Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America.

Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.

Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

Epigenome-Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH AND RESULTS: To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine-guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. CONCLUSIONS: Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.

Periodontally Accelerated Osteogenic Orthodontics (PAOO) technique in cleft patients: A complement to orthognathic surgery in dentoalveolar expansion. A case series report.

The aim of this study was to describe a surgical technique that can be used to solve dentofacial deformities in cleft palate patients with maxillary hypoplasia in order to increase maxillary alveolar bone width, without modifying the skeletal base, and therefore, keeping the velopharyngeal function unaltered. Four patients with a history of cleft palate not associated with syndrome and treated under conventional surgical protocol during their childhood, underwent PAOO surgery incorporating L-PRF, followed by an accelerated orthodontic treatment with checkups every two weeks. All patients reached the desired occlusion without modifying their skeletal bases and velopharyngeal function. Orthodontic treatments were finished between 10 and 14 months after surgery without complications. There were no observed complications in the velopharyngeal postsurgical function and an increase in the arch width was achieved in all cases, along with a reduced orthodontic treatment time. The clinical results obtained confirm that PAOO technique is a safe and reliable complement to orthognathic surgery in the surgical treatment of cleft patients. By increasing the perimeter of the maxillary dentoalveolar ridge, the segmentation of the maxilla could be avoided, increasing the post operatory stability of these patients.

ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans.

BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.

[Laugier-Hunziker syndrome in a patient with Sjögren’s syndrome: Report of one case]. / Posible asociación autoinmune entre síndrome de Laugier-Hunziker y síndrome de Sjögren: reporte de un caso y revisión de la literatura.

Laugier-Hunziker syndrome is a rare benign idiopathic condition characterized by acquired macular pigmentation of lips and buccal mucosa, often accompanied with melanonychia. The main concern with this condition is to rule out other differential diagnosis with systemic repercussions and similar hyperpigmentation patterns, such as Peutz-Jeghers syndrome, adrenal insufficiency and melanoma. We report a 58-year-old female with a 20-year history of Sjögren’s syndrome, presenting with melanonychia and hyperpigmentation in the buccal mucosa. She had no relevant medication history and is a non-smoker. The patient denied any other symptoms. The histopathology confirmed the diagnosis of Laugier-Hunziker syndrome.

Posible asociación autoinmune entre síndrome de Laugier-Hunziker y síndrome de Sjögren: reporte de un caso y revisión de la literatura / Laugier-Hunziker syndrome in a patient with Sjögren’s syndrome: report of one case

Laugier-Hunziker syndrome is a rare benign idiopathic condition characterized by acquired macular pigmentation of lips and buccal mucosa, often accompanied with melanonychia. The main concern with this condition is to rule out other differential diagnosis with systemic repercussions and similar hyperpigmentation patterns, such as Peutz-Jeghers syndrome, adrenal insufficiency and melanoma. We report a 58-year-old female with a 20-year history of Sjögren’s syndrome, presenting with melanonychia and hyperpigmentation in the buccal mucosa. She had no relevant medication history and is a non-smoker. The patient denied any other symptoms. The histopathology confirmed the diagnosis of Laugier-Hunziker syndrome.

Estimación del valor promedio del indicador COPD. Chile, 2012 / Estimated average value of the copd indicator COPD. Chile, 2012

Objetivo: Determinar el valor promedio nacional del indicador COPD en los Servicios de Odontología de una red de salud nacional y privada en Chile en 2012. Métodos: La población estudiada alcanzó a nivel nacional los 648235 casos y la muestra seleccionada fue de 16421 individuos. El único criterio de exclusión fue la condición de registro electrónico (ficha clínica) incompleto para las variables estudiadas. Los datos fueron registrados en una matriz excel ad doc, y de manera codificada, resguardando con ello el secreto estadístico y los derechos de los pacientes. Los datos se presentaron en rangos de edad, según los criterios aplicados en Chile por el Ministerio de Salud. La valoración del indicador COPD se realizó con base en clasificación de la Organización Mundial de la Salud. Los estadígrafos aplicados fueron de tendencia central y dispersión. La asociación entre las variables estudiadas y el COPD se estimó mediante las pruebas de Chi-cuadrado de Pearson. En todos los casos se empleó un nivel de significancia de α≤0,05. Resultados: El valor promedio nacional fue 3,76 (moderado). Se encontró asociación significativa entre COPD y las variables edad, sexo femenino y diagnóstico curativo.

Objective: To determine the national average value of the COPD indicator in dentistry services of a private national health network in Chile, 2012. Methods: The study population reached 648,235 cases, with a selected sample of 16,421 individuals. Exclusion criteria were the incomplete electronic records (medical records)for the variables studied. Data were recorded in an Excel matrix, and are encrypted, thus protecting the statistical confidentiality and patients’ rights. The data were presented in age ranges, according to the criteria applied in Chile by the Ministry of Health. COPD indicator assessment was made based on classification of the World Health Organization. Statistical graphics applied were central tendency and dispersion. The association between the study variables and COPD, was estimated using the Pearson´s Chi-square test. In all cases we used a significance level of alpha <_ 0.05. Results: The national average was 3.76 (moderate). Significant association was found between COPD and the variables age, female gender and healing diagnosis.

Actividad científica: un desafío para Chile / Scientific participation: a challenge for Chile

La participación científica de Chile en el período de análisis ha descendido respecto a Latinoamérica (4,22 por ciento); las ciencias biológicas y médicas concentran más de la mitad de las publicaciones ISI. El gasto promedio en investigación y desarrollo como porcentaje del PIB fue de 0.57 por ciento siendo el Estado la principal fuente de financiamiento (58 por ciento). Los investigadores, magíster y doctores, se incrementaron en un 39 por ciento, localizándose preferentemente en las universidades y en las especialidades de ciencias naturales y matemáticas (76,2 por ciento). Los índices promedio de producción científica y de eficiencia científica fueron 0,22 y 4,32 respectivamente. Las Ciencias de la Salud graduaron a 640 profesionales, lo que corresponde al 8,06 nacional, quienes alcanzaron, preferentemente, el grado académico de Magíster (96,25 por ciento).

Scientific participation of Chile in the period of time analyzes has decreased in relation to Latin America (4,22 percent), biological and medical sciences concentrate more than a half of publications ISI. The average expenditure in research and development as a percentage of GDP was 0,57 percent, being the State the main financing source (58 percent). Researchers, masters and PhD, increased a 39 percent, being located mainly at universities and in the specialties of natural and mathematical sciences (76,2 percent). The average indexes of scientific production and efficiency were 0,22 and 4,32, each. Health Sciences graduated 640 professionals, corresponding to 8,06 percent at a national level, which achieved, mainly, the academic degree of Master (96,25 percent).

Caracterización de los reclamos del sector salud recibidos en el servicio nacional del consumidor: Chile, enero de 2004-marzo de 2005 / Characterization of the health field complains received in the Servicio Nacional del Consumidor (Consumer National Service): Chile, January of 2004-March of 2005

El presente estudio buscar responder a la necesidad de información acerca de la situación actual de los reclamos del sector salud, considerando las características de los usuarios y principalmente, las del reclamo. Debido a esto, en conjunto con el Servicio Nacional del Consumidor, se ha tomado su población de reclamos, a nivel nacional, para realizar un estudio descriptivo, transversal y retrospectivo con el objetivo de caracterizar a los reclamos según género, zona geográfica de procedencia, lugar de atención, sector de salud, categoría de reclamo, categoría de la solicitud y resultado obtenido por el usuario. Como conclusión del estudio se observó que, a nivel nacional: entre el primer trimestre de 2004 e igual trimestre de 2005, el número de reclamos aumentó al doble; el mayor porcentaje de reclamos fue presentado por mujeres; la mayoría d reclamos proviene del sector privado; el área económico-administrativa concentró el mayor número de reclamos, tanto en el sector público como en el privado; la solicitud más frecuente fue la devolución de dinero, tanto en el área económico-administrativa como en la categoría mala prestación; la mayoría de los reclamos resultó desfavorable al consumidor; situación que se observó en todas las categorías de reclamo y en ambos sectores de salud. A nivel regional, la RM presentó el mayor porcentaje y la mayor tasa de reclamos. A nivel comunal, Las Condes y Santiago concentraron los mayores porcentajes de reclamos, la mayor tasa de reclamos correspondió a Providencia.

Antecedentes epidemiológicos y demográficos: escolares chilenos entre 6-14 años / Epidemiological and demographic background: chilean students between 6-14 years

Entre 1992 y 2002 Chile cambió. Las variables epidemiológicas y demográficas más significativas que afecta a la población escolar entre 6-14 años, son analizados desde la salud pública en forma sistémica y relacionadas con los procesos salud-enfermedad. Las variables revisadas son familia, pertenencia asociativa, uso del tiempo libre, antecedentes demográficos, antecedentes epidemiológicos, discapacidad y maltrato infantil. El artículo propone potenciar el rol del kinesiólogo en educación, así como de los educadores del nivel básico en promoción de salud para construir una sociedad más saludable, siendo la actividad física una herramienta poderosa de inclusión, participación, tolerancia y de intervención eficiente y directa sobre los escolares chilenos.