Actualización sobre la biología molecular de los gliomas: hacia una clasificación patomolecular de los gliomas

To review the current state of the classification and oncogenesis of gliomas, emphasizing those biologic parameters with special clinical significance. DEVELOPMENT: In the current classification, both histologic grade and phenotype are considered the pathological features with more relevant clinical impact. These factors are an obligatory reference for both all molecular studies and a new classification. The relationship between the oligodendroglial phenotype and the loss of chromosomes 1p and 19q is a useful data in the histopathologic differential diagnosis. The new pathologic-molecular classification should take into account the current state of knowledge about the malignization pathways of gliomas, which have prognostic significance. The neoplastic biological potential should be determined in each case according with the tumoral heterogeneity. Then, this evaluation can be based on tumoral microdissection. Although no well established prognostic molecular profiles are available, several molecular alterations are relevant such as chromosome 10 deletion, especially of the 10q23 region, mutation of PTEN and TP53 genes and amplification or mutation of EGFR. For treatment purposes, the combined deletion 1p/19q identifies the anaplastic type of oligodendrogliomas that are more responsive to chemotherapy. CONCLUSIONS: The new pathomolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification has clinical applicability and can integrate new molecular findings with some known histological features with prognostic value

Regeneración de la superficie ocular: stem cells/células madre y técnicas reconstructivas Regeneration of the ocular

La córnea es un tejido transparente constituido microscópicamente por 5 capas bien diferenciadas. El epitelio corneal es esencial para la transparencia corneal y se encuentra en continua renovación a lo largo de la vida a partir de la población de células madre limbocorneales. La localización de estas células madre limbocorneales parece residir en las capas basales del epitelio limbocorneal, de vital importancia para mantener el microambiente de estas células madre limbocorneales, que depende de una variedad de factores intrínsecos y extrínsecos. La insuficiencia límbica se produce cuando ocurre una pérdida parcial o total de estas células madre limbocorneales. Este cuadro lleva a una opacificación corneal con la consiguiente pérdida de visión. En estos casos, el trasplante corneal supone únicamente un reemplazo temporal del epitelio corneal; es necesario llevar a cabo un tratamiento previo con trasplante de limbo autólogo o alogénico, que permita regenerar la población de células limbocorneales dañadas. Para disminuir el riesgo que supone el trasplante de limbo en el ojo donante, se han propuesto técnicas de cultivo de células limbocorneales a partir de pequeñas biopsias limbocorneales

Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model

Background: TGF-β has been described as a mediator of fibrosis and scarring. Several studies achieved reduction in experimental scarring through the inhibition of TGF-β. Fibroblasts have been defined as the cell population originating fibrosis, blocking fibroblast invasion may impair epidural fibrosis appearance. For this purpose, biocompatible materials used as mechanical barriers and a TGF-β inhibitor peptide were evaluated in the reduction of epidural fibrosis. Methods: A L6 laminectomy was performed in 40 New Zealand white rabbits. Divided into four groups, each rabbit was assigned to receive either collagen sponge scaffold (CS group), gelatin-based gel (GCP group), P144® (iTGFβ group), or left untreated (control group). Four weeks after surgery, cell density, collagen content, and new bone formation of the scar area were determined by histomorphometry. Two experienced pathologists scored dura mater adhesion, scar density, and inflammatory infiltrate in a blinded manner. Results: In all groups, laminectomy site was filled with fibrous tissue and the dura mater presented adhesions. Only GCP group presented a significant reduction in collagen content and scar density. Conclusion: GCP treatment reduces epidural fibrosis although did not prevent dura mater adhesion completely

Structure and metamorphism of the La Modesta Formation in the El Tranquilo ranch (Santa Cruz), Patagonia

En este trabajo se exponen los resultados de un relevamiento de las metamorfitas del Paleozoico inferior correspondientes a la Formación La Modesta en la estancia El Tranquilo (Santa Cruz). Estudios estructurales, petrográficos y geoquímicos realizados en esta unidad indican que se trata de esquistos psamíticos y pelíticos cuarzo - muscovítico - cloríticos, que contienen biotita y que poseen evidencias de metamorfismo regional asociado a dos eventos deformacionales. Se ha reconocido al protolito como una sucesión sedimentaria marina homogénea pelítica a psamo-pelítica, que fue sometida a una temperatura menor a 550° y a una presión que osciló entre 2 y 4 Kb, alcanzando un bajo grado metamórfico en facies esquistos verdes (grados biotita-granate). Se determinó una esquistosidad S1 regional que es subparalela a las superficies de sedimentación S0. La S1 ha sido afectada por un segundo episodio de deformación, generando una S2/L2 no penetrativa. Estas rocas se diferenciaron de las metamorfitas del área tipo de la Formación La Modesta por sus protolitos de ambiente más profundo y porque el segundo episodio deformacional es más evidente en esta área. Asimismo, esta formación se ha correlacionado con metasedimentitas que se ubican al oeste y sus protolitos sedimentarios podrían integrarse en una cuenca de antearco desarrollada hacia el Pacífico que luego pasó a formar parte del prisma de acreción gondwánico. Nota: el año de publicación es 2012, fue cambiado para que aparezca en mi informe ya que el mismo incluye además del 2013 algunos meses del año 2012.In this paper are exposed the results of a geological survey about the lower Paleozoic metamorphic rocks of La Modesta Formation in the El Tranquilo farm in Santa Cruz province. Structural, petrographic and geochemical studies carried out in this rock unit indicated that it includes pelitic and psammitic quartz - muscovite - chorite schists, with blastesis of biotite. These rocks show evidences of a regional metamorphism associated with two deformational events. The protolith has been recognized as a pelitic and psamo-pelitic marine sedimentary succession that was affected by metamorphism with a temperature up to 550°C and a pressure between 2 and 4 Kb, reaching green schists metamorphic facies (biotite-garnet grade). It was established a regional metamorphic foliation, S1, subparallel to the sedimentary stratification S0. The schistosity S1 was deformed by a second deformational event, generating a non penetrative S2/L2. This rock unit is differentiated from the La Modesta Formation in the type locality because of its protoliths and the second deformational event is most evident in this area. Nevertheless, the Formation has been correlated with metasedimentites located to the west and its sedimentary protoliths could have been related with a forearc Pacific basin that afterwards formed part of the gondwanic accretionary prism.Fil: Moreira, Pilar. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Loustalot, Ivana I.. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Fernandez, Raul Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Echeveste, Horacio José. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Gonzalez, Pablo Diego. Universidad Nacional de Río Negro. Sede Alto Valle. Instituto de Investigaciones en Paleobiología y Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schalamuk, Isidoro A.. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentin

Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors

Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions

Structure and metamorphism of the La Modesta Formation in the El Tranquilo ranch (Santa Cruz), Patagonia

En este trabajo se exponen los resultados de un relevamiento de las metamorfitas del Paleozoico inferior correspondientes a la Formación La Modesta en la estancia El Tranquilo (Santa Cruz). Estudios estructurales, petrográficos y geoquímicos realizados en esta unidad indican que se trata de esquistos psamíticos y pelíticos cuarzo - muscovítico - cloríticos, que contienen biotita y que poseen evidencias de metamorfismo regional asociado a dos eventos deformacionales. Se ha reconocido al protolito como una sucesión sedimentaria marina homogénea pelítica a psamo-pelítica, que fue sometida a una temperatura menor a 550° y a una presión que osciló entre 2 y 4 Kb, alcanzando un bajo grado metamórfico en facies esquistos verdes (grados biotita-granate). Se determinó una esquistosidad S1 regional que es subparalela a las superficies de sedimentación S0. La S1 ha sido afectada por un segundo episodio de deformación, generando una S2/L2 no penetrativa. Estas rocas se diferenciaron de las metamorfitas del área tipo de la Formación La Modesta por sus protolitos de ambiente más profundo y porque el segundo episodio deformacional es más evidente en esta área. Asimismo, esta formación se ha correlacionado con metasedimentitas que se ubican al oeste y sus protolitos sedimentarios podrían integrarse en una cuenca de antearco desarrollada hacia el Pacífico que luego pasó a formar parte del prisma de acreción gondwánico. Nota: el año de publicación es 2012, fue cambiado para que aparezca en mi informe ya que el mismo incluye además del 2013 algunos meses del año 2012.In this paper are exposed the results of a geological survey about the lower Paleozoic metamorphic rocks of La Modesta Formation in the El Tranquilo farm in Santa Cruz province. Structural, petrographic and geochemical studies carried out in this rock unit indicated that it includes pelitic and psammitic quartz - muscovite - chorite schists, with blastesis of biotite. These rocks show evidences of a regional metamorphism associated with two deformational events. The protolith has been recognized as a pelitic and psamo-pelitic marine sedimentary succession that was affected by metamorphism with a temperature up to 550°C and a pressure between 2 and 4 Kb, reaching green schists metamorphic facies (biotite-garnet grade). It was established a regional metamorphic foliation, S1, subparallel to the sedimentary stratification S0. The schistosity S1 was deformed by a second deformational event, generating a non penetrative S2/L2. This rock unit is differentiated from the La Modesta Formation in the type locality because of its protoliths and the second deformational event is most evident in this area. Nevertheless, the Formation has been correlated with metasedimentites located to the west and its sedimentary protoliths could have been related with a forearc Pacific basin that afterwards formed part of the gondwanic accretionary prism.Fil: Moreira, Pilar. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Loustalot, Ivana I.. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Fernandez, Raul Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Echeveste, Horacio José. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; ArgentinaFil: Gonzalez, Pablo Diego. Universidad Nacional de Río Negro. Sede Alto Valle. Instituto de Investigaciones en Paleobiología y Geología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schalamuk, Isidoro A.. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Instituto de Recursos Minerales. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Recursos Minerales; Argentin

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes

Differentiation stage of myeloma plasma cells: biological and clinical significance

[EN] The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate-differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles

Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance

Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249