Frequency of BRAF V600E immunoexpression in ameloblastomas: a multi-institutional analysis of 86 cases in Latin America and comprehensive review of the literature.

BACKGROUND: The initiation of odontogenic tumorigenesis often involves the activation of the MAP-kinase pathway, with a pivotal role played by the BRAF V600E mutation. This study aimed to investigate the frequency of BRAF V600E immunoexpresion in ameloblastomas diagnosed in four Latin American centers and correlate this finding with the histological types and subtypes of the analyzed cases. MATERIAL AND METHODS: A total of 86 samples of ameloblastomas were examined for immunohistochemistry using anti-BRAF V600E antibody. The histopathological features of each case were analyzed. RESULTS:  Positivity for anti-BRAF V600E antibody was detected in 65/86 cases (75.6%). BRAF V600E was positive in 38/56 cases (67.9%) of conventional ameloblastomas and in 27/30 cases (90.0%) of unicystic ameloblastomas. A statistically significant difference in BRAF V600E positivity was observed when comparing unicystic ameloblastomas to conventional ameloblastomas (p=0.03). No statistically significant difference in BRAF V600E positivity was observed when comparing histological variants, both for conventional ameloblastomas and unicystic ameloblastomas. CONCLUSIONS: This study highlights a high frequency of BRAF V600E immunoreactivity in ameloblastomas among Latin American cases. The prevalence of the BRAF V600E immunoexpresion may suggest the feasibility of utilizing BRAF-targeted therapy for ameloblastomas with this mutation.

A systematic review and meta-analysis of human population studies on the association between exposure to toxic environmental chemicals and left ventricular dysfunction (LVD).

BACKGROUND: Exposure to environmental chemicals has been associated with an elevated risk of heart failure (HF). However, the impact on early markers of HF, such as left ventricular dysfunction (LVD), remains limited. OBJECTIVE: To establish a foundation of evidence regarding early HF markers and their association with environmental pollutants, a systematic review and meta-analysis was conducted. METHODS: The search, conducted on October 13th, 2023, encompassed PubMed, Embase, and Web of Science without filters, focusing on observational studies reporting myocardial geometrical, structural, or functional alterations in individuals without a history of heart disease. This included the general adult population, workers, young people, and the elderly. The risk of bias was assessed using the ROBINS-I tool at both study and item levels. RESULTS: The systematic review included 17 studies involving 43.358 individuals exposed to air pollution and 2038 exposed to heavy metals. Approximately 41% of the effect measures of associations reported significant abnormalities in myocardial structure or function. The metanalyses by pollutants categories indicated positive associations between LV systolic and diastolic abnormalities and exposure to PM2.5 [-0.069 (-0.104, -0.033); -0.044 (-0.062, -0.025)] and PM10 [-0.055 (-0.087, -0.022); -0.030 (-0.050, -0.010)] and NO2 [-0.042 (-0.071, -0.013); -0.021 (-0.037, -0.004)], as well as positive associations between lead exposure and LV systolic abnormalities [-0.033 (-0.051, -0.016)]. CONCLUSIONS: Existing evidence shows that specific early markers of HF may be associated with exposure to chemical pollutants. It is recommended to include such endpoints in new longitudinal and case-control studies to confirm further risk associations. These studies should consider co-exposures, account for vulnerable groups, and identify cardiotoxic compounds that may require regulation. When examining the link between myocardial abnormalities and environmental exposure, it is also advisable to explore the supportive use of Adverse Outcome Pathway (AOP) approaches to confirm a causal relationship.

The surgical challenge of carotid artery and Fallopian canal dehiscence in chronic ear disease: a pitfall for endoscopic approach.

OBJECTIVE: Endoscopic procedures are becoming common in middle ear surgery. Inflammation due to chronic ear disease can cause bony erosion of the carotid artery and Fallopian canals, making them more vulnerable during surgery. The objective of this study was to determine whether or not chronic ear disease increases dehiscence of the carotid artery and Fallopian canals. DESIGN: Comparative human temporal bone study. SETTING: Otopathology laboratory. PARTICIPANTS: We selected 78 temporal bones from 55 deceased donors with chronic otitis media or cholesteatoma and then compared those two groups with a control group of 27 temporal bones from 19 deceased donors with no middle ear disease. MAIN OUTCOME MEASURES: We analysed the middle ear, carotid artery canal and Fallopian canal, looking for signs of dehiscence of its bony coverage, using light microscopy. RESULTS: We found an increased incidence in dehiscence of the carotid artery and Fallopian canals in temporal bones with chronic middle ear disease. The size of the carotid artery canal dehiscence was larger in the middle ear-diseased groups, and its bony coverage, when present, was also thinner compared to the control group. Dehiscence of the carotid artery canal was more frequently located closer to the promontory. The incidence of Fallopian canal dehiscence was significantly higher in temporal bones from donors older than 18 years with chronic middle ear disease. CONCLUSION: The increased incidence of the carotid artery and Fallopian canal dehiscence in temporal bones with chronic middle ear disease elevates the risk of adverse events during middle ear surgery.

Results of a round-robin exercise on read-across.

A round-robin exercise was conducted within the CALEIDOS LIFE project. The participants were invited to assess the hazard posed by a substance, applying in silico methods and read-across approaches. The exercise was based on three endpoints: mutagenicity, bioconcentration factor and fish acute toxicity. Nine chemicals were assigned for each endpoint and the participants were invited to complete a specific questionnaire communicating their conclusions. The interesting aspect of this exercise is the justification behind the answers more than the final prediction in itself. Which tools were used? How did the approach selected affect the final answer?

Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring.

The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies.

Reactive lesions of peri-implant mucosa associated with titanium dental implants: a report of 2 cases.

The aim of this study was to report 2 novel clinical cases of reactive lesions of the peri-implant mucosa associated with titanium dental implants where metal-like particles were observed histologically. In both cases, the lesions were diagnosed as epulis, based on clinical evidence. Extirpation biopsies were carried out. Case 1 was diagnosed as pyogenic granuloma and case 2 as peripheral giant cell granuloma. The presence of metal-like particles in the tissues suggests that the etiology of the lesions might be related to the corrosion process of the metal structure. This is the first case of pyogenic granuloma to be reported in association with dental implants. All clinical cases of soft tissue lesions associated with implants should be reported to contribute to the understanding of the etiology and pathogeny of these lesions.

Granuloma gigantocelular central del maxilar inferior: Presentación de un caso pediátrico / Giant cell granuloma of the lower jaw: Description of a pediatric case

El granuloma gigantocelular central (GGCC), es una lesión tumoral o seudotumoral, infrecuente de los huesos de la cabeza y cuello, que afecta más frecuentemente los maxilares. Su etiología y patogenia son poco conocidas, sus características histológicas son benignas y su comportamiento biológico puede ser agresivo localmente. Presentamos el caso de un niño de 6 años con esta afección y realizamos una revisión de la entidad y sus diagnósticos diferenciales con otras lesiones de los maxilares.

Giant Cell Granuloma (GCG) is an uncommon condition affecting the bones of the head and neck. The ethiology and pathophysiology are not completely understood. The histlogic characteristics of GCG are benign, but its biologic behavior could locally aggressive. We describe the case of a 6 year-old boy with GCG and performed a review of the entity ant their differential diagnosis with other lesions of the maxillary bones.

The effects of solvents on embryonic stem cell differentiation.

Dimethyl sulfoxide (DMSO) and ethanol are common organic solvents used for dissolving lipophilic substances for in vitro testing. However, DMSO is known to induce differentiation in embryonic stem (ES) and embryonic teratocarcinoma (EC) cells. In order to clarify if solvents like DMSO and ethanol have an influence on in vitro developmental toxicity test systems, the presented study has evaluated their effects on differentiation by using different test systems. ES and EC cells were transfected with a construct containing the mTert promoter combined with the green fluorescent protein gene (GFP). A down-regulation of mTert, a marker for undifferentiated cells, results in a lower expression of GFP, which could be measured by flow cytometry. Taking the specific characteristics of ES and EC cells into account this effect could be a hint for the interaction of DMSO with embryonic development. Additionally, the effects of the solvents ethanol and DMSO on Oct-4 expression, another marker for undifferentiated cells, were measured in wild-type ES cells. Both selected molecular markers demonstrated an induction of differentiation after exposure to DMSO; in wild-type ES cells at a concentration of 0.125% and in transgenic EC cells at a concentration of 0.25% DMSO. All other differences from controls, including those which attained a level of statistical significance, were minor or not dosage related in degree, or were not consistent over time and are, therefore, considered to be of little toxicological importance. In addition, a cytotoxicity test demonstrated that the solvents affected the employed molecular markers in non-cytotoxic concentrations. The ES cells were the most sensitive towards the cytotoxic effects of the solvent DMSO while the EC cells were more sensitive when treated with the solvent ethanol.

The use of quantitative image analysis in the assessment of in vitro embryotoxicity endpoints based on a novel embryonic stem cell clone with endoderm-related GFP expression.

The capacity of pluripotent embryonic stem cells (ESC) to differentiate in vitro into various tissues provides the opportunity to develop an in vitro assay for investigating mechanisms of developmental toxicity. ESC clones carrying tissue specific reporter gene constructs are currently being developed. The clones should allow the quantification of the effects of chemicals on the development of germ layers and main target tissues. We report the establishment of the alpha-fetoprotein_GFP/D3 reporter gene clone: alpha-fetoprotein (AFP) enhancers and the homologous promoter regulate green fluorescent protein (GFP) expression in cells of the D3-ESC clone. AFP was used as a marker for endodermal cells. Differentiation of this clone via embryoid bodies (EBs, spheroids of cells) leads to green fluorescence on the surfaces of EBs. AFP- related GFP expression was confirmed. An easy and quick image analysis-based endpoint measurement was developed for quantifying low amounts of cells expressing GFP. As demonstrated with the embryotoxic chemical diphenylhydantoin, image analysis can be used to distinguish between a general effect on EB growth and a specific effect on the development of GFP-positive endodermal cells. Endoderm development was inhibited at a different dose than cardiomyocyte development.

Pattern changes of mucin gene expression with pneumococcal otitis media.

OBJECTIVE: mucins, known to be important components of the mucociliary transport system in the middle ear and Eustachian tube, are subject to changes under inflammatory conditions. Which mucin genes are up-regulated or activated during an inflammatory reaction of the middle ear and Eustachian tube, however, is poorly understood. The purpose of this study was to characterize mucin gene expression in middle ears and Eustachian tubes with pneumococcal ear infection. METHODS: sixteen rats received intrabullar inoculation of Streptococcus pneumoniae type 6A at 2.5x10(6) colony forming units (CFU). Four animals were sacrificed on days 1, 3, 7, and 14, respectively. The profile of mucin gene expression in the middle ear and Eustachian tube was examined by reverse transcription polymerase chain reaction (RT-PCR) at the above time points. Sixteen rats that received intrabullar inoculation of phosphate-buffered saline (PBS) served as controls. RESULTS: the Muc2 mucin gene was expressed in middle ear mucosa of the control rats. Following pneumococcal inoculation, Muc1-Muc5 mucin genes were expressed in the middle ear mucosa in a time-dependent manner. In the Eustachian tube, the Muc2, Muc4 and Muc5 mucin genes were expressed in both control and pneumococcal inoculation groups. CONCLUSION: Muc1, Muc3, Muc4, and Muc5 mucin genes were activated in the middle ear mucosa by pneumococci, which may contribute to hyper-production of mucin in acute pneumococcal otitis media.

Stapes mobilization in otosclerosis.

We performed a retrospective chart study (including surgeon's notes and audiometric results) and an analysis of the archival temporal bones from a patient who had undergone surgery for stapes mobilization in both ears. The stapes footplate was submerged into the vestibule on the right (as a complication of surgery) and absent on the left. One interesting finding was that the patient's hearing had improved on the right despite the presence of the depressed footplate and that the air-bone gap had widened on the left despite the absence of complications on that side.

Characterization of mucins in human middle ear and Eustachian tube.

Mucins are important glycoproteins in the mucociliary transport system of the middle ear and Eustachian tube. Little is known about mucin expression within this system under physiological and pathological conditions. This study demonstrated the expression of MUC5B, MUC5AC, MUC4, and MUC1 in the human Eustachian tube, whereas only MUC5B mucin expression was demonstrated in noninflamed middle ears. MUC5B and MUC4 mucin genes were upregulated 4.2- and 6-fold, respectively, in middle ears with chronic otitis media (COM) or mucoid otitis media (MOM). This upregulation of mucin genes was accompanied by an increase of MUC5B- and MUC4-producing cells in the middle ear mucosa. Electron microscopy of the secretions from COM and MOM showed the presence of chainlike polymeric mucin. These data indicate that the epithelium of the middle ear and Eustachian tube expresses distinct mucin profiles and that MUC5B and MUC4 mucins are highly produced and secreted in the diseased middle ear. These mucins may form thick mucous effusion in the middle ear cavity and compromise the function of the middle ear.

Establishment of an in vitro reporter gene assay for developmental cardiac toxicity.

This study is based on the unique potential of pluripotent embryonic stem (ES) cells to differentiate in vitro into embryoid bodies containing cell lineages representative of most cell types found in the mammalian fetus. However, the use of wild type ES cells as an in vitro assay for embryotoxicological studies is complicated by the simultaneous development of various cellular phenotypes. This prevents a quantitative assessment of drug effects on one specific cell type. Here we report the effects of 15 chemicals on cardiac differentiation as determined by various specific toxicological endpoints such as morphological inspection (contractile activity), quantitative mRNA analysis and cardiac-specific expression of green fluorescent protein (GFP), used as a quantitative reporter. The data from the different endpoints have been subjected to a statistical analysis, and a preliminary prediction model is proposed. The results demonstrate that genetically-engineered ES cells could provide a valuable tool for estimating the developmental cardiotoxic potential of compounds in vitro and form the basis for automated analysis in a high-throughput system.

Tympanic membrane and middle ear pathologic correlates in mucoid otitis media.

OBJECTIVE: The goal of this study was to correlate tympanic membrane (TM) and middle ear (ME) pathologies in mucoid otitis media (MOM). METHODS AND MATERIAL: Forty ears with MOM and 56 control ears were retrospectively evaluated for TM and ME pathologies. Comparisons of TM thicknesses in MOM versus control ears were correlated with the Student t test; chi(2) analysis was used to correlate pathologic findings of the TM and ME. RESULTS: Thicknesses in all quadrants except the umbo were increased in MOM because of infiltration of inflammatory cells and fibrosis. The most common ME pathologies were granulation tissue and fibrosis. Significant correlations included (1) TM retraction and ME granulation tissue and fibrosis and (2) pars flaccida, posterosuperior, and anteroinferior thickness and ME granulation tissue and fibrosis. CONCLUSION: TM changes are likely to occur in patients with otitis media with effusion (MOM), and their presence is a strong indication of underlying ME pathology.

Petrous high jugular bulb: a histological study.

PURPOSE: A high jugular bulb (JB) is thought to affect structures of the inner ear and possibly cause symptoms there, but clear histological findings of an anatomical relationship between a high JB and the inner ear have not yet been described. MATERIALS AND METHODS: We surveyed horizontal sections of 1,591 temporal bones from the collection of the Otopathology Laboratory at the University of Minnesota in Minneapolis, Minnesota, defining a high JB as a JB extending above the inferior margin of the basal cochlear turn. RESULTS: In 65 specimens (16%), we found a high JB with its vascular wall obviously thinner than that of a low JB. Bony resorption was occasionally observed around high JBs. Sixteen specimens showed a bony deshiscence between the JB and the endolymphatic sac. Clinical charts showed no obvious symptoms associated with a high JB. CONCLUSIONS: Our findings suggest that the JB may have potential to expand upward postnatally. Although our study confirmed occasional bony dehiscence between the JB and the endolymphatic sac, JBs with this involvement may have only a minor effect on function in the inner ear.

Glandular odontogenic cyst. A retrospective clinical, radiographic and histological study / Quiste odontogénico glandular. Estudio retrospectivo clínico-radiográfico e histológico

El quiste odontogénico glandular (QOG) foe recientemente descrito en base a un escaso número de casos. El propósito del presente trabajo fue tratar de ampliar su caracterización, analizando una serie do casos reunidos en un único Centro Diagnóstico. Para ello se realizó una búsqueda retrospectiva en el Laboratorio de Patología Quirúrgica, Cátedra de Anatomía Patológica, Facultad de Odontología Universidad de Buenos Aires, durante el período 1975-1998. Se revisaron todos los casos correspondientes a quistes odontogénicos embrionarios, seleccionando aquellos sin diagnóstico histopatológico definido y los carcinomas mucoepidermoides centrales. Los mismos se estudiaron microscópicamente y se separaron 10 casos quo reunían Ins caracterfsticas histológicas descritas par la OMS para los QOG. Se analizaron los datos clínicos de sexo, edad, localización, imagen radiográfica, diagnóstico clínico, tratamiento presuntivo y evolución. Esta serie mostró datos equivalentes a los previamente comunicados en alguno de los parámetros analizados, y una marcada diferencia en la distribución por sexos e imágenes radiográficas (AU)

Identification of MUC5B mucin gene in human middle ear with chronic otitis media.

OBJECTIVES: To identify the mucin gene and its expressing cells in the middle ear mucosa with chronic otitis media (COM), and to study the correlation between infiltration of inflammatory cells in the submucosa and expression of the mucin gene in the mucosal epithelium with COM. STUDY DESIGN: Middle ear mucosal specimens removed from the inferior promontory area of 19 patients undergoing middle ear surgery for COM were studied. METHODS: Sections were stained with H&E, Alcian blue-periodic acid Schiff (AB-PAS), polyclonal MUC5B antibody, and specific MUC5B riboprobe for histological, histochemical, immunohistochemical, and mucin mRNA analyses. RESULTS: H&E staining revealed pseudostratified epithelia in 18 of the middle ear specimens with COM and cuboidal secretory epithelia in one. AB-PAS staining of epithelia revealed abundant secretory cells and their products (glycoconjugates). In situ hybridization and immunohistochemistry studies demonstrated that the secretory cells of the middle ear mucosa with COM expressed MUC5B mucin mRNA and its product MUC5B mucin. CONCLUSIONS: The MUC5B mucin gene and its product were identified in the middle ear secretory cells of patients with COM. Its expression was extensive in pseudostratified mucosal epithelia and related to infiltration of inflammatory cells in the submucosa of the middle ear cleft with COM, suggestive that inflammatory cell products are involved in the production of MUC5B.

Facial neuroma in the internal auditory canal.

Authors presented two cases of facial neuromas in the internal auditory canal, one without facial palsy and the other with facial palsy. In both cases neuromas were occult and undiagnosed. Although in the first case neuroma was greater than the other, facial palsy was not developed. The mechanism of the facial palsy due to neuromas could not be clearly clarified.

Metastases to temporal bones from primary nonsystemic malignant neoplasms.

OBJECTIVES: To compare histopathological and clinical findings of metastasis to the temporal bone with previous reports and to determine the prevalence of these metastases in patients with nonsystemic cancer. STUDY DESIGN: Retrospective. METHODS: Autopsy records of 864 patients were screened to select those with primary nondisseminated malignant neoplasms. These were evaluated histopathologically for metastasis to and site of involvement within the temporal bone, and histological characteristics of the tumor. Clinical records and autopsy reports were reviewed for demographic data, clinical course, otologic and vestibular manifestations, site of primary and its histological features, extent of metastasis, and mode of spread. RESULTS: Of 212 patients with primary nondisseminated malignant neoplasms, 47 had metastases to the temporal bone (76 temporal bones). Twenty different primary tumors had metastasized, most commonly breast cancer. Hearing loss was the most common otologic symptom (seen in 19 patients [40%]), while 17 (36%) had no otologic or vestibular symptoms. Temporal bone involvement was bilateral in 29 patients (62%). Most metastases to the temporal bone demonstrated hematogenous spread in 58 temporal bones (76.7%), and petrous apex was the most common site of metastases in 63 temporal bones (82.9%). Temporal bone metastases were not observed in cases where the primary tumor was adequately treated. CONCLUSIONS: In the largest series to date, we found temporal bone metastases more frequently than previously reported. Absence of temporal bone involvement in cases in which the primary tumor was adequately treated stresses the need for early management of cancer. Metastatic disease must be considered as a cause of hearing loss in patients with a history of malignant neoplasm.