RESUMEN
BACKGROUND AND STUDY AIMS: Angiographic and surgical therapy are standards of care for persistent diverticular bleeding. Colonoscopic intervention using epinephrine injection, multipolar electrocautery, and placement of an Endoclip has not gained widespread acceptance due to concerns about complications,and the widespread management of severe lower gastrointestinal bleeding by surgeons and interventional radiologists. The utility of colonoscopic band ligation for control of diverticular bleeding was evaluated both in vivo and ex vivo. PATIENTS AND METHODS: Endoscopic band ligation of diverticula was performed on surgical resection specimens and in patients with actively bleeding colonic diverticula. RESULTS: In the in-vivo study, active diverticular bleeding was completely controlled in four patients by endoscopic band ligation. In two cases, a visible vessel was seen on the everted and banded diverticulum. Procedure time ranged from 45 to 140 min. The total lengths of hospital stays for the four patients were 2, 6, 14, and 35 days. The long hospital stays (> 7 days)were associated with non-gastrointestinal co-morbidity. There were no acute complications of band ligation. No rebleeding or need for surgery occurred during a follow-up period of 12 months in any of the patients. In the ex-vivo study, 11 diverticula were successfully everted and banded in five of nine surgical specimens (one right colon and four left colons). Mucosa was identified in all of the "banded" segments. Ten of 11 ligated diverticula revealed evidence of blood vessels or submucosal tissue. The presence of subserosal fat was suggested in three of the 11 "banded" segments, and none of the ex-vivo ligated diverticula contained muscularis propria or serosal involvement. There was no evidence of perforation. CONCLUSIONS: Both in-vivo and ex-vivo data suggest that endoscopic band ligation may be a safe and effective therapy for actively bleeding colonic diverticula.
Asunto(s)
Colonoscopía , Divertículo del Colon/cirugía , Hemorragia Gastrointestinal/cirugía , Anciano , Anciano de 80 o más Años , Divertículo del Colon/complicaciones , Estudios de Factibilidad , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Tiempo de Internación , Ligadura , Masculino , Proyectos Piloto , Neoplasias del Recto/cirugíaRESUMEN
BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.
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Antiinflamatorios/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/administración & dosificación , Fármacos Gastrointestinales/administración & dosificación , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Factor 10 de Crecimiento de Fibroblastos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Hipoglucemia/etiología , Islotes Pancreáticos/patología , Enfermedades Pancreáticas/patología , Diagnóstico Diferencial , Femenino , Glucosa/uso terapéutico , Humanos , Hiperinsulinismo/diagnóstico , Hiperplasia , Hipoglucemia/terapia , Recién Nacido , Páncreas/patología , Enfermedades Pancreáticas/complicaciones , Nutrición Parenteral Total , Convulsiones/etiologíaRESUMEN
OBJECTIVE: To determine the presence of telomerase activity in a variety of periampullary malignancies and pancreatic diseases and quantify its activity to establish any association with the stage or aggressiveness of malignancy. SUMMARY BACKGROUND DATA: Progressive shortening of telomeres, repetitive DNA sequences at the ends of chromosomes, plays a role in cell senescence. Telomerase catalyzes conservation of telomeric repeats and may promote cell immortality and hence malignancy. It is absent in normal tissues but upregulated in more than 80% of cancers. METHODS: Fresh specimens of 62 periampullary tumors were snap-frozen in liquid nitrogen and adjacent tissue was formalin-fixed for histopathology. The telomerase repeat amplification protocol (TRAP) was used to obtain telomerase DNA products. These were separated with gel electrophoresis, stained with SYBR green, and quantified by densitometry. Findings were confirmed with a fluorometric TRAP assay in which fluorescent primers specific for telomerase were selectively amplified in its presence. RESULTS: Telomerase activity was upregulated in 26 of 33 periampullary malignancies (79%): 17 of 21 pancreatic adenocarcinomas (81%), 2 of 2 cholangiocarcinomas, 2 of 2 duodenal carcinomas, and 5 of 8 ampullary carcinomas (63%). Poorly differentiated periampullary tumors had significantly higher telomerase activity than well-differentiated tumors, and tumors larger than 2 cm had significantly higher telomerase activity than those 2 cm or smaller. Pancreatic ductal adenocarcinomas with lymph node metastases had significantly greater activity than node-negative cancers. Two of 11 intraductal papillary mucinous tumors were positive for telomerase activity, but only in foci of invasive carcinoma. Chronic pancreatitis (n = 7), serous cystadenomas (n = 5), benign mucinous cystic neoplasms (n = 4), neuroendocrine cancer (n = 1), and acinar cell carcinoma (n = 1) had no detectable telomerase activity. CONCLUSION: Telomerase activity is common in periampullary carcinomas. The magnitude of activity correlates with aggressiveness in pancreatic adenocarcinoma and may prove useful as a molecular index for biologic staging.
Asunto(s)
Neoplasias Pancreáticas/patología , Telomerasa/análisis , Adenocarcinoma/enzimología , Adenocarcinoma Mucinoso/enzimología , Ampolla Hepatopancreática , Biomarcadores de Tumor/análisis , Carcinoma Papilar/enzimología , Colangiocarcinoma/enzimología , Neoplasias Duodenales/enzimología , Fluorometría , Humanos , Metástasis Linfática , Neoplasias Pancreáticas/enzimología , Pancreatitis/enzimología , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To investigate whether a high-fat/high-protein diet (HFPD) acts as a promoter of the natural course of cancer growth in the 7,12-dimethylbenzanthracene (DMBA)-induced ductal pancreatic cancer model in rats. SUMMARY BACKGROUND DATA: DMBA implantation to the rat pancreas induces ductal adenocarcinoma. Information regarding the effects of diet and the presence of K-ras mutation in this model is not available. METHODS: Rats were randomly assigned to regular rat chow or a diet with a 30% content in fat and protein (HFPD). The presentation of cancer, the histologic spectrum of neoplasia at 1 and 9 months, and the prevalence of cancer in relation to diet were assessed. Histologic specimens comprising normal ducts, hyperplasia, dysplasia/carcinoma in situ, or carcinoma were designated by a pathologist and microdissected. Genomic DNA was extracted, and K-ras and H-ras gene mutations were determined by a mutant-enriched polymerase chain reaction assay and direct sequencing. RESULTS: Rats fed HFPD increased their weight significantly compared with controls. DMBA induced characteristic stages of neoplasia at the implant site but not elsewhere. Macroscopic cancers of the pancreatic head presented regularly with common bile duct and gastric outlet obstruction. The prevalence of K-ras mutations was proportional to the degree of epithelial abnormality. K-ras mutations were significantly more frequent in cancer than in normal and hyperplastic ducts. H-ras mutations were not found. At 1 month in the HFPD-fed rats, the prevalence of cancer (16%) and dysplasia (16%) was not significantly different from the prevalence of cancer (29%) and dysplasia (8%) in the chow-fed rats. At 9 months the prevalence of cancer in the HFPD-fed rats increased to 29%, whereas that in the chow-fed rats decreased to 17%. The combined prevalence of cancer and dysplasia at 9 months in the HFPD-fed rats (34%) significantly exceeded that in the chow-fed rats. CONCLUSIONS: DMBA induces characteristic stages of neoplasia in the evolution of ductal pancreatic cancer in rats. K-ras mutations occur progressively in the ladder of oncogenesis, as in human pancreatic neoplasms. The addition of a diet with a high fat and protein content acts as a promoter of carcinogenesis, possibly by interfering with repair mechanisms and natural regression of early lesions.
Asunto(s)
Carcinoma Ductal Pancreático/etiología , Grasas de la Dieta/efectos adversos , Proteínas en la Dieta/efectos adversos , Neoplasias Pancreáticas/etiología , 9,10-Dimetil-1,2-benzantraceno , Animales , Genes ras/genética , Masculino , Mutación , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Pancreatic endocrine tumors (PETs) continue to be challenging diagnostic and prognostic lesions in surgical pathology and clinical medicine. These neoplasms can be graded into 1 of 3 tiers, based on histologic characteristics in likeness to epithelial neuroendocrine tumors in other anatomic sites. However, grade 1 tumors are by far the most common and are the most difficult to prognosticate. The most helpful features by which to gauge the behavior of such lesions include size (3 cm or larger); mitotic activity (2 or more mitoses per 10 high-power [x400] microscopic fields); marked nuclear atypia, especially with atypical mitoticfigures; predominant tumor synthesis of gastrin, vasoactive intestinal polypeptide, somatostatin, glucagon, calcitonin, or adrenocorticotropic hormone; complete nonfunctionality of the tumor at an immunohistochemical level; or invasion of blood vessels, nerves, or adjacent organs by the neoplasm. Differential diagnosis of PETs includes lesions such as solid-pseudopapillary neoplasms, acinar carcinomas, metastatic neuroendocrine tumors, and plasmacytomas.
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Tumores Neuroendocrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Núcleo Celular/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Microscopía Electrónica , Mitosis , Tumores Neuroendocrinos/clasificación , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pronóstico , Terminología como AsuntoRESUMEN
The molecular pathogenesis of human pancreatic endocrine tumors (PETs) is poorly understood. Three independent animal models have pointed to the pivotal role of the G1/S cell cycle transition in pancreatic endocrine cell proliferation. We thus hypothesized that the cell cycle regulator cyclin D1 may contribute to the pathogenesis of human PETs. Overexpression of cyclin D1 was identified in 43% of cases, and no correlation was observed with clinical phenotype. The novel observation of frequent overexpression of cyclin D1 suggests that this established oncogene may be implicated in the pathogenesis of human PETs. The absence of detectable alterations in cyclin D1 genomic structure suggests that the mechanism for its oncogenic activation in PETs may be transcriptional or posttranscriptional.
Asunto(s)
Ciclina D1/genética , Neoplasias Pancreáticas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Ciclina D1/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/patología , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugíaRESUMEN
Dietary inadequacy of folate enhances and folate supplementation suppresses colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an essential factor for DNA methylation and the de novo biosynthesis of nucleotides, aberrations of which play important roles in mutagenesis. This study investigated whether the mutational hot spots of the Apc and p53 genes for human colorectal cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether dietary folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg folate/kg diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Apc mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one adenocarcinoma. All mutations were single base substitutions, four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cluster region. Dietary folate had no effect on the frequency and type of Apc mutations. No mutations were detected in exons 5-9 of the p53 gene in neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutational hot spot of the p53 gene for human colorectal cancer is not commonly mutated. Although the low frequency of Apc mutations and the small number of neoplasms studied in this study might have precluded our ability to observe modulatory effects of folate, dietary folate appears to have no significant effect on Apc and p53 mutations.
Asunto(s)
Neoplasias Colorrectales/prevención & control , Dimetilhidrazinas/toxicidad , Ácido Fólico/administración & dosificación , Genes APC , Genes p53 , Mutación , Animales , Secuencia de Bases , Carcinógenos/toxicidad , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Cartilla de ADN , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Sprague-DawleyRESUMEN
Dimethylbenzanthracene (DMBA) induces pancreatic adenocarcinomas in rats 9 months after carcinogen exposure, with precursor lesions (tubular complexes) developing 1 month after initiation of treatment. Because previous studies have suggested an acinar cell of origin for these tumors, we investigated the expression pattern of ductal, acinar, and islet cell markers in these cancers to gain insight into their phenotype and cell of origin. Pancreatic neoplasms were induced in rats by implantation of DMBA into the head of the pancreas. Lesions studied included 10 early tubular complexes (DMBA for 2 weeks), 8 tubular complexes (DMBA for 1 month), and 10 adenocarcinomas (DMBA for 9 months). Normal rat pancreas served as a control. For comparison, 5 human ductal adenocarcinomas were also evaluated. Immunohistochemistry with ductal (keratin, cytokeratin 19, cytokeratin 20), acinar (chymotrypsin), and islet (chromogranin A) cell markers was performed to analyze the tissues. Rat tubular complexes and adenocarcinomas revealed strong expression of keratin, cytokeratin 19, and cytokeratin 20 in the cytoplasm of all neoplastic cells, absence of chymotrypsin, and rare immunoreactivity to chromogranin A. Human adenocarcinomas showed strong expression of keratin and cytokeratin 19 in all neoplastic cells, expression of cytokeratin 20 in 5-20% of cells, and absence of chymotrypsin and chromogranin A. Pancreatic adenocarcinomas induced by DMBA in rats express markers consistent with a ductal phenotype, as observed in human tumors. Ductal marker expression in early tumor stages suggests a ductal cell of origin.
Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Adenocarcinoma/inducido químicamente , Adenocarcinoma/patología , Anciano , Animales , Cromogranina A , Cromograninas/metabolismo , Quimotripsina/metabolismo , Femenino , Humanos , Inmunohistoquímica , Proteínas de Filamentos Intermediarios/metabolismo , Queratina-20 , Queratinas/metabolismo , Masculino , Páncreas/patología , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Although antibiotic therapy is emerging as effective initial treatment for patients with gastric lymphoma of mucosa-associated lymphoid tissue (MALT), there is a subset of patients for whom antibiotics are ineffective or inappropriate. Surgical resection can be curative, but total gastrectomy may be required for the eradication of all disease. To identify the optimal nonantibiotic therapy for early stage gastric MALT lymphoma, the authors retrospectively evaluated the Massachusetts General Hospital experience with gastric MALT lymphoma. METHODS: Disease patterns and treatment outcomes were retrospectively analyzed in data from 21 consecutive patients with gastric MALT lymphoma who were treated between 1978 and 1995 at the Massachusetts General Hospital. RESULTS: Sixteen patients were Stage IE, and 5 were in higher stages. Treatment consisted of resection with or without radiation or chemotherapy (14 patients), radiation alone (4 patients), or radiation plus chemotherapy (2 patients). Thirteen Stage IE patients received local therapy only. The 10-year actuarial relapse free survival rate for Stage IE patients was 93%, with 1 relapse among 15 treated patients. Because the patient who relapsed was treated successfully with chemotherapy, the 10-year cancer free survival was 100%. Overall survival for Stage IE patients was 93% at 5 years and 58% at 10 years, with no deaths from lymphoma. CONCLUSIONS: These data indicate that a high probability of long term remission can be achieved with only local treatment of patients with Stage I gastric MALT lymphoma. Preliminary results suggest that radiation therapy is well tolerated and effective and may well be the optimal nonantibiotic treatment for patients with localized gastric MALT lymphoma.
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Linfoma de Células B de la Zona Marginal/terapia , Neoplasias Gástricas/terapia , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Gastrectomía , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Humanos , Linfoma de Células B de la Zona Marginal/mortalidad , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/radioterapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Múltiples , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/radioterapia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Lymphomas arising in mucosa-associated lymphoid tissue (MALT) are indolent B-cell tumors that have a predilection for epithelial sites and often develop in a setting of chronic inflammation or autoimmunity. As many as 50% of low-grade MALT lymphomas contain an (11;18)(q21; q21) chromosomal translocation. Using fluorescence in situ hybridization, we have analyzed the position of recombination within chromosome 18 DNA in three examples of MALT lymphoma bearing this translocation. In all three cases, the breakpoint maps to DNA in BAC b357H2, covering about 150 kb of sequence. A previously undescribed, ubiquitously expressed gene, which we refer to as MALT1, was identified within this sequence and was found to be broken in one case for which we have definitively located the position of recombination between chromosomes 18 and 11. The sequence of this gene indicates the presence of two immunoglobulin-like C2 domains and a region of partial homology to caspases, suggesting a possible role for MALT1 in the regulation of apoptosis.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 18 , Linfoma de Células B de la Zona Marginal/genética , Proteínas de Neoplasias/genética , Translocación Genética , Secuencia de Aminoácidos , Secuencia de Bases , Caspasas/genética , Cromosomas Artificiales de Levadura/genética , Mapeo Contig , ADN de Neoplasias/análisis , Humanos , Intrones/genética , Datos de Secuencia Molecular , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Homología de Secuencia de Ácido Nucleico , Células Tumorales CultivadasRESUMEN
Fibrosing cholestatic hepatitis (FCH) has recently been described after solid organ transplantation in patients with hepatitis C virus (HCV) infection. Typically, FCH is characterized by an ominous clinical course leading to progressive hepatic failure and death if liver transplantation is not performed. Two HCV-infected patients underwent cadaveric renal transplantation for end-stage renal disease resulting from membranous nephropathy and diabetic nephropathy. The time intervals between transplantation and the biopsy diagnosis of FCH for the two patients were 7 months and 10 years. Both patients presented with jaundice, hyperbilirubinemia, and mild-to-moderate elevations in serum aspartate aminotransferase. One patient was also found to have type II mixed cryoglobulinemia. Interferon-alpha therapy was begun after a diagnosis of FCH was established by liver biopsy. Liver test abnormalities normalized rapidly. When cholestatic hepatic deterioration develops in an HCV-infected organ allograft recipient, the diagnosis of FCH should be considered and a liver biopsy performed. Our observations indicate that FCH can respond to antiviral therapy.
Asunto(s)
Colestasis Intrahepática/etiología , Hepatitis C/complicaciones , Trasplante de Riñón/efectos adversos , Cirrosis Hepática/etiología , Anciano , Antivirales/uso terapéutico , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/virología , Hepacivirus/inmunología , Hepatitis C/tratamiento farmacológico , Anticuerpos contra la Hepatitis C/sangre , Humanos , Interferón-alfa/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Masculino , Persona de Mediana EdadRESUMEN
Only two tumor suppressor gene loci, one on 3p25 and the MEN1 gene on 11q13, have thus far been implicated in the pathogenesis of sporadic human pancreatic endocrine tumors (PETs). A genome-wide allelotyping study of 28 human PETs was undertaken to identify other potential tumor suppressor gene loci. In addition to those on chromosomes 3p and 11q, frequent allelic deletions were identified on 3q (32%), 11p (36%), 16p (36%), and 22q (29%). Finer deletion mapping studies localized the smallest regions of common deletion to 3q27, 11p13, and 16p12.3-13.11. Potential candidate genes at these loci include WT1 (11p13), TSC2 (16p13), and NF2 (22q12), but no known tumor suppressor gene localizes to 3q27. The mean fractional allelic loss among these human PETs is 0.126, and no correlation was observed between allelic loss and clinical parameters, including age, sex, hormonal subtype, and disease stage. These findings highlight novel locations of tumor suppressor gene loci that contribute to the pathogenesis of human PETs, and several of these on 3p, 3q, and 22q are syntenic with loci on mouse chromosomes 9 and 16 that are implicated in a murine transgenic model of PETs.
Asunto(s)
Mapeo Cromosómico , Genes Supresores de Tumor , Neoplasias Pancreáticas/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 22/genética , Femenino , Eliminación de Gen , Marcadores Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patologíaRESUMEN
The molecular pathogenesis of pancreatic endocrine tumors is largely unknown. Such tumors are more likely to develop in individuals with the von Hippel-Lindau (VHL) syndrome. We sought to determine whether allelic loss of the recently identified VHL tumor suppressor gene on chromosome 3p25-26 occurs in the more common sporadic forms of these tumors. Allelic loss on chromosome 3p was identified in 33% of 43 patients with endocrine tumors of the pancreas. The smallest common region of allelic loss, however, centered not at the VHL locus, but rather at 3p25, centromeric to VHL. Furthermore, no mutations of the VHL gene were identified in these tumors. Loss of alleles on chromosome 3p was associated with clinically malignant disease, whereas tumors with retained 3p alleles were more likely to be benign. Thus, the VHL gene does not appear to play a pathogenic role in the development of sporadic pancreatic endocrine tumors. Instead, a locus at chromosome 3p25 may harbor a novel pancreatic endocrine tumor suppressor gene, and allelic loss of this chromosomal region may serve as a molecular marker that helps distinguish benign from clinically malignant disease.
Asunto(s)
Cromosomas Humanos Par 3/genética , Genes Supresores de Tumor/genética , Ligasas , Neoplasias Pancreáticas/genética , Proteínas Supresoras de Tumor , Ubiquitina-Proteína Ligasas , Adolescente , Adulto , Anciano , Alelos , Southern Blotting , Mapeo Cromosómico , Clonación Molecular , Femenino , Eliminación de Gen , Marcadores Genéticos , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Proteínas/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
BACKGROUND: Current experimental models of pancreatic cancer either fail to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal of pancreatic cancer that accurately mimics the human condition, we restricted carcinogenic exposure to the pancreas and specifically targeted ductal epithelial cells. Three different carcinogens were either implanted directly into the pancreas or infused into the pancreatic duct, with or without near-total pancreatectomy (as a means of inducing pancreatic ductal cell proliferation). METHODS: Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosoguanidine, or ethylnitronitrosoguanidine either through direct implantation into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation groups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pancreata were evaluated histologically. RESULTS: All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dysplasia beginning by 3 months and becoming more prominent at later time points. Only DMBA caused frequent invasive pancreatic ductal adenocarcinoma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreatic cancer development. CONCLUSIONS: Of the strategies tested, only direct implantation of DMBA into the rat pancreas frequently produces pancreatic cancer histologically similar to human ductal adenocarcinoma. The development of hyperplastic, atypical, and dysplastic changes preceding and accompanying carcinomas suggests that these lesions are preneoplastic. This model recapitulates the progression from normal to neoplastic epithelium and is likely to be useful for the study of morphologic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and therapeutic techniques.
Asunto(s)
Carcinógenos/farmacología , Carcinoma Ductal de Mama/inducido químicamente , Neoplasias Pancreáticas/inducido químicamente , 9,10-Dimetil-1,2-benzantraceno/efectos adversos , 9,10-Dimetil-1,2-benzantraceno/farmacología , Animales , Carcinógenos/efectos adversos , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Modelos Animales de Enfermedad , Fibrosarcoma/inducido químicamente , Fibrosarcoma/patología , Fibrosarcoma/cirugía , Hiperplasia , Masculino , Metilnitronitrosoguanidina/efectos adversos , Metilnitronitrosoguanidina/análogos & derivados , Metilnitronitrosoguanidina/farmacología , Pancreatectomía , Conductos Pancreáticos/patología , Conductos Pancreáticos/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Ratas , Ratas Sprague-Dawley , Sarcoma Experimental/inducido químicamente , Sarcoma Experimental/patología , Sarcoma Experimental/cirugíaRESUMEN
BACKGROUND: K-ras oncogene mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in their molecular pathogenesis. However, the earliest stage in which K-ras mutations can be detected in potential precursor lesions of pancreatic cancer remains unclear. This study evaluates pancreatic ductal hyperplasia in the setting of chronic pancreatitis, which predisposes to pancreatic cancer development, for K-ras codon 12 and 13 mutations. METHODS: Paraffin-embedded surgical specimens from 42 patients with chronic pancreatitis were examined microscopically for the presence of ductal hyperplasia. Both hyperplastic and nonhyperplastic ducts were microdissected from the specimens that contained hyperplasia (11 of 42). Four of the remaining specimens without hyperplasia served as controls. Genomic DNA was extracted, and polymerase chain reaction and amplification of the K-ras oncogene was performed. Polymerase chain reaction products were evaluated by means of hybridization to mutant specific oligonucleotide probes and by means of automated DNA sequencing. RESULTS: K-ras codon 12 mutations representing glycine to valine substitutions were present in 2 of (18%) 11 patients with ductal hyperplasia. No mutations were found in the controls without ductal hyperplasia. CONCLUSIONS: Our study supports the premise that K-ras mutations develop in a subset of chronic pancreatitis associated hyperplasia and provides a genetic basis for the potential progression of chronic pancreatitis to pancreatic cancer.
Asunto(s)
Genes ras , Mutación , Conductos Pancreáticos/patología , Pancreatitis/genética , Pancreatitis/patología , Adulto , Anciano , Secuencia de Bases , Enfermedad Crónica , ADN/genética , Femenino , Humanos , Hiperplasia , Masculino , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Sondas de Oligonucleótidos , Reacción en Cadena de la PolimerasaRESUMEN
Individuals with Prader-Willi syndrome (PWS) have excessive appetite with the ability to consume large quantities of food. Absence of vomiting and a high pain threshold are considered manifestations of the disorder. We present 6 patients with PWS with acute dramatic gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation with subsequent gastric necrosis. One individual died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy specimens--in 2 cases subtotal and distal, in the other with accompanying partial duodenectomy and pancreatectomy--showed similar changes. All cases demonstrated signs of ischaemic gastroenteritis. All specimens showed diffuse mucosal infarction with multifocal transmural necrosis. Vascular dilatation and small bifrin thrombi were apparent within the infarcted areas. These 6 women with PWS had acute idiopathic gastric dilatation. It is possible that a predisposition to acute gastric dilatation may be related to abnormal gastric homeostasis on a genetic basis. Understanding the mechanisms responsible for this event could increase the understanding of gastrointestinal and appetite regulation in individuals with PWS.
Asunto(s)
Dilatación Gástrica/genética , Dilatación Gástrica/patología , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/genética , Adulto , Niño , Preescolar , Cromosomas Humanos Par 15 , Femenino , Gastrectomía , Dilatación Gástrica/complicaciones , Humanos , Masculino , NecrosisRESUMEN
OBJECTIVES: The molecular pathogenesis of human pancreatic endocrine tumours (PETs) is largely unknown. One attractive candidate gene for involvement in pancreatic endocrine neoplasia is the retinoblastoma (Rb) tumour suppressor gene. A deletion of the Rb gene was recently described in a human insulinoma. In addition, mice harbouring a null mutation in the Rb gene bred with p53 mutant mice develop pancreatic endocrine tumours. Therefore, we sought to determine the role that allelic loss of Rb may play in a large series of human pancreatic endocrine tumours. PATIENTS AND MEASUREMENTS: 46 pancreatic endocrine tumours were obtained from 41 patients. Utilizing genomic DNA isolated from the tumour samples and control normal cells, 2 highly polymorphic microsatellite loci (D13S153 and Rb 1.20) located within the Rb gene were PCR amplified and examined for loss of heterozygosity. RESULTS: 2 patients were homozygous at both loci and thus uninformative. The remaining 39 had informative markers at one or both of these loci, and none of the tumours from these patients demonstrated allelic loss of Rb. CONCLUSIONS: In tumours in which Rb inactivation is pathogenetically important, somatic loss of one Rb allele commonly accompanies a point mutation or microdeletion within the other allele. Thus, the absence of demonstrable allelic loss in this large series strongly suggests that Rb gene inactivation is not frequently involved in the pathogenesis of human pancreatic endocrine tumours.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/genética , Eliminación de Gen , Genes de Retinoblastoma , Neoplasias Pancreáticas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Gastrinoma/genética , Marcadores Genéticos , Humanos , Insulinoma/genética , Masculino , Persona de Mediana EdadRESUMEN
We reviewed fine-needle aspiration biopsy (FNAB) cell blocks of hepatocellular carcinoma (HCC) (n = 16) and benign hepatic processes (n = 16) to evaluate the significance of reticulin staining (Gomori stain) in combination with standard cytomorphologic and architectural criteria. We analyzed the staining pattern using semiquantitative grading: normal, variable, decreased, or virtually absent. Also, we graded the cell thickness of the hepatic trabeculae as greater than or less than three cells. Fourteen of 16 biopsy specimens of benign processes demonstrated a normal reticulin framework, with staining outlining hepatic trabeculae less than three cell layers in thickness. Staining was markedly decreased in one case of steatosis and virtually absent in one case of cirrhosis. In contrast, all of the 16 HCCs demonstrated either a virtually absent (7 of 16), decreased (6 of 16), or variable (3 of 16) reticulin staining pattern, with thickened trabeculae greater than three cell layers. We conclude that the reticulin stain is a useful adjunct in the differential diagnosis of liver nodules on FNAB cell block preparations and that it is particularly useful in distinguishing HCC from benign hepatic processes. Virtually absent or decreased reticulin staining and staining outlining trabeculae greater than three cells in thickness support the diagnosis of HCC. Normal reticulin staining outlining well-defined hepatic trabeculae less than three cell layers in thickness supports the diagnosis of a benign hepatic process.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Técnicas Histológicas , Hepatopatías/diagnóstico , Reticulina/análisis , Biopsia con Aguja , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/patología , Diagnóstico Diferencial , Estudios de Evaluación como Asunto , Humanos , Hepatopatías/patologíaRESUMEN
BACKGROUND AND AIMS: Diminished folate status is associated with enhanced colorectal carcinogenesis. This study investigated the potential chemopreventive role of dietary folate in the dimethylhydrazine colorectal cancer model. SUBJECTS AND METHODS: Sprague-Dawley rats were fed diets containing either 0, 2 (daily dietary requirement), 8 or 40 mg folate/kg diet for 20 weeks. After five weeks of diet, rats were injected with dimethyl-hydrazine (44 mg/kg) weekly for 15 weeks. Fifteen weeks after the first injection of dimethylhydrazine, all rats were killed. Folate status was determined, and the entire colorectum from each rat was analysed for macroscopic and microscopic neoplasms. RESULTS: Plasma and colonic folate concentrations correlated directly with dietary folate levels (p < 0.005). The incidence of microscopic neoplasms was similar among the four groups. However, the incidence and the average number of macroscopic tumours per rat decreased progressively with increasing dietary folate levels up to 8 mg/kg diet (p < 0.05). In the strongly procarcinogenic milieu used in this study, folate supplementation at 20 times the basal requirement was associated with rates of macroscopic tumour development that were intermediate, and not statistically distinct, from rates observed at either 0 or 8 mg/kg diet. CONCLUSIONS: These data indicate that in this rat model, (a) increasing dietary folate up to four times the basal requirement leads to a progressive reduction in the evolution of macroscopic neoplasms from microscopic foci; and (b) folate supplementation beyond four times the requirement does not convey further benefit.