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Purpose: To create an easily applicable system based on a combination of the quantitative level of IMP3 (an oncofetal protein) and tumor stage to more accurately predict postoperative metastasis of localized renal cell carcinoma. Experimental Design: Three hundred sixty nine patients with localized renal cell carcinoma (without metastasis during nephrectomy) were investigated by the use of survival analysis. The expression of IMP3 was evaluated by immunohistochemistry and quantitated with a computerized image analyzer. Based on combining quantitative IMP3 results with tumor staging (QITS system), patients were divided into four distinct risk groups for the development of metastasis. Results: The four groups of patients in the QITS system showed significant differences in their metastasis-free (P < 0.0001) and overall survivals (P < 0.0001). Almost all patients of group IV with localized renal cell carcinomas developed metastasis and died after nephrectomy. The 5-and 10-year metastasis-free survival rates for the QITS groups were as follows: for group I, 97% and 91%; II, 62% and 55%; III, 46% and 19%; and IV, 17% and 4%, respectively. The 5-and 10-year overall survival rates for the QITS groups were as follows: for group I, 89% and 72%; II, 58% and 41%; III, 38% and 17%; and IV, 14% and 4%, respectively. Conclusions: The QITS is a simple and accurate system for the prediction of tumor metastasis. This system not only provides important prognostic information but also can be used at initial diagnosis of localized renal cell carcinoma to identify high-risk patients who may benefit from early systematic therapy.

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BACKGROUND.Whether an oncofetal protein, IMP3, can serve as a prognostic biomarker to predict metastasis for patients with localized papillary and chromophobe subtypes of renal cell carcinomas (RCCs) was investigated.METHODS.The expression of IMP3 in 334 patients with primary papillary and chromophobe RCC from multiple medical centers was evaluated by immunohistochemistry. The 317 patients with localized papillary and chromophobe RCCs were further evaluated for outcome analyses.RESULTS.IMP3 was significantly increased in a subset of localized papillary and chromophobe RCCs that subsequently metastasized. Patients with localized IMP3‐positive tumors (n = 33; 10%) were over 10 times more likely to metastasize (risk ratio [RR], 11.38; 95% confidence interval [CI], 5.40‐23.96; P < .001) and were nearly twice as likely to die (RR, 1.91; 95% CI, 1.13–3.22; P = .016) compared with patients with localized IMP3 negative tumors. The 5‐year metastasis‐free and overall survival rates were 64% and 58% for patients with IMP3‐positive localized papillary and chromophobe RCCs compared with 98% and 85% for patients with IMP3 negative tumors, respectively. In multivariable analysis adjusting for the TNM stage and nuclear grade, patients with IMP3‐positive tumors were still over 10 times more likely to progress to distant metastasis (RR, 13.45; 95% CI, 6.00–30.14; P < .001) and were still nearly twice as likely die (RR, 1.95; 95% CI, 1.15–3.31; P = .013) compared with patients with IMP3‐negative tumors.CONCLUSIONS.IMP3 is an independent prognostic biomarker that can be used to identify a subgroup of patients with localized papillary and chromophobe RCC who are at high risk for developing distant metastasis. Cancer 2008. © 2008 American Cancer Society.

Accurate diagnosis of dysplasia and adenocarcinoma in patients with Barrett esophagus is critical for clinical decision-making and patient management. IMP3 is an oncofetal protein and has been demonstrated to be associated with aggressive tumor behavior. The aim of this study was to establish the expression pattern and diagnostic value of IMP3 in Barrett esophagus, dysplasia, and carcinoma. A total of 217 cases (resection, n=56; biopsy, n=161) with 302 lesions (invasive esophageal adenocarcinoma, n=147; metastatic esophageal adenocarcinoma, n=14; high-grade dysplasia of the esophagus, n=52; low-grade dysplasia of the esophagus gland, n=21; and Barrett esophagus, n=68) were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic granular staining in 138 of 147 (94%) of invasive esophageal adenocarcinomas, 13 of 14 (93%) of metastatic esophageal adenocarcinomas, and 49 of 52 (94%) of high-grade dysplasias. In contrast, 3/21 (14%) of low-grade dysplasia and 5/68 (7%) Barrett esophagus were positive for IMP3. Expression of IMP3 was not found in adjacent benign squamous and glandular mucosa. Our findings indicate that IMP3 is a highly sensitive and specific biomarker for the diagnosis of invasive esophageal adenocarcinoma and high-grade dysplasia. The data also suggest that IMP3, an oncofetal protein, may play an important role in malignant transformation in esophageal adenocarcinoma.

Aims/hypothesis. Advanced glycation and lipoxidation endproducts have been implicated in the pathogenesis of diabetic complications, including diabetic nephropathy. LR-90, a new advanced glycation endproduct inhibitor, was investigated for its effects on the development of renal disease in diabetic rats. Methods. Diabetic animals were randomly allocated into groups receiving LR-90 or vehicle (untreated). Age-and weight-matched non-diabetic rats were studied concurrently. Body weight, plasma glucose, glycated haemoglobin, urinary albumin and creatine excretions were measured serially. Kidney histopathology, AGE accumulation in cells and tissues, protein oxidation, were also examined. In vitro assays were used to assess the possible mechanism of action of LR-90. Results. LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced crosslinking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine. Conclusion/interpretation. LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

N Context.-One of the major clinical challenges is to predict recurrence of meningioma. Recently, we have found that IMP3, an oncofetal RNA-binding protein, is a biomarker to predict aggressive tumors.Objective.-To investigate whether IMP3 can be used as a new biomarker to predict the recurrence and overall survival of patients with meningiomas.Design.-One hundred seven patients with primary meningiomas were investigated for expression of IMP3 by immunohistochemistry and whether expression of this molecule correlated with tumor recurrence and overall survival.Results.-Tumor recurrence was found in 13 of 107 patients with primary meningioma. Seven of 107 patients (6.5%) with primary meningiomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much higher recurrence rate (P = .004) and a poorer overall survival (P , .001) than did patients with IMP3-negative tumors. The 5-year recurrence-free and overall survival rates were 0% and 36% in IMP3-positive patients versus 89% and 94% in IMP3-negative patients, respectively. Multivariable analysis of IMP3 status (positive versus negative) in primary tumors showed a hazard ratio of 17.89 for recurrence (P = .01), which was much higher than hazard ratios associated with all other known risk factors including higher tumor grades and Ki-67 labeling index.Conclusions.-IMP3 is a potential independent prognostic biomarker that can be used at the time of initial diagnosis of meningioma to identify patients who have a high risk of developing a recurrence.

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