Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.
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Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake. (+info)
An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload.
(10/804)
The aim of this study is to establish a good animal model for esophageal adenocarcinoma (EAC) and to test the hypothesis that iron over-nutrition enhances EAC formation. With rats, esophagogastroduodenal anastomosis (EGDA) was accomplished by anastomosing the duodenum to the gastroesophageal junction. Iron supplementation was given by i.p. injection of iron dextran (4 mg Fe/kg/week). This model mimics the development of human EAC by introducing mixed reflux of gastric and duodenal contents. At 40 weeks after surgery, the body weight, food intake, hemoglobin, total serum iron, transferrin saturation, serum albumin, and plasma levels of alpha-tocopherol, gamma-tocopherol and retinol of the EGDA rats were not significantly different from those of the non-operated controls. The animals generally had only mild esophagitis, except that the area surrounding the anastomosis opening had more severe esophagitis. Columnar-lined esophagus (CLE), CLE with dysplasia, and EAC were diagnosed in 53.5, 34.9 and 25.6%, respectively, of the 43 rats. Intraperitoneal iron supplementation significantly enhanced esophageal lesions with CLE, CLE with dysplasia, and EAC to 78.0, 53. 7 and 53.7%, respectively, of the 41 rats. All the tumors were well-differentiated mucinous adenocarcinomas at the squamocolumnar junction area, where most iron deposition was observed. EGDA avoids nutritional problems seen in other animal models for EAC. We believe that direct anastomosis of squamous epithelium to columnar epithelium and mixed reflux of gastric and duodenal contents lead to the formation of CLE and EAC. With this model, we demonstrated that iron supplementation significantly enhanced EAC formation, suggesting that iron over-nutrition could also be a risk factor for human EAC. (+info)
Evaluation of the tyrosine kinase domain of the Met proto-oncogene in sporadic ovarian carcinomas*.
(11/804)
Most of the ovarian cancers originate from the ovarian surface epithelium derived from the coelomic mesothelium. The Met proto-oncogene encodes a transmembrane tyrosine kinase receptor (Met) that has the capacity to regulate cell proliferation and differentation and it is activated by hepatocyte growth factor. Trisomy of chromosome 7 and Met protein overexpression have been were observed in ovarian carcinomas, the papillary renal cancers and other solid tumors. Frequent mutations of Met proto-oncogene have been found in hereditary papillary renal cancer (HPRC) and most of the mutations are located in the tyrosine kinase domain. The aim of this study to perform a mutation analysis of exons 17 19 of Met proto-oncogene in epithelial ovarian tumors (EOTs). We have examined 24 tumor samples from patients, operated with EOTs. Mutation was detected in exon 18 in only one sample of 24 EOTs. Our results indicate that mutations located in the Met proto-oncogene is not a common event in EOT. It is not clear whether the mutation plays a role in the tumorigenesis or progression of EOT or not. (+info)
The significance of incidental noncardiac findings in Tc-99m sestamibi myocardial perfusion imaging: illustrated by a case.
(12/804)
Technetium 99m sestamibi is widely used in the evaluation of myocardial perfusion imaging. Although the aim of such imaging is cardiac evaluation, numerous other organs are included in the imaging field. Failure to identify incidental abnormal findings in these organs delays diagnosis and treatment. In common with other radiopharmaceutical agents, technetium 99m sestamibi is distributed throughout the body and accumulates in multiple tissues. When interpreting studies that involve this radiotracer, the physician must be aware of its physiologic distribution, in order to recognize abnormal uptake. We present an illustrative case in which areas of decreased tracer activity were noted incidentally during the evaluation of unprocessed single photon emission computed tomography data. These findings were due to metastasis of colon cancer to the liver. (+info)
Bcl-w expression in colorectal adenocarcinoma.
(13/804)
We have found that the anti-apoptotic Bcl-2 family protein, Bcl-w, was frequently expressed in colorectal adenocarcinomas, with 69/75 showing positive staining with anti-Bcl-w IgG. Adenomas demonstrated a much lower frequency of Bcl-w expression (only 1 of 17), as did adenocarcinomas from other epithelial tissues such as breast (0/8), stomach (1112) and cervix (0/12). Bcl-w status could be related to the histopathological classification of the tumours, with TNM stage III tumours showing significantly higher levels of expression than tumours of better prognostic grade (at P = 0.009). Those patients with node involvement also had tumours with significantly elevated levels of Bcl-w (at P = 0.02), compared to those which were node-negative. The results suggest that Bcl-w could play a general role in the progression from adenoma to adenocarcinoma in the colorectal epithelium. Currently, more data are being collected to allow us to assess the importance of Bcl-w for disease progression and patient survival. (+info)
Oxidative damage in an esophageal adenocarcinoma model with rats.
(14/804)
Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition. (+info)
Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence for monoclonal origin with subsequent divergence of the epithelial and sarcomatous components.
(15/804)
Neoplasms with mixed carcinomatous and sarcomatous growth patterns occur in many organs and tissues. The pathogenesis of these cancers is thought to be either the result of two independent neoplastic processes merging to form a single tumor, or a neoplasm of monoclonal origin that develops phenotypic diversity. To address this issue, we characterized molecular alterations in separately microdissected epithelial and sarcomatous areas in three cases of pancreatic mucinous cystic neoplasms with sarcomatous stroma. Using microsatellite markers for six chromosomal loci commonly deleted in infiltrating ductal adenocarcinomas of the pancreas, we found genetic alterations to be virtually identical between the sarcomatous and epithelial components of two of the three neoplasms. In the third neoplasm, we found allelic losses and retentions to be identical at five of the six chromosomal loci, but at a single locus, we noted allelic loss in the neoplastic epithelial component but not the sarcomatous component. The same neoplasms were also analyzed for activating point mutations in codon 12 of the K-ras gene by using mutant-enriched polymerase chain reaction and allele-specific oligonucleotide hybridization. A K-ras mutation was identified in the epithelial component of one of the three neoplasms (the same tumor with an additional allelic loss in the neoplastic epithelial cells), but the sarcomatous component of this tumor was wild-type at codon 12 of K-ras, as were both components of the other two neoplasms. Overall, these results suggest a monoclonal origin with subsequent divergence of the neoplastic epithelial and sarcomatous portions of these neoplasms. (+info)
Clinical and pathologic correlation of 84 mucinous cystic neoplasms of the pancreas: can one reliably differentiate benign from malignant (or premalignant) neoplasms?
(16/804)
OBJECTIVE: To determine whether the long-term behavior of cystic mucinous neoplasms of the pancreas could be predicted using a novel, precisely defined classification of benign mucinous cystadenomas, noninvasive proliferative cystic mucinous neoplasms, and invasive mucinous cystadenocarcinomas. The primary interest was to obtain long-term follow-up after complete resection to determine the recurrence rates based on this objective classification. BACKGROUND: Current understanding is that all cystic mucinous neoplasms of the pancreas are potentially malignant and that mucinous cystadenomas, when completely removed, are biologically benign. Cystadenocarcinomas are thought to be less aggressively malignant than ordinary ductal adenocarcinoma, but reported recurrence rates vary widely and are unpredictable. METHODS: All patients who underwent "curative" resection for cystic mucinous neoplasms at Mayo Clinic Rochester from 1940 to 1997 were identified. All available pathology slides, gross specimens, and clinical records were reviewed, eliminating patients with inadequate documentation. Neoplasms were reclassified as mucinous cystadenomas, noninvasive proliferative mucinous cystic neoplasms, or invasive cystadenocarcinomas based on specific histologic criteria. RESULTS: Of 84 patients (70 women, 14 men) with cystic mucinous neoplasms of the pancreas, 54 were classified as cystadenomas, 23 as noninvasive proliferative cystic mucinous neoplasms, and only 7 as cystadenocarcinomas. Recurrent disease developed in none of the 77 patients without invasion, but 5 of the 6 patients surviving resection for cystadenocarcinomas died of recurrent cystadenocarcinoma within 5 years. CONCLUSIONS: When the neoplasm is completely resected and subjected to adequate histopathologic examination based on these objective criteria, absence of tissue invasion predicts a curative operation and detailed follow-up may be unnecessary. In contrast, a histologic diagnosis of invasive cystadenocarcinoma portends a dismal prognosis, similar to that of typical ductal adenocarcinoma of the pancreas. (+info)