Understanding the role of Cripto-1 in cancer progression and therapeutic strategies

During the initial stages of gastrulation during embryonic differentiation and wound healing, Cripto-1 is a critical protein for human growth. The epithelial adhesion molecules’ downregulation, the mesenchymal overexpression, and mobile proteins are important mechanisms by which Cripto-1 initiates epithelial to mesenchymal transition (EMT). As a result, the function of Cripto-1 for inducing EMT to increase cell migration is advantageous during embryogenesis; however, it is deleterious during the formation, growth, and malignant tumor metastasis. The majority of malignancies are reported to have elevated levels of Cripto-1. Cripto-1 can modify cancerous cells through its function in EMT, which enables these cells to migrate via the extracellular matrix, bloodstream, and lymphatic vessels, on their way for metastasizing to other organs. The goal of this review is to explain what role Cripto-1 plays in common cancers and to summarize how therapeutic strategies are used to interfere with this molecule to target cancers (AU)

Targeting GLS1 to cancer therapy through glutamine metabolism

Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. Many malignant tumor cells always display glutamine addiction. The “kidney-type” glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. Interestingly, GLS1 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, GLS1 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that its inhibitors could provide a benefit strategy for cancer therapy. Herein, we summarize the prognostic value of GLS1 in multiple cancer type and its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for GLS1 inhibitors. On the basis of case studies, our perspectives for targeting GLS1 and development of GLS1 antagonist are discussed in the final part (AU)

CDK1 promotes the stemness of lung cancer cells through interacting with Sox2

Objectives The promoting roles of cyclin dependent kinase 1 (CDK1) have been revealed in various tumors, however, its effects in the progression of cancer stem cells are still confusing. This work aims to explore the roles of CDK1 in regulating the stemness of lung cancer cells. Methods Online dataset analysis was performed to evaluate the correlation between CDK1 exression and the survival of lung cancer patients. RT-qPCR, western blot, cell viability, sphere-formation analysis and ALDH activity detection were used to investigate the roles of CDK1 on lung cancer cell stemness, viability and chemotherapeutic sensitivity. Immunocoprecipitation (Co-IP) analysis and rescuing experiments were performed to reveal the underlying mechanisms contributing to CDK1-mediated effects on lung cancer cell stemness. Results CDK1 mRNA expression was negatively correlated with the overall survival of lung cancer patients and remarkably increased in tumor spheres formed by lung cancer cells compared to the parental cells. Additionally, CDK1 positively regulated the stemness of lung cancer cells. Mechanistically, CDK1 could interact with Sox2 protein, but not other stemness markers (Oct4, Nanog and CD133). Furthermore, CDK1 increased the phosphorylation, cytoplasm-nuclear translocation and transcriptional activity of Sox2 protein in lung cancer cells. Moreover, CDK1 positively regulated the stemness of lung cancer cells in a Sox2-dependent manner. Finally, we revealed that inhibition of CDK1 enhanced the chemotherapeutic sensitivity, which was also rescued by Sox2 overexpression. Conclusions This work reveals a novel CDK1/Sox2 axis responsible for maintaining the stemness of lung cancer cells (AU)

Suppression of MD2 inhibits breast cancer in vitro and in vivo

Purpose To explore the effects of the intervening measure targeting myeloid differentiation 2 (MD2) on breast cancer progression in vitro and in vivo. Methods The expression of MD2 in normal breast cells (Hs 578Bst) and three kinds of breast carcinoma cell lines (MCF-7, MDA-MB-231 s and 4T1) were detected by western blot. MTT assay was used to detect the proliferation of 4T1 cells treated by L6H21, cell migration and invasion was measured by wound healing assay and trans-well matrigel invasion assay, respectively. In addition, to further study the role of MD2 in tumor progression, we assessed the effects of inhibition of MD2 on the progression of xenograft tumors in vivo. Results The expression of MD2 is much higher in MDA-MB-231 s and 4T1cells than that in normal breast cells (Hs 578Bst) or MCF-7 cells (p < 0.05). In vitro, suppression of MD2 by L6H21 has a significant inhibition of proliferation, migration and invasion in 4T1 cells in dose-dependent manner. In vivo, L6H21 pretreatment significantly improved survival of 4T1-bearing mice (p < 0.05). Additionally, we also observed that none of the mice died from the toxic effect of 10 mg kg−1 L6H21 in 60 days. Conclusion Overall, this work indicates that suppression of MD2 shows progression inhibition in vitro and significantly prolong survival in vivo. These findings provide the potential experimental evidence for using MD2 as a therapeutic target of breast carcinoma (AU)

Expression of bone morphogenetic protein 10 in cases with endometrial carcinoma and its clinical significance

Purpose To investigate the expression of bone morphogenetic protein 10 (BMP-10) in patients with endometrial carcinoma (EC) and its clinical significance. Methods Totally 143 cancer tissue specimens were sampled from patients with EC and retrospectively analyzed. The immunohistochemical method was adopted for quantifying BMP-10 in EC tissues. Then the patients were assigned to high and low BMP-10 expression groups. The Kaplan–Meier method and log-rank test were adopted to compare the difference of tumor-free survival (TFS) rate and overall survival (OS) rate between the two groups. The COX proportional hazard model was used to analyze independent risk factors affecting the TFS rate and OS rate of patients with EC. Results There were 80 patients (55.94%) with low BMP-10 expression and 63 patients with high BMP-10 expression (54.06%). BMP-10 expression was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.001), myometrial invasion depth (P < 0.001), histological grade (P < 0.001), and lymph node metastasis (P = 0.009). Additionally, TFS rate (P = 0.004) and OS rate (P = 0.003) in the low BMP-10 expression group were notably lower than those in the high BMP-10 expression group. Multivariate analysis showed that BMP-10 expression (HR: 13.712, 95% CI 1.823–103.158, P = 0.011) was an independent risk factor for the TFS of patients with EC. FIGO stage (P = 0.001) and BMP-10 expression (HR: 8.655, 95% CI 1.098–68.215, P = 0.020) were independent risk factors for the OS of such patients. Conclusions BMP-10 can be adopted as a molecular marker for predicting the poor prognosis of patients with EC (AU)

Policondritis recidivante y glomeruloesclerosis segmentaria y focal: coincidencia o causalidad / Relapsing polychondritis and focal segmental glomerulosclerosis: Coincidence or causality

No disponible

Alteraciones de la motilidad ocular en el síndrome de Kabuki / Changes in ocular motility in Kabuki síndrome

El síndrome de Kabuki es una enfermedad genética rara debida a una mutación genética en los genes KMT2D y KDM6A, que afecta a múltiples órganos, entre ellos los ojos, en la mayoría de los pacientes. Las características clínicas más típicas son: facies peculiar, baja estatura, anormalidades esqueléticas y bajo coeficiente intelectual. Las manifestaciones oculares más frecuentes son el estrabismo, la ptosis y los defectos refractivos. Presentamos una serie de casos de 5 pacientes (3 mujeres), 4 de ellos con estrabismo en forma de esotropía, hiperacción de oblicuos inferiores e hipofunción de oblicuos superiores asociado a un síndrome V. Son pocos los casos publicados de síndrome de Kabuki que describan las afectaciones oftalmológicas y las estrabológicas. Podría ser conveniente la realización de resonancias magnéticas orbitarias para detectar cambios en los trayectos musculares que estén relacionados con la patología de los movimientos oculares encontrados

Kabuki syndrome is a rare genetic disorder, caused by mutation in the KMT2D or KDM6A genes, which affects several organs in the majority of patients, among which are the eyes. The most typical clinical characteristics are mental retardation, postnatal growth retardation, skeletal anomalies, and characteristic facial features. As the eyes are affected in most of the cases, ophthalmological examination is recommended for the early detection of ocular anomalies, in order to prevent visual impairment. The most frequent ocular signs are strabismus, ptosis, and refractive anomalies. A series of cases of Kabuki syndrome is described in five children, four of whom exhibited strabismus with esotropia, over action of inferior oblique muscles, and under action of superior oblique muscles associated with a V pattern. Most published papers do not report or might underestimate the ocular problems. It may be appropriate to perform orbital magnetic resonances in order to detect changes in the muscle paths that are related to the pathology of the eye movements found

Perfil inmunohistoquímico de los tumores de células renales / Immunohistochemical profile of renal cell tumours

CONTEXTO: El cáncer de riñón se encuentra entre los 10 cánceres más frecuentes a nivel mundial: cada año se diagnostican alrededor de 270.000 casos y 116.000 personas mueren a causa de la enfermedad. Aproximadamente el 90% de todas las neoplasias sólidas de riñón son carcinomas de células renales. La incidencia en Colombia es de aproximadamente 500-1.000 casos por año. OBJETIVO: Caracterizar a través del uso de marcadores de inmunohistoquímica los diferentes tumores de células renales que se han diagnosticado en el Laboratorio de Patología del Hospital San José (HSJ) y el Hospital Universitario Infantil de San José (HUISJ) de Bogotá. MATERIALES Y MÉTODOS: Se realizó una revisión retrospectiva de las láminas de hematoxilina y eosina y de inmunohistoquímica de todos los carcinomas de células renales diagnosticados en mujeres y hombres mayores de 18 años, en el Laboratorio de Patología del HSJ y el HUISJ de Bogotá desde enero de 2014 hasta diciembre de 2016. Se usaron los anticuerpos: CAIX (anhidrasa carbónica), RCC (marcador del carcinoma de células renales), vimentina, CD10, CK7, TFE3 (factor de transcripción de unión al potenciador IGHM 3), CD117, CD15, CK20, cadherina y PAX8. Se reportaron frecuencias absolutas y relativas de los distintos marcadores mediante análisis univariados y bivariados con una prueba de chi cuadrado. RESULTADOS: Comparando la expresión de los marcadores estadísticamente significativos, resultó un inmunoperfil para el carcinoma de células claras (CRCC) versus el RCC cromófobo (ChRCC) así: CRCC marcadores positivos: CAIX, vimentina, CD15, CD10, cadherina y marcadores negativos: CK7, CD117; ChRCC marcadores positivos: CK7, CD117, CD10, cadherina y marcadores negativos: CAIX, vimentina, CD15. El marcador PAX8 fue positivo o negativo en ambos tumores. CONCLUSIÓN: Cinco marcadores demostraron utilidad y validez para diferenciar entre los subtipos histológicos CRCC y ChRCC. Proponemos la combinación de los marcadores (CAIX, CK7, vimentina, CD15 y CD117) para el diagnóstico diferencial entre CRCC versus ChRCC

CONTEXT: Kidney cancer is among the 10 most frequent cancers in the world, each year about 270,000 cases are diagnosed and 116,000 people die from the disease. Approximately 90% of all solid kidney neoplasms are renal cell carcinomas. The incidence in Colombia is approximately 500-1000 cases per year. OBJECTIVE: To characterize through the use of immunohistochemical markers the different renal cell tumours diagnosed in the pathology laboratory of the San José Hospital (HSJ) and the University Infantil Hospital of San José (HUISJ) in Bogotá. MATERIALS AND METHODS: A retrospective review was performed of the Hematoxylin and eosin and immunohistochemistry slides of all renal cell carcinomas diagnosed in women and men over 18 years in the pathology laboratory of the HSJ and the HUISJ from Bogotá from January 2014 to December 2016. The antibodies used were: CAIX (carbonic anhydrase), RCC (renal cell carcinoma marker), vimentin, CD10, CK7, TFE3 (transcription factor binding to IGHM enhancer 3), CD117, CD15, CK20, cadherin and PAX8. Absolute and relative frequencies of the different markers were reported through univariate and bivariate analyses with a chi-square test. RESULTS: Comparing the expression of statistically significant markers, an immunoprofile resulted for clear cell carcinoma (CRCC) versus RCC chromophobe (ChRCC) as follows: CRCC positive markers: CAIX, vimentin, CD15, CD10, cadherin and negative markers: CK7, CD117; ChRCC positive markers: CK7, CD117, CD10, cadherin and CAIX negative markers: vimentin, CD15. The PAX8 marker was positive or negative in both tumors. CONCLUSIONS: Five markers demonstrated utility and validity to differentiate between histological subtypes of CRCC and ChRCC. We propose the combination of markers (CAIX, CK7, vimentin, CD15 and CD117) for the differential diagnosis between CRCC versus ChRCC

Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes / An integral view of cancer (II). Fields of investigation and emerging biomarkers

El mundo de la Patología cobra sentido de la mano de la Oncología Clínica, donde técnicas y tratamientos, biomarcadores y anticuerpos, comparten el objetivo de hallar nuevas posibilidades de intervención, más eficaces, menos agresivas y más integrales. En esta búsqueda, la evidencia muestra como la mecánica tisular afecta la carcinogénesis y como la heterogeneidad tumoral depende de la alteración metabólica del estroma y del efecto Warburg de las células malignas, regulado directamente por PD-1 y diana del tratamiento inmunoterápico. Proliferación y apoptosis dependen de la disfunción mitocondrial de la célula tumoral que determina el grado de quimio- y radiorresistencia. El estado de la microbiota intestinal determina la respuesta inmune, la estructura del microambiente del tumor y la respuesta al tratamiento oncológico, y el receptor de la vitamina D permite la reprogramación del estroma tumoral. En la actualidad, la colaboración entre los mundos de la investigación básica y clínica establece como zonas de desarrollo próximo el estudio del microambiente tumoral y la mecanoterapia molecular, el metabolismo y la inmunoterapia, la mitocondria y la oncogénesis, la microbiota y la quimioterapia, el eje psiconeuroendocrino y el desequilibrio homeostático, la epigenética y las posibilidades de reprogramación del fenotipo tumoral. De todos estos campos de conocimiento surgen nuevos biomarcadores, pronósticos y predictivos, que revisamos en este artículo al servicio de nuevas posibilidades de intervención terapéutica

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities

Angiomiolipoma epitelioide/PEComa hepático e hiperplasia nodular focal en una paciente con antecedentes de melanoma cutáneo / Hepatic epithelioid angiomyolipoma/PEComa and focal nodular hyperplasia in a patient with a previous history of cutaneous melanoma

Los tumores de células epitelioides perivasculares (PEComas) hepáticos son lesiones mesenquimales poco comunes. La ocurrencia simultánea de PEComas y otras lesiones hepáticas es inusual, con solo dos reportes de casos adicionales en la literatura inglesa. Reportamos un caso de PEComa primario hepático asociado con una hiperplasia nodular focal en una paciente con antecedentes de melanoma cutáneo. El diagnóstico radiológico fue sugestivo de adenoma hepático, por lo que se realizó una resección segmentaria hepática. El tumor estaba constituido por una proliferación de células epitelioides, tejido adiposo y fibras de músculo liso entremezcladas con vasos sanguíneos. Las células tumorales mostraron positividad difusa e intensa para HMB-45, Melan-A y actina de músculo liso, siendo negativas para Hepatocyte, S100, MITF y BRAF. No se detectó mutación BRAFV600 en el estudio por biología molecular. El diagnóstico patológico final fue de angiomiolipoma epitelioide hepático/PEComa. Se realiza una discusión del diagnóstico diferencial de los PEComas hepáticos

Hepatic perivascular epithelioid cell tumors (PEComas) are uncommon mesenchymal neoplasms. PEComas concurrent with other hepatic lesions is a very rare occurrence, with only two previously reported cases. We report a primary hepatic PEComa associated with focal nodular hyperplasia in a patient with a previous history of cutaneous melanoma. Diagnostic imaging studies suggested a hepatic adenoma and the patient underwent a segmentectomy. The tumor was mainly composed of epithelioid cells, adipose tissue and smooth muscle fibers intermixed with blood vessels. The neoplastic cells were diffusely immunoreactive for HMB-45, Melan-A and smooth muscle actin, but not for Hepatocyte, S100, MITF or BRAF. Molecular studies were negative for BRAFV600 mutation. The final diagnosis was hepatic epithelioid angiomyolipoma/PEComa. The differential diagnosis of hepatic PEComa is discussed

Expression of anoctamin 1 is associated with advanced tumor stage in patients with non-small cell lung cancer and predicts recurrence after surgery

Purpose. Anoctamin 1 (ANO1), a recently identified calcium-activated chloride channel, has been found to have a critical role in tumorigenesis and tumor progression in several types of cancer. However, its role in non-small cell lung cancer (NSCLC) remains to be elucidated. In this study, we evaluated the utility of ANO1 as a prognostic marker. Patients and methods. ANO1 expression was detected in tumor tissues and paraneoplastic tissues of I-IV stage NSCLC patients who received surgical treatment by using immunohistochemical and quantitative RT-PCR analyses. Epidermal growth factor receptor (EGFR) was investigated using immunohistochemistry. Then the TNM stage of the tumor samples was assessed and patients were followed up for developing recurrence. Results. ANO1 expression was significantly increased in NSCLC tumor tissues compared to the paraneoplastic tissues at both RNA and protein level. In addition, ANO1 overexpression was correlated with the high expression of EGFR and led to an advanced tumor stage. And also high ANO1 expression was significantly correlated with high recurrence rate at 1-year follow-up. Conclusions. ANO1 overexpression associated with the high expression of EGFR can be a predictive marker of recurrence after surgery in NSCLC patients (AU)

No disponible

La expresión de microARN-133 inhibe la transición epitelio-mesenquimatosa en las células del cáncer de pulmón apuntando directamente al FOXQ1 / Expression of microRNA-133 inhibits epithelial-mesenchymal transition in lung cancer cells by directly targeting FOXQ1

Introducción: El microARN (miR) se ha relacionado con la génesis tumoral en muchos tipos de cáncer, pero ningún estudio ha examinado el rol exacto del miR-133 en el cáncer de pulmón. Métodos: Identificamos el miR-133 como posible regulador de la expresión de la FOXQ1 e investigamos la posible implicación del miR-133 en la migración y la invasión de células de cáncer de pulmón, y el mecanismo molecular subyacente. Resultados: El miR-133 se dirigió directamente y redujo la expresión de la FOXQ1, que a su vez redujo la concentración de TGF-β. El miR-133 disminuyó en líneas celulares de cáncer de pulmón A549 y HCC827, y su reexpresión inhibió significativamente la migración y la invasión de células de cáncer de pulmón. Investigaciones subsiguientes revelaron que dicha inhibición estaba provocada por una inversión de la transición epitelio-mesenquimatosa, constatada por una elevación del marcador epitelial E-cadherina inducida por el miR-133 y una reducción del marcador vimentina. Conclusiones: Nuestro estudio es el primero que ha identificado el miR-133 como biomarcador del cáncer de pulmón. Su función es reducir la FOXQ1 e inhibir la transición epitelio-mesenquimatosa, la cual antagoniza la génesis tumoral en el cáncer de pulmón. Por consiguiente, nuestros datos respaldan el papel del miR-133 como posible instrumento terapéutico molecular en el tratamiento del cáncer de pulmón

Introduction: MicroRNA (miR) was implicated in the tumorigenesis of many types of cancer, but no study was conducted on the exact role of miR-133 in lung cancer. Methods: We have identified miR-133 as a putative regulator of FOXQ1 expression, and investigated the potential involvement of miR-133 in the migration and invasion of lung cancer cells, as well as the underlying molecular mechanism. Results: MiR-133 directly targeted and down-regulated FOXQ1 expression, which in turn reduced TGF-β level. MiR-133 was down-regulated in lung cancer cell lines A549 and HCC827, and its re-expression significantly inhibited the migration and invasion of the lung cancer cells. Further investigation revealed that this inhibition was caused by reversing the epithelial-mesenchymal transition, evidenced by miR-133 induced elevation of epithelial marker E-cadherin, and reduction of mesenchymal marker Vimentin. Conclusions: Our study is the first to identify miR-133 as a biomarker for lung cancer. It functions to down-regulate FOXQ1, and inhibit epithelial mesenchymal transition, which antagonizes lung cancer tumorigenesis. Therefore our data support the role of miR-133 as a potential molecular therapeutic tool in treating lung cancer

Genome-wide association studies (GWAS) and their importance in asthma

Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease

No disponible

Validación externa de los ARNm: FXYD3 y KRT20 como biomarcadores predictivos de la presencia de micrometástasis en ganglios de pacientes con tumor vesical infiltrante / External validation of FXYD3 and KRT20 as predictive biomarkers for the presence of micrometastasis in muscle invasive bladder cancer lymph nodes

Introducción: Recientes estudios han propuesto que los ARNm FXYD3 y KRT20 cuantificados por qrtPCR en material parafinado podrían ser biomarcadores capaces de detectar los ganglios portadores de micrometástasis que se escapaban al análisis convencional por hematoxilina-eosina (HE). Se decidió hacer un estudio de validación en ganglios de pacientes a los que se les practicó una cistectomía radical. Objetivo: Clasificar el estado adenopático de una muestra de pacientes cistectomizados, según la expresión ganglionar de FXYD3 y KRT20. Como objetivo secundario valorar si existe una evolución oncológica diferencial de los pacientes, según la expresión ganglionar de dichas proteínas. Material y método: Se incluyeron ganglios linfáticos de 64 pacientes cistectomizados por tumor vesical infiltrante. El modelo se desarrolló a expensas de ganglios metastásicos de 15 pacientes y ganglios de 4 pacientes sin tumor conocido. La expresión génica se midió mediante PCR cuantitativa en tiempo real. Se calculó la expresión mediana mediante q-rtPCR de los ARNm de FXYD3 y KRT20 en el tejido ganglionar. Se continuó con un análisis de curvas ROC, según la función y = 0.1400 + 0.250FXYD3-2.532. Se estableció el punto de corte mediante una curva ROC. Dicha fórmula se aplicó al tejido ganglionar restante; en función del punto de corte antes establecido la muestra quedó clasificada en 4 subgrupos: HE- qrtPCR-, HE- qrtPCR+, HE+ qrtPCR+ y HE+ qrtPCR-. Se procedió a un análisis descriptivo, comparativo y a un análisis de supervivencia libre de progresión metastásica, calculando las curvas de Kaplan y Meyer para los 3 subgrupos establecidos. Los test se consideraron estadísticamente significativos cuando p < 0,05. Resultados: Mediante q-rtPCR se comprobó que había diferencias en la expresión mediana de FXYD3 (p = 0,05) y de KRT20 (p = 0,009) entre el tejido ganglionar de los pacientes con HBP y los pacientes con metástasis adenopáticas. Se asignó como punto de corte de 0,377. La muestra se clasificó en: un 37,5% de los pacientes eran pN0 por HE y pN0 por qrtPCR (-HE -qrtPCR), el 39,1% eran pN0 por HE pero eran metastásicos por qrtPCR (-HE +qrtPCR) y 15 pacientes (23,4%) eran metastásicos por ambas técnicas (+HE +qrtPCR). Las curvas de Kaplan y Meyer mostraron una peor supervivencia libre de progresión metastásica para los pacientes (+HE +qrtPCR) que para el resto de los subgrupos, no observando diferencias significativas entre (-HE +qrtPCR) y (-HE -qrtPCR). Conclusiones: Según nuestros resultados un 39,1% de los pacientes con tumor vesical infiltrante sobreexpresarían los biomarcadores FXYD3 y KRT20, siendo N0 por HE. No observamos un comportamiento clínico diferencial de los pacientes cistectomizados según su expresión de FXYD3 y KRT20 cuando son N0 por HE

Introduction: Recent studies have proposed that FXYD3 and KRT20 mRNA quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paraffin could be biomarkers to detect lymph nodes with micrometastases that avoid detection by conventional analysis with hematoxylin-eosin (HE). A validation study was conducted on the lymph nodes of patients who underwent radical cystectomy. Objective: To classify the adenopathic state of a sample of patients who underwent cystectomy, based on the lymph node expression of FXYD3 and KRT20. The secondary objective was to assess whether there is a differential oncologic evolution for the patients, depending on the lymph node expression of these proteins. Material and method: The study included lymph nodes from 64 patients who underwent cystectomy for infiltrating bladder tumor: The model was developed using metastatic lymph nodes from 15 patients and lymph nodes from 4 patients with no known tumor. Genetic expression was measured using real-time qRT-PCR. We calculated (using qRT-PCR) the median expression of FXYD3 and KRT20 mRNA in the lymph node tissue. We then analyzed the receiver operating characteristic (ROC) curves, according to the function y = 0.1400 + 0.250FXYD3-2.532. The cutoff was established using an ROC curve. The formula was applied to the remaining lymph node tissue, based on the previously established cutoff. The sample was classified into 4 subgroups: HE- qRT-PCR-, HE- qRT-PCR+, HE+ qRT-PCR+ y HE+, qRT-PCR-. A descriptive, comparative analysis was performed, as well as a metastatic progression-free survival analysis, calculating the Kaplan and Meyer curves for the 3 established subgroups. The test results were considered statistically significant at P < .05. Results: Using qRT-PCR, we verified that there were differences in the median expression of FXYD3 (P = .05) and KRT20 (P = .009) between the lymph node tissues of patients with benign prostate hyperplasia and those of patients with lymph node metastasis. A cutoff was assigned to 0.377. The sample was classified as follows: 37.5% of the patients were pN0 by HE and pN0 by qRT-PCR (-HE -qRT-PCR), 39.1% were pN0 by HE but metastatic by qRT-PCR (-HE +qRT-PCR), and 15 patients (23.4%) were metastatic by both techniques (+HE +qRT-PCR). The Kaplan and Meyer curves showed poorer metastatic progression-free survival for the patients who were +HE and +qRT-PCR than for the other subgroups, with no significant differences between -HE +qRT-PCR and -HE -qRT-PCR. Conclusions: According to our results, 39.1% of the patients with infiltrating vesical tumors overexpressed the FXYD3 and KRT20 biomarkers and were N0 by HE. We observed no differential clinical behavior among the patients who underwent cystectomy according to their expression of FXYD3 and KRT20 when they were N0 by HE

Melanoma primario cutáneo angiomatoide. Un patrón morfológico excepcional en los melanomas de piel. Presentación de caso con revisión de la literatura / Primary Angiomatoid Melanoma as an Exceptional Morphologic Pattern in Cutaneous Melanoma. A Case Report and Review of the Literature

Presentamos un caso de melanoma angiomatoide localizado en la piel del muslo derecho en un hombre de 59 años de edad. La neoplasia mostró un patrón de crecimiento semejante a una proliferación vascular donde las células que revestían esos espacios ''pseudovasculares'' fueron positivas a la proteína S-100, al HMB45 y al MiTF1. El diagnóstico diferencial incluye el angiosarcoma y el carcinoma escamoso pseudovascular. El caso que aquí informamos es el quinto de la literatura mundial

We report a case of angiomatoid melanoma on the right thigh of a 59-year-old man. The histologic growth pattern of the tumor mimicked vascular proliferation, and the cells lining the pseudovascular spaces were positive for protein S-100, HMB-45, and MITF-1. The differential diagnosis is with angiosarcoma and pseudovascular adenoid squamous cell carcinoma. The case we present is the fifth reported to dat

Utilidad del análisis inmunohistoquímico de diversos marcadores moleculares en la caracterización del carcinoma papilar de tiroides con metástasis linfáticas iniciales / Usefulness of the immunohistochemical analysis of several molecular markers in the characterization of papillary thyroid carcinoma with initial lymph node metastasis

Introducción y objetivo En el carcinoma papilar de tiroides, la detección de metástasis linfáticas (ML) en la región cervical es frecuente, observándose en cerca de la mitad de los casos en el momento del diagnóstico. El objetivo del estudio es analizar mediante técnica inmunohistoquímica la expresión combinada de diversas moléculas con el fin de establecer las características de aquellos casos con mayor tendencia a desarrollar ML. Pacientes y métodos Treinta y cinco pacientes con carcinoma papilar de tiroides fueron distribuidos en 2 grupos. El grupo i incluyó 19 pacientes que no presentaron ML al diagnóstico. En el grupo ii se incluyeron 16 pacientes en los cuales se había demostrado la presencia de ML. En todos los casos se practicó tinción inmunohistoquímica para RET/PTC, receptor del factor de crecimiento epidérmico (EGFR), p16INk4a, p21cip1, p27kip1, BCL2 y pAKT. Resultados No se apreciaron diferencias en ambos grupos en relación a p21cip1, p27kip1, p16INk4a, Bcl-2 y pAKT. No obstante, se observaron diferencias de expresión para RET/PTC y para EGFR, siendo ambas más frecuentes en los pacientes con ML. Asimismo se vio que la doble positividad de RET/PTC y el EGFR discriminaba de manera significativa los casos con ML. Finalmente, la triple combinación: RET/PTC negativo, EGFR negativo y p16INk4a negativo no se daba en ningún paciente del grupo ii y en casi la mitad del grupo i. Conclusiones El estudio de la expresión de diversas moléculas de manera combinada puede resultar eficaz en la caracterización fenotípica del carcinoma papilar de tiroides. Con ello se podría mejorar el manejo de los pacientes con cáncer de tiroides (AU)

Introduction and objective Regional lymph node metastases (LNM) are a common finding in papillary thyroid cancer (PTC). Approximately half of patients have LNM at diagnosis. The aim of this study was to analyze immunohistochemically the combined expression of different PTC-related molecules in order to identify cases with a tendency to show LNM. Patients and methods Thirty-five patients were included in the study. The patients were distributed in two groups. Group I included 19 patients with no histological evidence of LNM at diagnosis. Group II included 16 patients with histological evidence of cervical LNM. Samples were stained for RET/PTC, EGFR, p16INk4a, p21cip1, p27kip1, BCL2, and pAKT. Results Expression of p21cip1, p27kip1, p16INk4a, Bcl-2, and pAKT showed no differences between the two groups. However, RET/PTC and EGFR expression showed significant differences: in both cases, staining was more frequent in patients with LNM. Simultaneous positivity of RET/PTC and EGFR was a discriminative marker in patients with LNM. Finally, the combination of RET/PTC negative, EGFR negative and p16INk4a negative was found in none of the patients with LNM but in nearly half of those in group I. ConclusionsI mmunohistochemical analysis of several molecular markers could be useful in the phenotypic characterization of PTC. Application of these markers could enhance diagnosis and improve the management of patients with thyroid cancer (AU)

Papel de pituitary tumour-transforming gene (PTTG) en los adenomas hipofisarios / Rol of Pituitary Tumour-Transforming Gene (PTTG) in the pituitary adenomas

El pituitary transforming tumour gene (PTTG) está involucrado en una gran variedad de mecanismos fisiológicos. Se ha descrito sobreexpresión proteínica de PTTG en múltiples neoplasias, como los tumores hipofisarios, la cual favorece la aneuploidía, la inestabilidad genética, la proliferación celular y la angiogénesis, todos ellos procesos clave en la transformación neoplásica. Los estudios llevados a cabo en adenomas hipofisarios indican su asociación con un mayor grado de infiltración y de recidivas. Actualmente se plantea su función potencial como diana terapéutica (AU)

The pathogenesis of pituitary tumours is far to be understood. Pituitary transforming tumour gene (PTTG), a gen that induces aneuploidy, genetic instability, cellular proliferation and to stimulate angiogenesis, has been involved in neoplasic transformation and shown overexpressed in many neoplasm as lung, breast, endometrium, thyroid and colon malignant tumours. On the other hand, PTTG has been inconsistently studied in pituitary tumours. The majority of studies have been performed in animals and there is a great variability in the methods used in its determination. The goal of this review is to resume the role of PTTG in tumourogenesis and critically to revise the studies published in humans in order to advance in the knowledge of the pathogenesis of pituitary adenomas and to find clinical useful predictors of the behavior of these tumours (AU)

Phosphoproteomics and cancer research

Protein phosphorylation plays key roles in the regulation of normal and cancer cells. It is a highly dynamic process. Protein kinases are the targets of several new cancer drugs and drug candidates. However, some of the main issues related to new drugs are how they function and the selection of those patients that will likely respond best to a particular treatment regime. There is an urgent need to understand and monitor kinase signalling pathways. Phosphoproteomics requires the enrichment of phosphorylated proteins or peptides from tissue or bodily fluids, and the application of technologies such as mass spectrometry (MS) to the identification and quantification of protein phosphorylation sites. As the field develops it will provide pharmacodynamic readouts of disease states and cellular drug responses in tumour samples. There have been a number of recent advances, but there are still technical hurdles and bioinformatics challenges that need to be addressed (AU)

La expresión inmunohistoquímica de ciclina B1 conlleva mayores valores de SUV en la 18F-FDG-PET de pacientes con carcinomas no microcíticos de pulmón. Primeros resultados / The immunohistochemical expression of cyclin B1 is associated with higher SUV in 18F-FDG-PET in non-sma ll cell lung cancer patients. Initial results

Objetivo: estudiar la posible correlación entre la expresión de ciclina B1, proliferación celular y la SUV máxima-18F-FDG-PET en pacientes con carcinomas no microcíticos pulmonares. Material y metodo: se incluyó a 49 pacientes (15 adenocarcinomas, 27 carcinomas escamosos y 7 carcinomas broncoalveolares) y se realizó la expresión inmunohistoquímica de ciclina B1 mediante tissue-arrays. Asimismo, analizamos la proliferación celular (MIB-1). El PET se realizó 60 min después de la administración intravenosa (i.v.) de 350-518 MBq de 18F-FDG en un PET (Advance, GE) y adquisión en 2D. Resultados: la expresión inmunohistoquímica de ciclina B1 se detectó en 40 (81,6%) casos y no se relacionó con el estadio clínico (I-II: 17/21 frente a III-IV: 23/28). Los valores de SUV fueron mayores (p = 0,04) en los casos positivos (16,4 ± 8,1) que en los negativos (10,9 ± 6,2) y no difirieron en función del estadio clínico. La expresión de ciclina B1 se correlacionó (p < 0,0001) con la de MIB1. Tras análisis univariable, la ciclina B1 y los valores SUV no fueron factores pronósticos, pero sí la proliferación celular (p = 0,037). Conclusiones: nuestros resultados muestran una relación directa entre la expresión de ciclina B1 y los valores max SUV en el PET de pacientes afectos de carcinomas no microcíticos de pulmón, lo cual, unido a la asociación de aquella con la positividad del MIB1, apoya el papel de la proliferación celular en la captación del radiofármaco por el tumor(AU)

Aim: to study the expression of cyclin B1 and its possible relationship with the maximum SUV in FDG-PET and MIB1 expression in patients with NSCLC. Materials and methods: 49 patients (15 adenocarcinomas, 27 squamous cell carcinomas and 7 bronchoalveolar carcinomas) were included in this study; the immunohistochemical expression of cyclin B1 was determined using the tissue-array technique. Each PET was performed 60 minutes after the i.v. administration of 350-518 MBq of FDG on an Advance system (GE) in 2D acquisition mode. Results: cyclin B1 expression was detected in 40 out of 45 cases. The SUV values were higher (p = 0.04) in the cyclin B1+ cases than in the negative cases (16.4 ± 8.1 vs 10.9 ± 6.2). Cyclin B1 expression and SUV values were not correlated with the clinical stage. The expression of cyclin B1+ correlated positively (p < 0.0001) with that of MIB1. After univariate analysis, only the cellular proliferation was a prognostic factor (p = 0.037). Conclusions: our results suggest that there is a direct correlation between cyclin B1 expression and max-SUV values in the PET of NSCLC patients. When the association of cyclin B1 with positive MIB1 is also considered(AU)

Tumor neuroendocrino del sistema gastroenteropancreático metastásico: imagen con 111In-pentetreótido y PET-FDG / Metastatic gastroenteropancreatic neuroendocrine tumours: 111in-pentetreotide and PET-FDG imaging

Presentamos el caso de una paciente con el antecedente de un tumor neuroendocrino de la cabeza del páncreas, bien diferenciado, que es tratada mediante cirugía. Dos años después, ante la sospecha clínica de recidiva se le practica una endoscopia, una TAC y un rastreo con 111In-pentetreótido. En la imagen de las 4 horas se observaron lesiones con receptores de somatostatina en el hígado y en la región peripancreática. No obstante, esta captación desaparece a las 24 horas. Ante este hallazgo se realiza una PET-FDG mostrando focos de elevado metabolismo en ambas lesiones. La biodistribución del 111In-pentetreótido puede ser variable en el tiempo, y ser captada por tumores sin expresión previa de receptores de somatostatina en las recidivas. La PET-FDG puede ayudar en estos casos (AU)

We present a patient with previous history of neuroendocrine tumour in the head of the pancreas, well differentiated and treated surgically. Two years later, there was suspicion of relapse. An endoscopy, CT scan and 111In-pentetreotide scintigraphy were performed. The 4 hour image showed two uptake lesions in the liver and the peripancreatic region. However, these focal uptakes had disappeared in the 24 hour image. In view of this result, a PET-FDG scan was carried out, showing two hypermetabolic lesions. The biodistribution of 111In-pentetreotide may be influenced by various parameters, including the time of scanning, and may show neuroendocrine tumours without somatostatin receptors in relapses. PET-FDG is an interesting tool to help characterise these cases (AU)