Encefalitis amebiana granulomatosa por Balamuthia mandrillaris en Chile confirmada con secuenciación de ADN / Granulomatous amoebic encephalitis due to Balamuthia mandrillaris in Chile confirmed with DNA sequencing

Las enfermedades causadas por amebas de vida libre son infecciones oportunistas que pueden tener un curso fatal. Pueden producir afecciones diseminadas graves con compromiso del sistema nervioso central, como la encefalitis amebiana granulomatosa. Esta infección es cada vez más frecuente en América Latina, aunque se reconocen tardíamente debido a la similitud con otras patologías o porque es inusual incluirla en el diagnóstico diferencial. Comunicamos un caso fatal de una encefalitis amebiana granulomatosa por Balamuthia mandrillaris en una niña de 10 años. Destacamos la gravedad de la afectación cerebral y la falta de esquemas antimicrobianos validados para su tratamiento. Hoy en el mundo esta infección es considerada una enfermedad emergente, influenciada por el cambio climático, lo que llama a estar atentos a su presencia.

Diseases caused by free-living amoebae are opportunistic infections that can have a fatal course. They can cause very serious disseminated conditions with involvement of the central nervous system such as granulomatous amoebic encephalitis. This infection has become more common in Latin America, although its recognition is late due to the similarity with other pathological conditions or because it is unusual to include it in the differential diagnosis. We report a fatal case of granulomatous amoebic encephalitis due to Balamuthia mandrillaris in a 10-year-old girl. We highlight the severity of the brain involvement and the lack of validated schemes for its treatment. Today in the world this infection is considered an emerging disease, influenced by climate change, which calls for being attentive to its presence.

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Impacto del diagnóstico y tratamiento del cáncer de pulmón en dieciocho meses de COVID-19 en Matanzas

Introducción: el diagnóstico y tratamiento del cáncer de pulmón representa un desafío para la sociedad en tiempos de pandemia de COVID-19. Objetivo: analizar el impacto del diagnóstico y tratamiento de pacientes con cáncer de pulmón durante dieciocho meses de COVID-19 en Matanzas. Materiales y métodos: se realizó un estudio analítico, prospectivo y longitudinal. El universo lo constituyeron los 135 pacientes inscritos en el Servicio Provincial de Oncología, de Matanzas, entre el 1 de marzo de 2020 y el 31 de agosto de 2021. Los datos se obtuvieron de las historias clínicas y se analizaron con el paquete estadístico SPSS v. 23. Resultados: los meses con más diagnóstico fueron septiembre, octubre y noviembre. La edad de mayor incidencia fue la comprendida entre 60 y 69 años, con predominio del sexo masculino. Con relación al hábito tabáquico, la incidencia más alta estuvo representada por los fumadores (59,2 %), y la menor por los no fumadores (17,8 %). Respecto al tipo histológico, el carcinoma de células escamosas fue el más frecuente, y al estado general de los pacientes, el grupo 1 de la escala del Easter Cooperative Oncology Group, el de mayor prevalencia. La etapa clínica al diagnóstico predominante fue la IV, y las modalidades de tratamiento más usadas fueron la quimioterapia y la inmunoterapia. Conclusiones: el impacto del diagnóstico oportuno y el tratamiento adecuado del cáncer de pulmón en los primeros dieciocho meses de COVID-19 en Matanzas, fue negativo.

Introduction: the diagnosis and treatment of lung cancer represents a challenge for society in times of COVID-1 pandemics. Objective: to analyze the impact of the diagnosis and treatment of lung cancer patients during 18 months of COVID-19 pandemics in Matanzas. Matertials and methods: an analytical, prospective and longitudinal study was carried out. The universe were 135 patients registered in the Oncology Provincial Service of Matanzas between March 1st 2020 and August 31st 2021. Data were obtained from the clinical records and analyzed with SPSS v.23 statistical packet. Results: the months with higher quantity of diagnosis were September, October and November. The age with the highest incidence was from 60 to 69 years, with predominance of male sex. In relation to smoking, the highest incidence was represented by smokers (59.2%), and the lowest by non-smokers. Respecting the histological type, the squamous cell carcinoma was the most frequent, and respecting the general status of the patient, the group 1 of the Easter Cooperative Oncology Group was the one with highest prevalence. IV stage was the predominant clinical stage at diagnosis, and chemotherapy and immunotherapy were the most used treatment modalities. Conclusions: the impact of lung cancer opportune diagnosis and adequate treatment in the first eighteen months of COVID-19 in Matanzas was negative.

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis.

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

miR-138-5p induces aggressive traits by targeting Trp53 expression in murine melanoma cells, and correlates with poor prognosis of melanoma patients.

Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis. The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic (4C11-) and metastatic melanoma (4C11+) cells. A significant increase in miR-138-5p expression was found in the metastatic 4C11+ melanoma cells compared to 4C11-, which prompted us to investigate its role in melanoma aggressiveness. Functional assays, including anoikis resistance, colony formation, collective migration, serum-deprived growth capacity, as well as in vivo tumor growth and experimental metastasis were performed in 4C11- cells stably overexpressing miR-138-5p. miR-138-5p induced an aggressive phenotype in mouse melanoma cell lines leading to increased proliferation, migration and cell viability under stress conditions. Moreover, by overexpressing miR-138-5p, low-growing and non-metastatic 4C11- cells became highly proliferative and metastatic in vivo, similar to the metastatic 4C11+ cells. Luciferase reporter analysis identified the tumor suppressor Trp53 as a direct target of miR-138-5p. Using data sets from independent melanoma cohorts, miR-138-5p and P53 expression were also found deregulated in human melanoma samples, with their levels negatively and positively correlated with prognosis, respectively. Our data shows that the overexpression of miR-138-5p contributes to melanoma metastasis through the direct suppression of Trp53.

Osteoporosis, un problema de salud de estos tiempos / Osteoporosis, a health problem of our times

RESUMEN En los adultos mayores existen múltiples enfermedades que afectan su calidad de vida y el logro de una longevidad satisfactoria. Una de ellas es la osteoporosis, enfermedad de elevada incidencia a nivel mundial, lo cual también se refleja en Cuba. Siendo una afección que conlleva a un alto grado de discapacidad, constituye un problema en el campo de la salud y de magnitud epidémica, más aún cuando la supervivencia de la humanidad tiende al aumento. Con el objetivo de estructurar los referentes teóricos sobre la osteoporosis, que contribuyan a la capacitación de médicos y estudiantes de Medicina como promotores de salud en prevención primaria de esta enfermedad, se realizó el siguiente artículo científico. Los factores que predisponen la aparición de la enfermedad son diversos, algunos modificables. Se señaló la importancia de su prevención, diagnóstico y tratamiento, así como formas de actuar sobre la misma, para modificar estilos de vida en la comunidad (AU).

ABSTRACT There are many diseases affecting life quality and the achievement of a satisfactory longevity in elder people; osteoporosis, a disease of high incidence around the world that also strikes in Cuba, is found among them. It is an affection leading to a high disability level, being a problem in the health field with an epidemic magnitude, even more when the human kind survival tends to increase. The current scientific article was written with the objective of structuring the theoretical referents on osteoporosis contributing to train Medicine doctors and students as health promoters in the primary prevention of this disease. The factors predisposing the disease's appearance are different, some of them modifiable. It is also stated the importance of its prevention, diagnosis and treatment, and also forms and ways of working on it to modify life styles in the community (AU).

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment.

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.

Carlos de la Torre y Huerta. Paradigma del quehacer científico cubano / Carlos de la Torre y Huerta. Paradigma of Cuban scientific activity

RESUMEN La dimensión científica educativa constituye uno de los aportes más sólidos de la obra de Carlos de la Torre y Huerta. Su extensa obra investigativa se nutre de las asignaturas que impartió en la Universidad de la Habana entre las que se desatacan Paleontología, Arqueología, Antropología, Zoología, Geología, Biología y Entomología. Estos estudios favorecieron el descubrimiento de la gran riqueza existente en el país, destacándose una trayectoria ejemplar cuyos cimientos se insertan en la malacología. El descubrimiento de las Polymitas lo llevan a describir una diversidad de subespecies que lo insertan en el escenario internacional aclamado como un referente de obligatoria consulta para los especialistas. La divulgación sistemática de su obra lo conducen a la formación de una escuela cubana de naturalistas en la que los discípulos marcaron impronta en el quehacer científico nacional al apropiarse de las herramientas que le permiten hacer ciencia utilizando medios de enseñanza, imágenes proyectadas, láminas, dibujos y ejemplares autóctonos del país (AU).

ABSTRACT The educational scientific dimension is one of the strongest contributions of the work of Carlos de la Torre and Huerta. His extensive research work draws on the subjects he taught at the University of Havana, including Paleontology, Archeology, Anthropology, Zoology, Geology, Biology and Entomology. These studies favored the discovery of the great wealth existing in the country, highlighting an exemplary trajectory whose foundations are inserted in malacology. The discovery of the Polymites leads him to describe a diversity of subspecies that insert him in the acclaimed international scenario as a mandatory reference for specialists. The systematic dissemination of his work lead him to the formation of a Cuban school of naturalists in which the disciples marked imprint on the national scientific work by appropriating the tools that allow him to do science using teaching means, projected images, prints, drawings and native copies of the country (AU).

External validation of the Gleason grade group system in Argentinian patients that underwent surgery for prostate cancer.

INTRODUCTION: The aim of this article was to evaluate the effectiveness of the Gleason grade groups (GGG) system on a group of Argentinian patients with prostate cancer (PC) who underwent radical prostatectomy (RP). MATERIAL AND METHODS: We retrospectively studied 262 patients who underwent RP between 1996 and 2014. To determine the performance and validity of the GGG system, a Kaplan-Meier analysis and multivariate analysis with Cox proportional method were performed to evaluate biochemical recurrence, distance metastases and specific cancer mortality. The area under the curve (AUC) was calculated to compare new groups of degrees of the GGG system with the classical scheme of stratification into 3 groups. RESULTS: The median follow-up was 84 months. As the groups ascend, there is less confined organ disease (p <0.001) and greater extraprostatic extension (p <0.001), greater invasion of seminal vesicles (p <0.001) and greater lymph node involvement (p <0.001). The biochemical recurrence-free survival at 5 years was 68%, 55%, 22%, 9%, 0% of the 1-5 groups, respectively. Ten-years cancer-specific survival was 96%, 95%, 78%, 64%, 25% for group 1-5, respectively. In the multivariate analysis, the GGG system is presented as the only independent predictor of biochemical recurrence and specific cancer mortality. The AUC indicates that the GGG system has a higher prognostic discrimination compared to the classic 3-group system (6, 7, ≥8). CONCLUSIONS: The International Society of Urological Pathology (ISUP) GGG system is an independent predictor of biochemical recurrence and mortality from prostate cancer in patients treated with RP. The classification into 5 groups shows greater discrimination in the prognosis than the traditional Gleason classification.

Tumor-associated status epilepticus: A prospective cohort in a tertiary hospital.

INTRODUCTION: Tumor-associated status epilepticus (TASE) follows a relatively benign course compared with SE in the general population. Little, however, is known about associated prognostic factors. METHODS: We conducted a prospective, observational study of all cases of TASE treated at a tertiary hospital in Barcelona, Spain between May 2011 and May 2019. We collected data on tumor and SE characteristics and baseline functional status and analyzed associations with outcomes at discharge and 1-year follow-up. RESULTS: Eighty-two patients were studied; 58.5% (n = 48) had an aggressive tumor (glioblastoma or brain metastasis). Fifty-one patients (62.2%) had a favorable outcome at discharge compared with just 30 patients (25.8%) at 1-year follow-up. Fourteen patients (17.1%) died during hospitalization. Lateralized period discharges (LPDs) on the baseline electroencephalography (EEG), presence of metastasis, and SE severity were significantly associated with a worse outcome at discharge. The independent predictors of poor prognosis at 1-year follow-up were SE duration of at least 21 h, an aggressive brain tumor, and a nonsurgical treatment before SE onset. Lateralized period discharges, super-refractory SE, and an aggressive tumor type were independently associated with increased mortality. CONCLUSIONS: Status epilepticus duration is the main modifiable factor associated with poor prognosis at 1-year follow-up. Accordingly, patients with TASE, like those with SE of any etiology, should receive early, aggressive treatment.

Aggregatibacter Actinomycetemcomitans Induces Autophagy in Human Junctional Epithelium Keratinocytes.

The adverse environmental conditions found in the periodontium during periodontitis pathogenesis stimulate local autophagy responses, mainly due to a continuous inflammatory response against the dysbiotic subgingival microbiome. The junctional epithelium represents the main site of the initial interaction between the host and the dysbiotic biofilm. Here, we investigated the role of autophagy in junctional epithelium keratinocytes (JEKs) in response to Aggregatibacter actinomycetemcomitans or its purified lipopolysaccharides (LPS). Immunofluorescence confocal analysis revealed an extensive nuclear translocation of transcription factor EB (TFEB) and consequently, an increase in autophagy markers and LC3-turnover assessed by immunoblotting and qRT-PCR. Correspondingly, challenged JEKs showed a punctuate cytosolic profile of LC3 protein contrasting with the diffuse distribution observed in untreated controls. Three-dimensional reconstructions of confocal images displayed a close association between intracellular bacteria and LC3-positive vesicles. Similarly, a close association between autophagic vesicles and the protein p62 was observed in challenged JEKs, indicating that p62 is the main adapter protein recruited during A. actinomycetemcomitans infection. Finally, the pharmacological inhibition of autophagy significantly increased the number of bacteria-infected cells as well as their death, similar to treatment with LPS. Our results indicate that A. actinomycetemcomitans infection induces autophagy in JEKs, and this homeostatic process has a cytoprotective effect on the host cells during the early stages of infection.

A rare case of an intramedullary metastasis of a myxopapillary ependymoma.

BACKGROUND: Myxopapillary ependimoma (MPE) is a benign slow-growing tumor, and it has been designated histologically as a Grade I neoplasm according to the 2016 World Health Organization classification. Despite the benign character, dissemination and metastasis have occasionally been reported. The retrograde dissemination to other levels of the neuraxis is extremely rare, being more frequent to the intracranial compartment. CASE DESCRIPTION: We hereby present a case of medullary metastasis of cauda equina MPE, with a history of having undergone a subtotal resection and postoperative adjuvant radiotherapy. The patient presents complaints of night dorsal pain attributable to intradural metastasis twenty-one years after the first surgical intervention. CONCLUSION: The case reported highlights the importance of long follow-up in patients with MPE, since the possibility of secondary seeding to distant craniospinal sites or local spinal sites after surgery, and radiotherapy should be considered in metastatic disease.

Signal peptide recognition in Trypanosoma cruzi GP82 adhesin relies on its localization at protein N-terminus.

Trypanosoma cruzi, the causative agent of Chagas disease, has a dense coat of GPI-anchored virulence factors. T. cruzi GPI-anchored adhesin GP82 is encoded by a repertoire of transcripts containing several in-frame initiation codons located up-stream from that adjacent to the predicted signal peptide (SP). Transfection of T. cruzi epimastigotes with constructs encoding GP82 starting at the SP or from the farthest up-stream methionine confirmed protein expression on the parasite cell surface, comparable to the native GP82. Proteins were fully functional, inducing parasite adhesion to HeLa cells and lysosome mobilization, events required for parasite invasion. Transgenic and native GP82 proteins showed indistinguishable electrophoretic mobility, suggesting similar processing of the SP. Deletion of SP generated a ~72 kDa protein devoid of N-linked oligosaccharides allowing irrefutable identification of GP82 precursor. SP transposition to an internal region of GP82 rendered the signal unrecognizable by the signal peptidase and incapable to direct the nascent protein for ER-membrane association. Altogether our data strongly suggests that GP82 SP fails to function as transmembrane domain and its recognition by the signal peptidase shows strict dependence on the signal localization at protein N-terminus. This report presents the first experimental characterization of the full-length GP82 and its signal peptide.

[Impact of tumor diameter on prognosis in patients with renal cancer stage pT3a.] / Impacto pronóstico del diámetro tumoral en pacientes con cáncer renal estadío pT3a.

OBJECTIVE: To determine the prognostic impact that tumor size has in patients with pathological renal cancer stage pT3a. METHODS: Retrospective, descriptive study evaluating 261 patients diagnosed with renal cancer pathological stage pT1-3aN0M0 between 1995 and 2013. Clinical and pathological characteristics were evaluated in each group. A ROC curve was used to determine the optimum cutting point of tumor size in relation to the death by cancer. Metastasis-free survival and cancer specific survival were evaluated by the Kaplan Meier method and the differences between the groups were evaluated by the Log Rank test. Multivariate Cox regression analysis was used to evaluate the relationship of tumor size and survival of these patients. RESULTS: 261 patients were studied, 166 of which (63.6%) were Stage pT1a-b, 49 (18.8%) pT2 and 46 (17.6%) pT3a. Patients with pT3a tumors had higher proportion of symptomatic tumors (56.5% vs 33.6% p 0.003), tumor size (7.1 cm vs 5.5 cm; 0.0007), Fuhrman grade 3-4 (52.2% vs 19.1% p 0.0001), coagulative necrosis (62.8% vs 28.8% p 0.0001), distance metastasis (39.1% vs 14.9%; p 0.0001) and death by cancer (23.9% vs 8.9%; p 0.003) when compared with localized tumors (pT1-2). The ROC curve demonstrated that a cut-off point of 7cm is the ideal tumor size to determine renal cancer mortality. Metastasis-free survival at 5 year was 90% for tumors pT1a-b, 71% for pT2, 83% for pT3a <7cm and 48% for pT3a >7cm, with significant statistical differences (Log-rank test <0.001). In the multivariate analysis, only pT3a >7cm stage was an independent predictor of death by renal cancer. CONCLUSIONS: Although perirenal fat invasion and renal vein invasion (pT3a stage) are accepted as prognostic factors, to differentiate this category by tumor size could improve its predictive quality. The tumor diameter (7cm) should be applied to pT3a tumors in order to improve the accuracy of TNM system.

Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid.

Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies.Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors.Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas.Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812-9. ©2018 AACR.

A Carbohydrate Moiety of Secreted Stage-Specific Glycoprotein 4 Participates in Host Cell Invasion by Trypanosoma cruzi Extracellular Amastigotes.

Trypanosoma cruzi is the etiologic agent of Chagas' disease. It is known that amastigotes derived from trypomastigotes in the extracellular milieu are infective in vitro and in vivo. Extracellular amastigotes (EAs) have a stage-specific surface antigen called Ssp-4, a GPI-anchored glycoprotein that is secreted by the parasites. By immunoprecipitation with the Ssp-4-specific monoclonal antibodies (mAb) 2C2 and 1D9, we isolated the glycoprotein from EAs. By mass spectrometry, we identified the core protein of Ssp-4 and evaluated mRNA expression and the presence of Ssp-4 carbohydrate epitopes recognized by mAb1D9. We demonstrated that the carbohydrate epitope recognized by mAb1D9 could promote host cell invasion by EAs. Although infectious EAs express lower amounts of Ssp-4 compared with less-infectious EAs (at the mRNA and protein levels), it is the glycosylation of Ssp-4 (identified by mAb1D9 staining only in infectious strains and recognized by galectin-3 on host cells) that is the determinant of EA invasion of host cells. Furthermore, Ssp-4 is secreted by EAs, either free or associated with parasite vesicles, and can participate in host-cell interactions. The results presented here describe the possible role of a carbohydrate moiety of T. cruzi surface glycoproteins in host cell invasion by EA forms, highlighting the potential of these moieties as therapeutic and vaccine targets for the treatment of Chagas' disease.

Evaluation of microvascular invasion as a prognostic factor in the progression of non-metastatic renal cancer.

INTRODUCTION: The aim of this study was to describe the prognostic impact of microvascular invasion (MVI) in patients with non-metastatic renal cell cancer. MATERIAL AND METHODS: We carried out a retrospective, descriptive and analytical study of patients with non-metastatic renal cell carcinoma who had undergone a radical or partial nephrectomy. Patients were divided according to the presence of MVI. In each group, clinical and pathological characteristics were evaluated. Metastasis-free and cancer-specific survival was evaluated by the Kaplan Meier method. The multivariate analysis was performed with Cox proportional method in order to predict risk factors of metastasis and cancer-specific mortality. RESULTS: A total of 221 patients with a median of 40-month long follow-up were evaluated. Patients with MVI+ were 40 (18%) while those with MVI - were 181 (82%). In the univariate analysis, the presence of MVI had a strong correlation with symptomatic tumors (OR 3.56; p 0.0003), tumor size (OR 12.08; p <0.0001), nuclear grade (OR 6.99; p <0.0001), pathological stage (OR 35.8; p <0.0001), distance metastasis (OR 4.16; p 0.0001), and death by cancer (OR 4.7; p 0.0004). However, in the multivariate analysis it is not presented as an independent predictor of metastasis (HR 0.45; p 0.11) or cancer-specific mortality (HR 0.93; p 0.91). CONCLUSIONS: In our series, MVI is associated with unfavorable tumors characteristics. In spite of this, it does not seem to be an independent predictor for metastasis and death by non-metastatic renal cancer.

¿Existen diferencias clínicas, patológicas y evolutivas del cáncer renal en relación con la edad? / Are there Clinical, Pathological and Evolutionary Differences in Renal Cancer Related to Age?

Objetivos: Evaluar las características clínicas, patológicas y evolutivas en diferentes grupos etarios con cáncer renal. Materiales y métodos: Se llevó a cabo un análisis retrospectivo, descriptivo y analítico de 269 pacientes con carcinoma de células renales. Los pacientes fueron divididos en tres grupos de acuerdo con la edad al momento del diagnóstico: <50 años, entre 50 y 65 años y >65 años. En cada grupo se evaluaron características clínicas (edad, sexo, presencia de manifestaciones clínicas), patológicas (diámetro tumoral, tipo histológico, estadío patológico [TNM 2009], grado histológico, presencia de necrosis coagulativa, invasión microvascular, presencia de elementos sarcomatoides, compromiso de la grasa periférica, compromiso vascular macroscópico de vena renal o cava inferior e invasión ganglionar) y presencia de metástasis a distancia al diagnóstico. El análisis univariado de las variables categóricas fue realizado por el método de chi cuadrado o test de Fischer según correspondiera; las variables continuas fueron calculadas según el test de Student. Los puntos principales del trabajo, la sobrevida libre de metástasis y la sobrevida cáncer-específica fueron evaluados mediante el método de Kaplan-Meier y las diferencias entre los grupos fueron evaluadas por el Log-Rank test. Resultados: De los 269 pacientes estudiados, 40 (14,88%) corresponden a <50 años, 136 (50,55%) corresponden a pacientes entre 50 y 65 años y 93 (34,57%) corresponden a pacientes >65 años de edad. No existieron diferencias significativas al evaluar variables clínicas. Los pacientes <50 años presentaron mayor número de nefrectomías parciales (p=0,04), menor grado histológico (p=0,05), necrosis coagulativa (p=0,002), infiltración de la grasa periférica (p=0,02) y compromiso ganglionar (p=0,05). La sobrevida libre de metástasis a 5 años en pacientes <50 años fue del 95%; en los grupos entre 50-65 años y >65 años fue del 70% y el 71%, respectivamente, con diferencias significativas (Log-Rank test=0,004). De la misma manera, al comparar la sobrevida cáncerespecífica a 5 años entre los grupos se pudo evidenciar que las diferencias también fueron significativas a favor de pacientes <50 años (<50 años del 98%, 50-65 años del 79% y >65 años del 83%; Log-Rank test=0,02). Conclusiones: En nuestra serie, los pacientes >50 años de edad se asociaron a características patológicas y evolutivas desfavorables al ser comparados con pacientes de menor edad. Sin embargo, creemos que el seguimiento no debiera limitarse exclusivamente a la edad, sino que debiera incluir el resultado de todas las variables pronósticas de malignidad en cáncer renal (AU)

Objectives: To evaluate clinical, pathological and evolutionary characteristics in different age groups with renal cancer. Materials and methods: A retrospective, descriptive and analytics analysis of 269 patients with renal cell cancer was made. Patients were divided in three groups according to age at the moment of diagnosis: <50 years old, between 50 y 65 years old and >65 years old. In each group clinical (age, sex, presence of clinical manifestations), pathological (tumor diameter, histological type, pathological stage (TNM2009), histological grade, presence of coagulative necrosis, microvascular invasion, presence of sarcomatoid elements, peripheral fat compromise, renal vein or inferior cava vein macroscopic vascular compromise, and nodes invasion) characteristics and presence of distance metastasis at diagnosis were evaluated. Univariated analysis of categorical variables was made by Chi square or Fischer test just as correspond; continuous variables were calculated by Student test. Main points, metastasis free and cancer-specific survival, were evaluated by Kaplan-Meier method and differences between groups by the Log-Rank test. Results: Of 269 patients studied, 40 (14.88%) were <50 years old group, 136 (50.55%) between 50 and 65 years old group and 93 (34.57%) >65 years old group. There are no significative differences when we evaluate clinical variables. Patients in <50 years old group had higher number of nephron-sparing surgery (p=0.04), lower histological grade (p=0.05), coagulative necrosis (p=0.002), peripheral fat invasion (p=0.02) and node invasion (p=0.05). Metastasis free survival at 5 years in this group was 95%; in 50-65 years old group and >65 years old group was 70% and 71%, respectively, with significant differences (Log-Rank test=0.004). Likewise, when we compared cancer-specific survival at 5 years between groups, we demonstrate that differences are significant in favor of patients younger than 50 years old (<50 years old 98%, 50-65 years old 79% and >65 years old 83%; Log-Rank test=0.02). Conclusions: In our series, age >50 years old is associated with unfavorable pathological and evolutionary characteristics to be compared with younger patients. However, we believe that the follow-up should not be limited only to the age but should include the results of all prognostic variables of malignancy in kidney cancer. (AU)