpoint Inhibitors (CPI) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. Methods We conducted a multi-centre (six cancer centres), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with CTCAE grade 0 for diarrhoea at 12 weeks after IFX initiation. We also assessed cancer outcomes at one year using RECIST criteria. Results 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhoea CTCAE grade >2 and 115 (90.6%) required hospitalisation for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistical regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04-0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13-8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared to patients with IFX-responsive enterocolitis (37.5%; p=0.013). Conclusion This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Utilizing pre-defined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI-therapy

New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours.

The latest (4th) edition of the World Health Organization Classification of Head and Neck tumours has recently been published with a number of significant changes across all tumour sites. In particular, there has been a major attempt to simplify classifications and to use defining criteria which can be used globally in all situations, avoiding wherever possible the use of complex molecular techniques which may not be affordable or widely available. This review summarises the changes in Chapter 8: Odontogenic and maxillofacial bone lesions. The most significant change is the re-introduction of the classification of the odontogenic cysts, restoring this books status as the only text which classifies and defines the full range of lesions of the odontogenic tissues. The consensus group considered carefully the terminology of lesions and were concerned to ensure that the names used properly reflected the best evidence regarding the true nature of specific entities. For this reason, this new edition restores the odontogenic keratocyst and calcifying odontogenic cyst to the classification of odontogenic cysts and rejects the previous terminology (keratocystic odontogenic tumour and calcifying cystic odontogenic tumour) which were intended to suggest that they are true neoplasms. New entities which have been introduced include the sclerosing odontogenic carcinoma and primordial odontogenic tumour. In addition, some previously poorly defined lesions have been removed, including the ameloblastic fibrodentinoma, ameloblastic fibro-odontoma, which are probably developing odontomas, and the odontoameloblastoma, which is not regarded as an entity. Finally, the terminology "cemento" has been restored to cemento-ossifying fibroma and cemento-osseous dysplasias, to properly reflect that they are of odontogenic origin and are found in the tooth-bearing areas of the jaws

Immunoexpression of HOXB7 and HOXB9 in salivary gland tumours

BACKGROUND : Salivary gland carcinomas are uncommon neoplasms and the identification of new prognostic indicators could improve their management. HOXB7 and HOXB9 are members of the class I homeobox-containing genes important for normal embryogenesis and that are dysregulated in several human neoplasms. This study investigated HOXB7 and HOXB9 expression in salivary gland tumourigenesis, they correlation with neoplastic proliferative and angiogenic features, and their importance as prognostic markers. METHODS : A hundred and fifty salivary gland tumours were organized in tissue microarray and expression of CD105, Ki67, HOXB7 and HOXB9 were determined through immunohistochemistry. Reactions were quantified and correlated with clinicopathological parameters. RESULTS : In normal glands HOXB7 was found in basal cells, whereas HOXB9 was seen in serous acinar and scattered ductal cells. Malignancies exhibited an increased vascular density, proliferative index, HOXB7 and HOXB9 expression when compared with pleomorphic adenoma and Warthin tumour. Significant correlation was found between HOXB7 and CD105 (p = 0.004) in adenoid cystic carcinomas, and HOXB7 higher expression significantly correlated with the presence of paresthesia (p = 0.02). No marker exhibited a significant association with survival rates (p > 0.05). CONCLUSION : HOXB7 and HOXB9 were expressed in normal salivary gland and were present in benign and malignant tumours derived from these structures, and HOXB7 significantly correlated with neoangiogenesis in AdCC. These findings suggest that both proteins might play a role in salivary gland tumourigenesis, but they were not significant prognostic determinants in this sample.Grants from the São Paulo State Research Foundation (Brazil), processes numbers 2009/53839-2, 2012/07519-9 and 2012/10781-7, and from the Brazilian Coordination of Higher Education (CAPES/PDSE 2892/13-8).http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1600-07142017-10-31hb2016Oral Pathology and Oral Biolog

Characterisation of DOG-1 expression in salivary gland tumours and comparison with myoepithelial markers

DOG1 is an established diagnostic marker for gastrointestinal stromal tumours (GIST), but has been reported in salivary gland tumours (SGT) as an acinar and intercalated duct marker. However, its specificity and distribution is not well established. The aim of this study was to evaluate the diagnostic utility of DOG-1 expression in SGT in addition to comparing it with myoepithelial markers. Normal salivary tissue and SGT (n = 184) were examined for expression of DOG1 and a range of myoepithelial markers. SGT included: acinic cell carcinoma (ACC, n = 15), secretory carcinoma (SC, n = 9), pleomorphic adenoma (PA, n = 49), carcinoma ex-PA (Ca ex-PA, n = 11), adenoid cystic carcinoma (AdCC, n = 20), polymorphous adenocarcinoma (PAC, n = 6), myoepithelioma (n = 6), myoepithelial carcinoma (MC, n = 2), basal cell adenoma (BCA, n = 14), canalicular adenoma (CA, n = 19), mucoepidermoid carcinoma (MEC, n = 11), oncocytoma (n = 2), adenocarcinoma NOS (AdNOS, n = 4), basal cell adenocarcinoma (BCAC, n = 2), salivary duct carcinoma (SDC, n = 3) and papillary cystadenocarcinoma (PCAC, n = 1). Normal acini and ACC (14/15) showed strong luminal DOG1 staining; SC were largely negative with only focal expression in 3/9 cases. Luminal staining was seen in PA (14/49), PAC (4/6), Ca ex-PA (4/11) and AdCC (6/20). 8/11 MEC showed luminal and/or mucous cell staining. No staining was seen in myoepithelioma, MC, CA, adNOS and BCAC. BCA showed strong staining of myoepithelial cells in some cases (5/14). Variable myoepithelial DOG1 staining was seen in PA, Ca ex PA, BCA, SDC and PCAC which was not as consistent as myoepithelial markers such as calponin, p63 and αSMA. Absence of DOG1 can differentiate ACC from SC, but staining is variable in PA, PLGA and Ca ex-PA. Myoepithelial staining in some tumours but not in normal gland suggests a wider distribution in SGT than originally envisaged

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Cysts of the Oral and Maxillofacial Regions

x. 228 hal.; 28 c