Fluorescent In Situ Hybridization Must be Preferred to pan-TRK Immunohistochemistry to Diagnose NTRK3-rearranged Gastrointestinal Stromal Tumors (GIST).

Tyrosine kinase inhibitors have revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Nevertheless, some GISTs do not contain any targetable KIT or PDGFRA mutations classically encountered in this field. Novel approved therapies targeting TRK chimeric proteins products of NTRK genes fusions consist in a promising approach to treat some patients with GISTs lacking any identified driver oncogenic mutation in KIT, PDGFRA or BRAF genes. Thus, an adequate testing strategy permitting to diagnose the rare NTRK-rearranged GISTs is required. In this work, we studied about the performances of pan-TRK immunohistochemistry (IHC) and NTRK1/2/3 fluorescent in situ hybridization in a series of 39 GISTs samples. Among 22 patients with GISTs lacking KIT or PDGFRA mutations, BRAFV600E IHC permitted to diagnose 2/22 (9%) BRAFV600E-mutated GISTs and, among the 20 KIT, PDGFRA, and BRAF wild type tumors, 1/20 (5%), NTRK3-rearranged tumor was diagnosed using NTRK3 fluorescent in situ hybridization. Pan-TRK IHC using EPR17341 and A7H6R clones was negative in this NTRK3-rearranged sample. Pan-TRK IHC was frequently positive in NTRK not rearranged tumors without (24 samples analyzed) or with (15 samples analyzed) KIT or PDGFRA mutations with major discrepancies between the 2 IHC clones (intraclass correlation coefficient of 0.3042). Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.

Estética en periodoncia: integrando la microcirugía plástica periodontal y las cerámicas adheridas / Esthetics in periodontics: integrating periodontal plastic surgery and bonded ceramics

La percepción hacia el alcance de la excelencia estética se traduce especialmente en saber interpretar y satisfacer los deseos del paciente, empleándose para eso, todos los conocimientos disponibles en la literatura científica. La utilización de carillas, coronas cerámicas o de Circonio pueden representar un tratamiento, predecible y confiable, cuando las condiciones, básicas de salud se encuentran ya resueltas. Una de estas condiciones, se refiere a un marco de salud Periodontal, con contornos gingivales estéticos y naturales. En algunos casos, donde esto no sucede, la microcirugía estética puede ser un recurso práctico y predecible. A su vez la evidencia científica nos ofrece parámetros para guiarnos y así alcanzar un correcto diagnóstico, planeamiento seguro, técnica adecuada y la utilización del material más indicado para cada situación clínica. La subjetividad estética puede estar escondida entre líneas en la ciencia. Con ésta recopilación acompañado con la ejemplificación de los casos clínicos desarrollados, intentaremos aproximarnos a la excelencia (AU)

Estética y color en dientes calcificados: Informe de tres casos clínicos con blanqueamiento / Esthetics and shade in calcified teeth. Report of three clinical cases with whitening

Objetivo: El objetivo de este informe es presentar tres casos clínicos de piezas dentarias anterosuperiores calcificadas y con decoloración, resueltos según tres protocolos clínicos de blanqueamiento diferentes, con un mismo fin: devolver la estética al sector anterior. Casos clínicos: Cada una de las tres situaciones clínicas de decoloración dentaria se trató siguiendo un protocolo diferente. A partir del análisis clínico y radiográfico, se estableció un diagnóstico y un plan de tratamiento acorde. Todos los casos evolucionaron de manera favorable y siguen siendo controlados periódicamente. Conclusiones: En casos clínicos como los que se muestran en este trabajo, en los que el conducto y la cámara pulpar están calcificados u obliterados totalmente, sería posible realizar blanqueamiento interno y externo para recuperar la armonía óptica de forma conservadora. Este tipo de tratamientos permitiría responder a la alta prevalencia de demanda estética debido a traumatismos y cambios de coloración (AU)

Aim: To present three clinical cases of discoloration in calcified upper anterior teeth, that were resolved following different clinical protocols for teeth whitening to return the aesthetics of the anterior teeth. Clinical cases: Each clinical case of discoloration was treated following a different treatment protocol based on a correct clinical and radiographic diagnosis. All cases had a favourable outcome and have no regular review. Conclusion: In clinical cases as those presented in this article where the canal and pulp chamber are totally calcified or obliterated, it was possible to perform internal and or external whitening to restore optical harmony in a conservative way. This type of treatment would allow responding to the high prevalence of aesthetic demand due to trauma and colour changes (AU)

Twice upon a time: The progression of canine visceral leishmaniasis in an Argentinean city.

Canine Visceral Leishmaniasis (CVL) prevalence, spatial distribution and associated factors were assessed in four locations in Iguazú department in 2014 and in Puerto Iguazú city again in 2018. The city areas were divided into a grid of 400x400m cells. All cells were sampled in 2014 and a random subsampling was developed in 2018. In each cell, five dogs clustered in a 'critical scenario' (prone to have vectors) were sampled. A rapid immunochromatographic dipstick was used to detect antibodies against Leishmania infantum, confirming by lymph node smears observation and PCR. For Puerto Iguazú, Generalized Linear Models (GLMs) were constructed considering environmental, dog and clinical variables. Pearson's Chi square and Fisher's exact tests were employed to evaluate the association between CVL, dog clinical signs and infestation with other parasites. Cartographic outputs were made and Moran's I indices were calculated as spatial autocorrelation indicators. CVL prevalence rates were 26.18% in 2014 and 17.50% in 2018. No associations were established in environmental models, but dog age and repellent use were significant when running 2014 dog models. Clinical models showed significant associations between seropositive dogs and ophthalmological, dermal signs and onychogryphosis in 2014. In 2018, only adenomegaly was associated. The results of global Moran´s I were not significant but regarding local analysis, six sites in 2014 and one in 2018 presented autocorrelation with neighboring sites. The decrease in CVL prevalence may be associated to transmission stabilization, which could explain the lack of associations with dog-related variables. Further, spatial distribution of CVL is a poor evidence for design of transmission control measures but could be important in case of intensive parasite circulation or when the first autochthonous cases appear. For control success, sensitivity of diagnostic methods, political will and adequate material resources remain critical. Modeling of multiple variables will be required to identify factors that drive disease stabilization/destabilization.

Assessment of major salivary gland size in primary Sjögren's syndrome: Comparison between clinical examination and ultrasonography.

OBJECTIVE: Parotidomegaly is a criterion of the EULAR Primary Sjögren Syndrome Disease Activity Index (ESSDAI). The cut-off value was set at 3 cm in length for the parotid gland, 2 cm for the submandibular glands. However, clinical appreciation of salivary glands size remains hazardous. The objective is to evaluate inter-observer reproducibility of parotid gland measurement by palpation, and to secondary evaluate its reliability compared to US assessment. METHODS: Outpatients with primary Sjögren Syndrome (pSS) or with a diagnostic suspicion, in a single reference centre, were included. They underwent clinical examination by two independent investigators (VDP and DC), evaluating: parotid gland swelling, parotid gland size (direct measurement with a decameter under the mandibular angle), and pain. Cohen's kappa coefficient was calculated to determine inter-observer concordance for parotid gland swelling, and intraclass correlation coefficient to determine inter-observer agreement of gland size measurement. RESULTS: Thirty-four patients (33 women, 1 man) were included. Clinical data were complete for 33 patients. Inter-observer concordance Kappa coefficient was 0.90 [0.76-1.00] for detection of parotidomegaly over 66 parotid glands. It was of 0.60 [0.42-0.73] for gland length measurement. For one observer, the median cut-off for defining parotidomegaly was 4.15 cm; for the second observer, it was of 4.92 cm. For submandibular glands palpation, no correlation was found between investigators. A significant association between clinical parotidomegaly and a larger echographic surface was found. CONCLUSION: Clinical measurement of parotidomegaly was concordant between two observers on a binary mode (presence/absence). However, concordance on direct measurement was weak. US could be a complementary examination.

Factors associated with hard tick (Acari: Ixodidae) parasitism in medium-sized mammals in the Atlantic Rainforest region of Argentina.

Associations with environmental and host parameters were assessed to describe tick parasitism patterns in two medium-sized mammals of the Atlantic rainforest region of Argentina. Ticks found on 93 specimens of Nasua nasua and 26 specimens of Didelphis aurita captured at six sites in the Iguazú National Park were collected. Generalized linear models were constructed to explain the presence and abundance of ticks and the most appropriate ones were selected after stepwise simplification. The season, site and host body mass variables were important to explain the abundance of Amblyomma coelebs nymphs, while site was important to describe larval abundance of this species. Season was the most important variable for larvae and nymphs of Haemaphysalis juxtakochi, while Amblyomma brasiliense nymphs were associated with host age. Amblyomma ovale larvae were related to host age, and adult ticks with host sex. The results indicate that these medium-sized mammals are important to support the immature tick stages and that both host and environmental factors may be associated with parasite loads.

Jaguar movement database: a GPS-based movement dataset of an apex predator in the Neotropics.

The field of movement ecology has rapidly grown during the last decade, with important advancements in tracking devices and analytical tools that have provided unprecedented insights into where, when, and why species move across a landscape. Although there has been an increasing emphasis on making animal movement data publicly available, there has also been a conspicuous dearth in the availability of such data on large carnivores. Globally, large predators are of conservation concern. However, due to their secretive behavior and low densities, obtaining movement data on apex predators is expensive and logistically challenging. Consequently, the relatively small sample sizes typical of large carnivore movement studies may limit insights into the ecology and behavior of these elusive predators. The aim of this initiative is to make available to the conservation-scientific community a dataset of 134,690 locations of jaguars (Panthera onca) collected from 117 individuals (54 males and 63 females) tracked by GPS technology. Individual jaguars were monitored in five different range countries representing a large portion of the species' distribution. This dataset may be used to answer a variety of ecological questions including but not limited to: improved models of connectivity from local to continental scales; the use of natural or human-modified landscapes by jaguars; movement behavior of jaguars in regions not represented in this dataset; intraspecific interactions; and predator-prey interactions. In making our dataset publicly available, we hope to motivate other research groups to do the same in the near future. Specifically, we aim to help inform a better understanding of jaguar movement ecology with applications towards effective decision making and maximizing long-term conservation efforts for this ecologically important species. There are no costs, copyright, or proprietary restrictions associated with this data set. When using this data set, please cite this article to recognize the effort involved in gathering and collating the data and the willingness of the authors to make it publicly available.

Comparison of 2002 AECG and 2016 ACR/EULAR classification criteria and added value of salivary gland ultrasonography in a patient cohort with suspected primary Sjögren's syndrome.

BACKGROUND: The objective was to evaluate concordance between 2002 American-European Consensus Group (AECG) and 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's syndrome (pSS) and to assess how salivary gland ultrasonography (SGUS) might improve the classification of patients. METHODS: Patients with suspected pSS underwent a standardised evaluation, including SGUS, at inclusion into the single-centre Brittany DIApSS cohort. Agreement between the two criteria sets was assessed using Cohen's κ coefficient. Characteristics of discordantly categorised patients were detailed. RESULTS: We prospectively included 290 patients between 2006 and 2016, among whom 125 (43%) met ACR/EULAR criteria and 114 (39%) also met AECG criteria; thus, 11 (4%) patients fulfilled only ACR/EULAR, no patients AECG only, and 165 (57%) patients neither criteria set. Concordance was excellent (κ = 0.92). Compared to patients fulfilling both criteria sets, the 11 patients fulfilling only ACR/EULAR criteria had similar age and symptom duration but lower frequencies of xerophthalmia and xerostomia (p < 0.01 for each) and salivary gland dysfunction (p < 0.01); most had systemic involvement (91%), including three (27%) with no sicca symptoms; 91% had abnormal salivary gland biopsy and 46% anti-Sjögren's-syndrome-related antigen A (anti-SSA); 64% were diagnosed with pSS by the physician. SGUS was abnormal in 12% of the 165 patients fulfilling no criteria set. Including SGUS among the ACR/EULAR criteria increased sensitivity from 87.4% to 91.1% when physician diagnosis was the reference standard. CONCLUSIONS: Agreement between AECG and ACR/EULAR criteria sets is excellent. ACR/EULAR criteria are slightly more sensitive and classified some patients without sicca symptoms as having pSS. Including SGUS in the ACR/EULAR criteria may further improve their sensitivity.

Manejo farmacológico del dolor en la odontología actual / Pharmacological management of pain in today´s dentistry

Una de las principales preocupaciones de los pacientes que van a ser sometidos a un procedimiento odontológico es el dolor que dicho procedimiento pueda ocasionar. Por lotanto, lograr un control eficaz y seguro de ese dolor es una parte esencial de la práctica odontológica diaria. Los fármacos de primera elección para el tratamiento del dolor y el edemason, sin lugar a dudas, los antiinflamatorios no esteroideos(AINEs). Principios activos como el ibuprofeno (y sus congéneres) o sus derivados permiten controlar simultáneamente el dolor y el edema posquirúrgicos de una forma eficaz y segura. En muchas ocasiones, el AINE prescrito para mantener al paciente asintomático o con síntomas tolerables es suficiente. Sin embargo, cuando esto no ocurre, debemos recurrir a otrosfármacos, o realizar asociaciones con fármacos que complementen el efecto analgésico y trabajen logrando un sinergismo de potenciación que incremente el efecto buscado y disminuya los efectos adversos de cada una de las sustancias por separado, utilizando menores dosis. Un ejemplo comprobado de esas asociaciones es la de ibuprofeno con paracetamol. En el presente artículo se sugieren diversas estrategias pre- y posoperatorias para el manejo del dolor de origen inflamatorio, y un protocolo para su tratamiento.

Echinococcus oligarthrus in the subtropical region of Argentina: First integration of morphological and molecular analyses determines two distinct populations.

Echinococcosis is a parasitic zoonosis that is considered as a neglected disease by the World Health Organization. The species Echinococcus oligarthrus is one of the causative agents of Neotropical echinococcosis, which is a poorly understood disease that requires a complex medical examination, may threaten human life, and is frequently associated with a low socioeconomic status. Morphological and genetic diversity in E. oligarthrus remains unknown. The aim of this work is to identify and characterize E. oligarthrus infections in sylvatic animals from the Upper Paraná Atlantic Forest in the province of Misiones, Argentina, by following an integrative approach that links morphological, genetic and ecological aspects. This study demonstrates, for the first time, one of the complete life cycles of E. oligarthrus in an important ecoregion. The Upper Paraná Atlantic Forest constitutes the largest remnant continuous forest of the Atlantic Forest, representing 7% of the world's biodiversity. This is the first molecular determination of E. oligarthrus in Argentina. In addition, the agouti (Dasyprocta azarae), the ocelot (Leopardus pardalis) and the puma (Puma concolor) were identified as sylvatic hosts of Neotropical echinococcosis caused by E. oligarthrus. Mitochondrial and nuclear molecular marker analyses showed a high genetic diversity in E. oligarthrus. Moreover, the genetic distance found among E. oligarthrus isolates is higher than the one observed among Echinococcus granulosus genotypes, which clearly indicates that there are at least two different E. oligarthrus populations in Argentina. This study provides valuable information to understand the underlying conditions that favour the maintenance of E. oligarthrus in sylvatic cycles and to evaluate its zoonotic significance for devising preventive measures for human and animal wellbeing.

Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome.

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

A biodiversity hotspot losing its top predator: The challenge of jaguar conservation in the Atlantic Forest of South America.

The jaguar is the top predator of the Atlantic Forest (AF), which is a highly threatened biodiversity hotspot that occurs in Brazil, Paraguay and Argentina. By combining data sets from 14 research groups across the region, we determine the population status of the jaguar and propose a spatial prioritization for conservation actions. About 85% of the jaguar's habitat in the AF has been lost and only 7% remains in good condition. Jaguars persist in around 2.8% of the region, and live in very low densities in most of the areas. The population of jaguars in the AF is probably lower than 300 individuals scattered in small sub-populations. We identified seven Jaguar Conservation Units (JCUs) and seven potential JCUs, and only three of these areas may have ≥50 individuals. A connectivity analysis shows that most of the JCUs are isolated. Habitat loss and fragmentation were the major causes for jaguar decline, but human induced mortality is the main threat for the remaining population. We classified areas according to their contribution to jaguar conservation and we recommend management actions for each of them. The methodology in this study could be used for conservation planning of other carnivore species.

High-Grade Salivary-Gland Involvement, Assessed by Histology or Ultrasonography, Is Associated with a Poor Response to a Single Rituximab Course in Primary Sjögren's Syndrome: Data from the TEARS Randomized Trial.

PURPOSE: To determine whether the severity of salivary-gland involvement, assessed using salivary gland ultrasonography [SGUS], histological focus score, or the unstimulated whole salivary flow [UWSF], was associated with the response to rituximab in patients with primary Sjögren's syndrome [pSS]. MATERIALS AND METHODS: Among the 120 patients with pSS enrolled in the randomised TEARS trial of rituximab versus placebo, 35 underwent either centralised minor salivary-gland biopsy or SGUS at inclusion. The echostructure of each parotid and submandibular gland was graded on a scale of 0 to 4. Histologic minor salivary gland involvement was assessed by the focus score. Among rituximab-treated patients with available data (n = 14), half met the Sjögren's Syndrome Responder Index [SSRI]-30 definition of a response at week 24. RESULTS: The SGUS score correlated positively to the focus score [r = 0.61] and negatively to the UWSF [r = -0.68]. The focus score was not correlated to the UWSF. The median total SGUS grade at inclusion was 9 [6-11] in responders versus 16 [11-16] in non-responders [p = 0.04]. The proportion of SSRI-30 responders was 0% among patients with SGUS grade 4 and 88% among those with SGUS grade ≤3. Low baseline SGUS scores were associated with sicca-related outcomes improvement, but not with fatigue or biological improvement. Median baseline focus score was 0.3 [0.0-1.3] in the responders versus 4.0 [2.7-5.3] in the non-responders [p = 0.02]. Baseline UWSF was not associated with the response rate. CONCLUSION: In patients with pSS, the highest SGUS grade or a high histological focus score is associated with absence of a response to a single rituximab course after 6 months. Further studies, including more patients and different treatment strategies, are required to confirm the clinical utility of these potential biomarkers in pSS.

B-cell and T-cell quantification in minor salivary glands in primary Sjögren's syndrome: development and validation of a pixel-based digital procedure.

BACKGROUND: Evaluating lymphocytic infiltration of minor salivary gland biopsy in primary Sjögren's syndrome is challenging. We developed and evaluated a digital method for quantifying B and T lymphocytes in whole minor salivary gland biopsy slides. METHODS: Minor salivary gland biopsies were immunostained with anti-CD20/anti-CD3 antibodies using red/brown chromogens. Slides were digitised and spliced into mosaics of smaller JPEG format images in which red and brown pixels were counted. ImageJ Cell counter was used for validation. Agreement between the digital and manual methods was evaluated using Bland-Altman plots and the interclass correlation coefficient. External validation relied on the Chisholm-Mason, Tarpley, and focus-score methods. RESULTS: Of 62 minor salivary gland biopsy slides, 61.3 % had a Chisholm-Mason grade ≥ III or a focus score ≥1. The number of pixels correlated well with manual cell counts (r = 0.95 for red pixels vs. B cell count and r = 0.91 for brown pixels vs. T cell count). Interclass correlation coefficients between digital and manual counts were excellent (0.92 for B/T cells). B-cell proportion showed a significant positive correlation with the focus score (Spearman's coefficient 0.463, p < 0.0001). Median B-cell proportion was lower in minor salivary gland biopsies with Chisholm grades I-II (2.5 % (0.2-13.9)) than III-IV (30.0 % (15.5-45.2)) and increased with Tarpley's class (1, 2.2 % (0.2-6.6); 2, 27.2 % (13.0-38.9); and 3-4, 48.5 % (29.4-56.4); p < 0.001 for all comparisons). Minor salivary gland biopsy B-cell proportion was also significantly correlated with several markers of clinical and biological activity of the disease, especially with markers of systemic B-cell hyperactivation. CONCLUSION: The digital procedure proved accurate compared to the reference standard, producing reliable results for whole tissue sections. TRIAL REGISTRATION: ClinicalTrials.gov [ NCT00740948 ]. Registered 22 August 2008.

Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp.

Melanomas associated with blue nevi (MABN) or mimicking cellular blue nevi (MMCBN) represent exceptional variants of malignant cutaneous melanocytic tumors. Uveal and leptomeningeal melanomas frequently have somatic mutations of GNAQ or GNA11, which are believed to be early driver mutations. In uveal melanomas, monosomy 3, linked to the BAP1 gene, is an adverse prognostic factor. We have studied the clinical, histologic, BAP1 expression profile, and molecular data of 11 cases of MABN/MMCBN and 24 cellular blue nevi. Most of the cases of MABN/MMCBN occurred on the scalps of adult patients and presented as rapidly growing nodules, typically >1 cm, often arising at the site of a preexisting melanocytic lesion. The MABN/MMCBN were composed of dense nests of large dermal atypical melanocytes, in some cases lying adjacent to a blue nevus. Four patients developed metastatic disease, and 2 died from their disease. A GNA11 mutation was found in 8/11 cases and a GNAQ mutation in 1 case. Seven of 11 cases showed loss of nuclear BAP1 immunohistochemical (IHC) expression in the malignant component, sparing the adjacent nevus. Array comparative genomic hybridization revealed recurrent deletions of chromosomes 1p, 3p, 4q, 6q, 8p, 16q, and 17q and recurrent gains of chromosomes 6p, 8q, and 21q. The 24 cases of cellular blue nevi frequently occurred on the sacrum, had GNAQ mutations, and showed normal positive IHC staining for BAP1. These results underscore overlapping features in all blue-like malignant melanocytic tumors. Loss of BAP1 IHC expression was restricted to melanomas, including all metastatic cases.