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Background: Integration of transcriptomic testing into EUS-FNA samples is a growing need for precision oncology in pancreatic ductal adenocarcinoma (PDAC). The NanoString platform is suitable for transcriptome profiling in low yield RNA samples. Methods: Inclusion of patients that underwent EUS-FNA cytological diagnosis of pancreatic ductal adenocarcinoma using 19G and/or 22G needles and subsequent surgical resection. Formalin-fixed, paraffin-embedded (FFPE) cytological and surgical samples underwent RNA extraction and transcriptomic analysis using a custom 52-gene NanoString panel of stromal PDAC features. Cell type abundance was quantified in FFPE specimens and correlated. Results: 18 PDAC patients were included. Mean EUS-FNA passes was 2 + 0.7. All FFPE passed the RNA quality control for genomic analysis. Hierarchical clustering on the global gene expression data showed that genes were differentially expressed between EUS and surgical samples. A more enriched cancer-associated fibroblasts and epithelial-mesenchymal transition transcriptomic profile was observed across surgical specimens whereas immunological biomarkers were more represented in EUS-FNA samples. Cytological examination confirmed a scanty representation of CAF and more immunological cell abundance in cytological samples in comparison to surgical specimens. Conclusion: Targeted transcriptomic NanoString profiling of PDAC samples obtained by EUS-FNA is a feasible approach for pre-surgical molecular analysis although stromal CAF/EMT mRNA biomarkers are underrepresented.
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In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.
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Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Consenso , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Biopsia Líquida , Oncología Médica , Mutación , Patología , Sociedades Médicas , EspañaRESUMEN
Allograft infiltration has been described in up to 20% of all patients with posttransplant lymphoproliferative disorder (PTLD), most representing EBV-positive B-cell lymphomas. Plasma cells are often observed in humoral rejection biopsies, but graft infiltration by plasmacytoma-like PTLD is rare. We report the case of a 54-year-old simultaneous pancreas-kidney transplant recipient (immunosuppression: OKT3, methylprednisolone, cyclosporine, and azathioprine), diagnosed with an IgG-kappa monoclonal gammopathy of undetermined significance eighteen years after transplant. Nine months later, pancreas allograft biopsy performed due to new-onset hyperglycemia (HgA1C 8.6%, C-peptide 6.15ng/mL and anti-GAD 0.9UI/mL) revealed a monotypic plasma cell infiltrate, CD19, CD79a, CD138 positive, with IgG-kappa light chain restriction, and EBV negative. PET-scan FDG uptake was limited to pancreas allograft. Tumor origin could not be established (using DNA microsatellite analysis). Despite treatment with bortezomib and dexamethasone, patient eventually died one month later. This is the first report of a late onset extramedullary plasmacytoma involving a pancreas allograft.
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Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.
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Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Neoplasias/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , ARN Mensajero/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , ARN Mensajero/genética , Tasa de SupervivenciaRESUMEN
BACKGROUND AND AIMS: Endoscopic resection techniques require use of submucosal injection. The aim of this study was to assess a new solution that combines hyaluronic acid, chondroitin sulfate, and poloxamer 407 for submucosal injection. METHODS: A total of 48 gastric submucosal cushions were created in fresh porcine stomachs using gelafundin (nâ=â16) or the new solution diluted at 50â% (nâ=â16), or 80â% (nâ=â16). The duration of mucosal elevation was measured. In an in vivo model, 10 gastric submucosal cushions were created by injecting 2âmL of the new solution at 80â% and the animal was euthanized 30 minutes after the last injection. RESULTS: Submucosal cushions with the new solution at 80â% and 50â% concentration lasted longer than with gelafundin (23.13â±â15.57, 13.1â±â6.6, 3.94â±â1.53 minutes, respectively; P â=â0.000). In the in vivo study, no damage or necrosis was observed in the mucosa or muscularis propria. CONCLUSION: The combination of hyaluronic acid, chondroitin sulfate, and poloxamer 407 produces a long-lasting submucosal cushion and does not seem to induce acute damage in the tissue making it suitable for submucosal injection.
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BACKGROUND: We assessed the impact of complications on recurrence and survival after curative gastric cancer resection. METHODS: Patients undergoing R0 resections between 1990 and 2009 were identified in a prospectively maintained database and were categorized by presence of any complication Clavien-Dindo (CD) ≥ II, sepsis or intra-abdominal sepsis. Cox regression analyses to relate complications and clinico-pathological variables to time to recurrence (TTR) and overall survival (OS) were performed. RESULTS: A total of 271 patients were included with a median follow-up of 149.9 months (range 140.1-159.9). Complications CD ≥ II occurred in 162 (59.8%) patients, sepsis in 66 (22.5%), and intra-abdominal sepsis in 37 (13.6%). Recurrence developed in 88 (32.4%) patients. Independent predictors of short TTR were pTNM stage (IIIB-IIIC vs. IA-IIA) (hazard ratio [HR] = 37.55, 95% confidence interval [CI] 17.57-80.24; p < 0.001), D1 lymphadenectomy (HR = 3.14, 95% CI 1.94-5.07; p < 0.001), and male gender (HR = 1.65, 95% CI 1.06-2.57; p = 0.026). pTNM stage (IIIB-IIIC vs. IA-IIA, HR = 10.28, 95% CI 6.51-16.23; p < 0.001), male gender (HR = 1.64, 95% CI 1.17-2.31; p = 0.005), age (HR = 1.03, 95% CI 1.02-1.05; p < 0.001), and adjuvant therapy (HR = 0.55, 95% CI 0.37-0.83; p = 0.004) were identified as independent predictors of OS.. CONCLUSIONS: Evidence provided by this study does not support a negative impact of postoperative complications CD ≥ II, sepsis, and intra-abdominal sepsis on the oncologic outcome after curative gastric cancer resection.
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Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Recurrencia Local de Neoplasia/mortalidad , Complicaciones Posoperatorias/mortalidad , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Gastrectomía/efectos adversos , Gastrectomía/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Complicaciones Posoperatorias/fisiopatología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , España , Neoplasias Gástricas/patología , Análisis de SupervivenciaRESUMEN
Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Receptores ErbB/genética , GTP Fosfohidrolasas/genética , Humanos , Oncología Médica/organización & administración , Proteínas de la Membrana/genética , Reacción en Cadena de la Polimerasa/métodos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Sociedades Médicas/organización & administración , España , Proteínas ras/genéticaRESUMEN
The annual incidence of neuroendocrine tumours in the Caucasian population ranges from 2.5 to 5 new cases per 100,000 inhabitants. Gastroenteropancreatic neuroendocrine tumours is a family of neoplasms widely variable in terms of anatomical location, hormone composition, clinical syndromes they cause and in their biological behaviour. This high complexity and clinical heterogeneity, together with the known difficulty of predicting their behaviour from their pathological features, are reflected in the many classifications that have been developed over the years in this field. This article reviews the main tissue and clinical biomarkers and makes recommendations for their use in medical practice. This document represents a consensus reached jointly by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP).
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Biomarcadores de Tumor/análisis , Neoplasias Intestinales/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico , Humanos , Neoplasias Intestinales/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41-4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped.
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Neoplasias Encefálicas/terapia , Hemangiopericitoma/terapia , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/etiología , Radiocirugia/métodosRESUMEN
Gastrointestinal (GI) GVHD after allo-SCT is diagnosed on the basis of symptoms and findings in endoscopic mucosal biopsy specimens. However, GI symptoms often persist despite treatment and whether a second endoscopy may be helpful in determining the most suitable therapy is not established. We identified 31 patients with persistent diarrhea who underwent more than one endoscopic study. All cases underwent serial microbiological stool analysis and CMV-detecting assays on serum and biopsies. Of the 31 initial GI biopsies, 20 (64.5%) were classified as GVHD, two (6.5%) as GVHD with CMV, four (13%) as non-CMV infection, and five (16%) as normal or unspecific. The second GI biopsies were diagnostic of GVHD in nine cases (29%), GVHD simultaneously with CMV infection in four (13%), regenerative changes post-GVHD in five (16%), CMV infection in four (13%), and normal or unspecific in nine (29%). In 22 of the 31 patients (71%), the histological findings of the second/third endoscopic biopsies differed from the findings of the first endoscopy and led to a therapy change in 77%. In conclusion, serial GI endoscopies are of reliable diagnostic value and can impact on therapeutic decision-making for patients with persistent diarrhea after allo-SCT.
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Infecciones por Citomegalovirus/diagnóstico , Diarrea/etiología , Endoscopía Gastrointestinal , Enfermedades Gastrointestinales/diagnóstico , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto , Anciano , Biopsia , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/patología , Diarrea/diagnóstico , Femenino , Enfermedades Gastrointestinales/patología , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Persona de Mediana Edad , Trasplante Homólogo/efectos adversosRESUMEN
Loss of E-cadherin is a key initial step in the transdifferentiation of epithelial cells to a mesenchymal phenotype, which occurs when tumor epithelial cells invade into surrounding tissues. Expression of the nuclear factor ZEB1 induces an epithelial-to-mesenchymal transition and confers a metastatic phenotype on carcinomas by repressing the E-cadherin gene at the transcriptional level. In this study, we show that ZEB1 interacts with the SWI/SNF chromatin-remodeling protein BRG1 to regulate E-cadherin independently of CtBP, its traditional co-repressor. Blocking the interaction between ZEB1 and BRG1 induces expression of E-cadherin and downregulation of the mesenchymal marker vimentin. ZEB1 and BRG1 colocalize in E-cadherin-negative cells from cancer lines and in the stroma of normal colon. Colocalization of ZEB1 and BRG1 in epithelial cells is only found in those de-differentiated cells characterized by nuclear beta-catenin staining at the invasive edge of the tumor. Our results identify ZEB1/BRG1 as a new transcriptional mechanism regulating E-cadherin expression and epithelial-to-mesenchymal transdifferentiation that may be involved during the initial stages of tumor invasion.
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Cadherinas/antagonistas & inhibidores , ADN Helicasas/metabolismo , Células Epiteliales/citología , Proteínas de Homeodominio/metabolismo , Mesodermo/citología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Desdiferenciación Celular , Línea Celular Tumoral , Colon/citología , Colon/metabolismo , Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Especificidad de Órganos , Regiones Promotoras Genéticas/genética , Transporte de Proteínas , Transcripción Genética , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Human epithelial tumors need to accumulate multiple genetic alterations to form invasive carcinomas. These genetic alterations are related with growth factor receptors, cell signalling, the cell cycle and cell invasiveness. Importantly, cells need to avoid senescence and become immortalized for this process. Recently, five genes: RPS6KA6, HDAC4, KIAA0828, TCP1 and Tip60, which modulate p53-dependent function and avoid senescence were identified in a large-scale RNA interference screen. Twenty colon, 20 prostate and 20 lung carcinomas were studied to investigate whether these genes might be related with human tumors. RNA was extracted from both normal and tumor tissue from each patient. Real-time RT-PCR was performed using TaqMan probes corresponding to the RPS6KA6, HDAC4, KIAA0828, TCP1, Tip60 and p53 genes. In colon carcinomas, the RPS6KA6, HDAC4, KIAA0828 and Tip60 genes were downregulated in tumor tissue as compared with normal tissue (P < 0.001 for all genes). In lung carcinomas, HDAC4, KIAA0820 and Tip60 were downregulated (P < 0.01, P < 0.001 and P < 0.001 respectively). Whereas no significant differences were observed in prostate carcinomas, striking downregulation of the RPS6KA6 and KIAA0828 genes was observed in colon carcinomas and KIAA0828 in a subset of lung carcinomas. mRNA expression of these genes may control p53 function as well as the ras-MAPK pathway, methylation and transcriptional cellular programs. These results could unravel a novel set of regulatory suppressor genes involved in human colon and lung tumors.
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Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Pulmonares/genética , Proteína p53 Supresora de Tumor/genética , Chaperonina con TCP-1 , Chaperoninas/genética , Chaperoninas/metabolismo , Neoplasias del Colon/metabolismo , Regulación hacia Abajo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Lisina Acetiltransferasa 5 , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Factores de Intercambio de Guanina Nucleótido rasRESUMEN
UNLABELLED: The product of the ATM gene, mutated in the human genetic disorder ataxia-telangiectasia (A-T) plays a key role in the detection and repair of DNA double-strand breaks. A-T is defined by progressive cerebellar ataxia, telangiectasia, sensitivity to ionising radiation and genomic instability with cancer predisposition. On the other hand, increased angiogenesis is essential for tumor growth and metastasis. The aim of this study was to investigate ATM expression in breast carcinomas and its relationship to neoangiogenesis. METHODS AND RESULTS: Fifty-two breast tumors from 51 patients, 38 of them with concomitant in situ component (CIS), were analyzed by immunohistochemistry for the expression of ATM. CD34 expression was used for the morphometric evaluation of vasculature. ATM was positive in 1 to 10% of normal epithelial cells. ATM expression was reduced in 55.8% of infiltrating carcinomas, non-reduced in 34.6%, and increased in 9.6%. Expression of ATM in CIS was similar to the infiltrating component in 71% of cases and reduced in 23.7% of them. High-grade ductal infiltrating carcinomas showed lower ATM expression than low-grade ones. Reduced ATM expression also correlated with increased microvascular area. CONCLUSIONS: Reduced ATM expression in breast carcinomas correlated with tumor differentiation and increased microvascular parameters, supporting its role in neoangiogenesis and tumor progression in breast carcinogenesis.
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Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Neovascularización Patológica/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Antígenos CD34/análisis , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/irrigación sanguínea , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/patología , Proteínas de Ciclo Celular/fisiología , Diferenciación Celular , Daño del ADN , Proteínas de Unión al ADN/fisiología , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Inmunohistoquímica , Neovascularización Patológica/fisiopatología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Supresoras de Tumor/fisiologíaRESUMEN
PURPOSE: Intense investigation has reshaped concepts about undifferentiated tumors occurring in young people (small round-cell tumors). Tumors associated with t(11;22)(p13;q12) and descriptively designated desmoplastic small round-cell tumor (DSRCT) are a distinctive, rare, poorly understood member of this family. We reviewed 109 cases of DSRCT to further characterize this entity better. METHODS: Clinical information and histology were reviewed. Immunohistochemistry and immunoblotting were performed using standard techniques. Chimeric EWS-WT1 RNA and DNA were detected by polymerase chain reaction (PCR) and genomic translocation breakpoints mapped in a subset of cases. RESULTS: There were 90 males and 19 females from 6 to 49 years of age (mean, 22 years). A total of 103 had tumor in the abdominal cavity, four in the thoracic region, one in the posterior cranial fossa, and one in the hand. Typical histologic and immunohistochemical features were usually evident in well-sampled tumors, but variations in cellularity, stromal components, cytology, architecture, and immunoreactivity occurred. Tumor cells were usually reactive with antibodies to keratin (67 of 78 cases, 86%), epithelial membrane antigen (50 of 54, 93%), vimentin (64 of 66, 97%), desmin (70 of 78, 90%), neuron-specific enolase (60 of 74, 81%), and the EWS-WT1 chimeric protein (25 of 27, 93%); typically nonreactive for muscle common actin (one of 58, 2%), myogenin (zero of eight, 0%), and chromogranin (one of 46, 2%); and variably reactive for MIC2 (nine of 47, 20%) and p53 (five of 17 with > 20% tumor cells reactive). Functional EWS-WT1 gene fusion was evident in 25 of 26 cases with genomic breakpoints in WT1 intron 7, and EWS introns 7, 8, and 9. Prognosis in general is poor, but tumors are responsive to aggressive therapy. CONCLUSION: This large review identifies a greater degree of clinical, pathologic, and molecular variation than originally appreciated for tumors associated with t(11;22)(p13;q12). Translocation and functional fusion of the EWS and WT1 genes appears to be a consistent feature of this unique tumor.
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Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 22 , Translocación Genética , Neoplasias Abdominales/genética , Neoplasias Abdominales/metabolismo , Neoplasias Abdominales/patología , Adulto , Carcinoma de Células Pequeñas/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Femenino , Ribonucleoproteínas Nucleares Heterogéneas , Humanos , Masculino , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteína EWS de Unión a ARN , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Ribonucleoproteínas/biosíntesis , Ribonucleoproteínas/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Proteínas WT1RESUMEN
BACKGROUND: To assess the putative prognostic value of K-ras mutations in nonmucinous ovarian tumors, the authors looked for K-ras point mutations at codons 12 and 13 in 144 nonmucinous ovarian tumors. METHODS: A series of 144 consecutive, unselected, archival, nonmucinous ovarian tumors (35 benign, 12 borderline, and 97 malignant) were studied. K-ras mutations at codons 12 and 13 were determined by polymerase chain reaction using the restriction fragment length polymorphism method with mismatched nested primers. Extensive clinicopathologic and follow-up data on all patients were evaluated. RESULTS: The overall prevalence of K-ras mutations at codons 12 and 13 was 30.5% (44/144). In benign tumors, it was 20% (7/35); in borderline tumors, 25% (3/12); and in carcinomas, 35% (34/97). The presence of K-ras point mutations did not correlate with survival. Among the benign tumors, K-ras mutations were detected in three Brenner tumors with a mucinous component. CONCLUSIONS: These results indicate that K-ras mutations are not initial events in the pathogenesis of nonmucinous ovarian tumors and do not appear to be related to survival.
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Carcinoma/genética , Genes ras/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Mutación Puntual , Adulto , Anciano , Anciano de 80 o más Años , Codón , ADN de Neoplasias/análisis , Femenino , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: To assess the role of K-ras mutations in the pathogenesis of mucinous ovarian tumors, the authors looked for K-ras point mutations at codons 12 and 13 in 95 mucinous ovarian neoplasms. The results were subsequently correlated with the clinicopathologic data. METHODS: Benign, borderline, and malignant mucinous ovarian tumors were identified microscopically. DNA was extracted from formalin fixed, paraffin embedded tissue, and target sequences were amplified in vitro by polymerase chain reaction. Mutations were detected by the presence of restriction fragment length polymorphisms artificially introduced by the use of mutant amplimers. In tumors containing areas that exhibited different histologic grade, precise microdissection of each of these areas was performed. The results were correlated with the clinical data and the morphologic features of the neoplasms. RESULTS: The overall frequency of codon 12/13 ras gene mutations was 68%. Codon 12 point mutations were present in 63% of the cases (55.7% of mucinous cystadenomas, 73% of borderline tumors, and 85% of carcinomas). Codon 13 mutations were detected in 11.5% of the tumors (five cystadenomas, three borderline tumors, and three carcinomas). Eight tumors (three benign, two borderline, and three malignant) exhibited mutations at codons 12 and 13. In 12 of the 15 tumors with 2 areas showing different histologic grade, identical point mutations were detected separately in both areas. CONCLUSIONS: The results of this study confirm that K-ras mutations do occur in benign and particularly in malignant mucinous ovarian tumors. The authors' findings support the hypothesis that K-ras mutational activation is an early event in mucinous ovarian tumorigenesis.
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Codón/genética , Cistadenocarcinoma Mucinoso/genética , Cistoadenoma Mucinoso/genética , Genes ras/genética , Neoplasias Ováricas/genética , Mutación Puntual/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Cistadenocarcinoma Mucinoso/patología , Cistoadenoma Mucinoso/patología , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-->TGT; Tyr-->Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.
Asunto(s)
Adenocarcinoma Folicular/metabolismo , Neoplasias Encefálicas/secundario , Carcinoma/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias de la Tiroides/patología , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/secundario , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Carcinoma/genética , Carcinoma/secundario , Diferenciación Celular , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Tiroglobulina/metabolismo , Neoplasias de la Tiroides/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
K-ras and p53 gene alterations are frequently found in human pancreatic carcinomas and cell lines. The aim of this study was to analyze for the presence of K-ras and p53 gene mutations in hamster pancreatic tumors and cell lines. Mutations at the first coding exon of the K-ras gene and in exons V to VIII of the hamster p53 gene were analyzed in six cell lines (H2T, PC1, PC1.2, PC1.0, WD, and PD) and in N-nitroso-bis(2-oxopropyl)amine-induced pancreatic (n = 9) and extra-pancreatic (n = 4) tumors. K-ras mutations were present in seven of the nine pancreatic tumors and in all extra-pancreatic tumors. No p53 mutations were detected in the tumors. All cell lines analyzed contained K-ras mutations. Moreover, four of the six cell lines contained single amino acid substitutions in the p53 gene. Cell lines derived from nitrosamine-induced pancreatic tumors in the hamster contained K-ras and p53 alterations similar to those found in cell lines derived from human pancreatic carcinomas.
Asunto(s)
Carcinoma Ductal de Mama/genética , Genes p53/genética , Genes ras/genética , Mutación/genética , Neoplasias Pancreáticas/genética , Animales , Carcinógenos , Carcinoma Ductal de Mama/inducido químicamente , Cricetinae , Nitrosaminas , Neoplasias Pancreáticas/inducido químicamente , Polimorfismo Conformacional Retorcido-Simple , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To assess the sensitivity and specificity of pancreatic fine needle aspiration. STUDY DESIGN: Two hundred five fine needle aspirates were obtained from 149 patients over seven years. After excluding 40 patients lacking biopsy or follow-up, 125 aspirates from 109 patients were selected to analyze the accuracy of this method. (male:female ratio, 1.4:1; age range 43-79 years). RESULTS: The cytologic diagnosis was true positive in 50 studies (45.9%), false positive in 0, true negative in 25 (22.9%), false negative in 19 (17.4%) and suspicious for malignancy in 17 (15.6%); 14 aspirations (12.8%) yielded material unsatisfactory for a diagnosis. Of the 17 suspicious studies, 15 were from patients in whom a malignancy was confirmed later. The other two patients had chronic pancreatitis. CONCLUSION: The efficiency was 79.8%, sensitivity 72.5%, and specificity and predictive value of a positive result 100%. Cell blocks provided sufficient material in 96.8% of cases and smears in 90.4%. No major complications were reported after fine needle aspiration.
Asunto(s)
Biopsia con Aguja , Páncreas/patología , Neoplasias Pancreáticas/patología , Pancreatitis/patología , Adulto , Anciano , Enfermedad Crónica , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Mucinous tumors of the ovary are often associated with mucinous tumors of the appendix. It has not been clearly determined whether they are independent or metastatic neoplasms. A clinicopathologic study and a comparative analysis of c-Ki-ras mutations were done in six cases of synchronous ovarian and appendiceal tumors. The clinicopathologic features (simultaneous presentation, bilaterality or right-sided predominance, similar histopathologic findings, presence of pseudomyxoma peritonei) suggested that they were primary appendiceal tumors metastatic to the ovaries. DNA was extracted from formalin-fixed, paraffin-embedded tissue, and target sequences were amplified in vitro by the polymerase chain reaction. Mutations were detected by the presence of restriction fragment length polymorphism, artificially introduced by the use of mutant amplimers. The pattern of c-Ki-ras mutations was identical in the ovarian and appendiceal tumors of all patients. Four patients had a GGT --> GAT (Gly --> Asp) transition and one a GGT --> GTT (Gly --> Val) transversion, all detected in codon 12. No mutation was found in the sixth patient in either the ovarian or the appendiceal tumor. Because c-Ki-ras mutations are considered to represent an early event in tumorigenesis, our results support a clonal nature for both tumors and suggest that they are not independent tumors but rather originate one from another.