RESUMEN
BACKGROUND: We report the immunological and pathological findings of a 52-year-old woman, who died two years after the second of two islet transplants performed using the Edmonton protocol. After each islet transplant, she gradually lost insulin independence while maintaining low levels of C-peptide secretion. METHODS: A complete autopsy was performed including pathological and immunohistochemical analysis of hepatic allogeneic islets and native pancreatic islets to identify rejection or autoimmunity. Elispots assays for allogeneic sensitization and autoantibody assays for autoimmunity were performed antemortem after her islet transplantations to test in vitro for evidence of allogeneic sensitization or autoimmunity. RESULTS: The cause of death was a hypertensive stroke. Small numbers of islets without inflammation were identified within portal venules and stained with insulin. The atrophic pancreas contained small numbers of islets, which stained for insulin, and lacked any inflammation within or adjacent to the islets. In vitro assays for alloantibodies were negative, and Elispots assays failed to identify allogeneic sensitization. In vitro assays for diabetic associated autoantibodies did not identify autoimmune resensitization. The allografted kidney showed only early changes of recurrent diabetic nephropathy, and no evidence of rejection. CONCLUSIONS: In summary, no evidence was found to support an immunological basis (either allo or autoimmunity) for the slow loss of intrahepatic islets, which may, therefore, be related to nonimmunological anatomic and physiological abnormalities of islets infused into the portal veins or to drug toxicity.
Asunto(s)
Diabetes Mellitus Tipo 1/cirugía , Rechazo de Injerto/patología , Supervivencia de Injerto , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/patología , Atrofia , Autopsia , Péptido C/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Resultado Fatal , Femenino , Hemoglobina Glucada/metabolismo , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Insulina/uso terapéutico , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/cirugía , Persona de Mediana Edad , Vena Porta/patología , Insuficiencia del TratamientoRESUMEN
The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2(-/-)) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2(-/-) mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2(-/-) mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2(-/-) tumors contained similar numbers of mitotic cells, but IRS-2(-/-) tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2(-/-) mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1(-/-) tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.
Asunto(s)
Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/secundario , Fosfoproteínas/metabolismo , Animales , Apoptosis , Secuencia de Bases , Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , ADN de Neoplasias/genética , Femenino , Humanos , Proteínas Sustrato del Receptor de Insulina , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mitosis , Invasividad Neoplásica , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , FosforilaciónRESUMEN
Endoscopic ultrasound-guided pancreatic fine-needle aspiration biopsy very frequently produces gastrointestinal epithelial contamination (GIC). We studied the cytomorphology and B72.3 immunoreactivity of lesional epithelium of benign and malignant ductal lesions of the pancreas and compared the findings to our previously established template of GIC. Air-dried smears, fixed smears, and ThinPrep (TP) specimens were obtained using a cytobrush, directly from benign and malignant ductal lesions of 18 Whipple specimens, to ensure purity of the epithelium studied. Smear background, cell architecture, and cellular features were analyzed. Immunocytochemical staining with B72.3 was performed in 14 cases. Epithelium of ductal carcinoma was distinguished from benign ductal epithelium in chronic pancreatitis and GIC primarily by crowded architecture and atypical cellular features, including high nuclear-to-cytoplasmic ratio, irregular nuclei, nucleoli, and vacuolated cytoplasm. Benign ductal and GIC epithelium were only distinguished by architecture (goblet cells and brush borders), but not consistently, especially gastric epithelium that lacked these features. B72.3 shows promise in the differentiation between GIC and benign and malignant ductal epithelium, with no staining supporting benign ductal cells, fine punctate perinuclear staining correlating with GIC, and strong cytoplasmic staining supporting malignancy.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Carcinoma Ductal Pancreático/patología , Mucosa Gástrica/patología , Mucosa Intestinal/patología , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/patología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antineoplásicos/metabolismo , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Citodiagnóstico/métodos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Mucosa Gástrica/metabolismo , Humanos , Técnicas para Inmunoenzimas , Mucosa Intestinal/metabolismo , Conductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatitis Crónica/metabolismo , Coloración y EtiquetadoRESUMEN
Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) has become a widely used method of pre-operatively evaluating pancreatic masses. This technique introduces gastrointestinal contamination into the specimen, which poses a diagnostic pitfall. The cytomorphologic features of these contaminants have not been fully characterized. The current study was designed to systematically document the cytomorphology of gastric and duodenal epithelium on fixed and air-dried smears, as well as ThinPrep (TP) preparations, and to assess the reactivity of the epithelial cells to the tumor marker B72.3 so as to establish a baseline for future comparative studies with EUS-FNAB of the pancreas. Air-dried and fixed smears and TP specimens were obtained using a cytobrush from gastric (GM) and duodenal (DM) mucosa from 14 Whipple specimens. Cytologic features of cell architecture, cellular features and smear background were analysed. Immunocytochemical staining with B72.3 was performed in 10/14 cases. Mucin was present in all preparations except one case from the duodenum. It was consistently present as isolated thick to thin clumps but never as diffuse 'colloid-type' mucin; it was most prominent on air-dried smears, and most abundant from the GM. Epithelial cells were admixed with mucin, but degenerated cells and inflammation were not present within the mucin. Mucin on TP appeared as fragmented wisps of pale blue staining material. Background inflammation and debris were not significant findings. The epithelial cells were arranged in large and small monolayered sheets. Smaller groups were more common from GM on smears and more abundant on TP than smears. Luminal edges (DM>GM) were a prominent feature, with a brush border noted in DM. The nuclei of GM and DM were round, evenly spaced and without atypia, and dense, non-vacuolated cytoplasm was the rule, with the exception of goblet cells and occasional gastric foveolar cells noted in one case. In both GM and DM, B72.3 stained goblet cells with a strong, coarsely granular pattern and stained epithelial cells focally in a finely granular, punctate, perinuclear distribution; mucin also stained strongly in all cases. These baseline characteristics provide a template for assessing mucin and epithelial GM and DM contamination on pancreatic EUS-FNAB specimens.