Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (110 [17%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days...

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

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Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G 1 -S and G 2 -M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIA in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting. (Cancer Res 2005; 65(13): 5628-37)

Since its reported discovery in 1994, maspin (mammary serine protease inhibitor) has been characterized as a class II tumor suppressor by its ability to promote apoptosis and inhibit cell invasion. Maspin is highly expressed in normal mammary epithelial cells but reduced or absent in aggressive breast carcinomas. However, despite efforts to characterize the mechanism(s) by which maspin functions as a tumor suppressor, its molecular characterization has remained somewhat elusive. Therefore, in an attempt to identify maspin-interacting proteins and thereby gain insight into the functional pathways of maspin, we employed a maspin-baited yeast twohybrid system and subsequently identified Interferon Regulatory Factor 6 (IRF6) as a maspin-binding protein. IRF6 belongs to the IRF family of transcription factors, which is best known for its regulation of interferon and interferon-inducible genes following a pathogenic stimulus. Although many of the IRF family members have been well characterized, IRF6 remains poorly understood. We report that IRF6 is expressed in normal mammary epithelial cells and that it directly associates with maspin in a yeast two-hybrid system and in vitro. The interaction occurs via the conserved IRF protein association domain and is regulated by phosphorylation of IRF6. We have shown that, similar to maspin, IRF6 expression is inversely correlated with breast cancer invasiveness. We further demonstrated that the transient re-expression of IRF6 in breast cancer cells results in an increase of N-cadherin and a redistribution of vimentin commensurate with changes in cell morphology, suggestive of an epithelial-to-mesenchymal transition event. Concomitantly, we showed that maspin acts as a negative regulator of this process. These findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation. Maspin2 (mammary serine protease inhibitor, SerpinB5) was first isolated by subtractive hybridization and differential display as a protein that is expressed in normal mammary epithelial cells but reduced or absent in breast carcinomas (1). Since its initial discovery, maspin has been shown to inhibit tumor invasion and metastasis in breast cancer cells (2). Further studies implicate maspin as an angiogenesis inhibitor by its ability to block neovascularization and reduce tumor-associated microvessels and also demonstrate a role for maspin in the induction of apoptosis of tumor cells (3-4). In addition, the overexpression of maspin in transgenic mice disrupts normal mammary gland development by increasing apoptosis and disrupting cell differentiation (5). Despite the characterization of maspin as a tumor suppressor, the molecular mechanisms underlying maspin function are complex and remain predominantly unknown. Therefore, in an effort to decipher the molecular mechanisms of maspin, we employed a yeast two-hybrid system, in which we expressed full-length maspin as bai...

Pancreatic cystic lesions include inflammatory pseudocysts, benign serous tumors, and mucinous neoplasms, some of which are malignant. Clinical and radiologic indices are often inadequate to discriminate reliably among these possibilities. In an attempt to develop new preoperative diagnostic criteria to assist in decisions regarding therapy, the authors have performed cyst fluid analysis for tumor markers (carcinoembryonic antigen: CEA, CA 125, and CA 19.9), amylase content, amylase isoenzymes, relative viscosity, and cytology on 26 pancreatic cysts. The cases included nine pseudocysts, five serous cystadenomas, 4 mucinous cystic neoplasms, 7 mucinous cystadenocarcinomas, and one mucinous ductal adenocarcinoma with cystic degeneration. Carcinoembryonic antigen levels were high (> 367) in all benign and malignant mucinous cysts, but were low (< 23) in the pseudocysts and benign serous cystadenomas, an indication that CEA discriminates between mucinous and nonmucinous cysts (p < 0.0001). Values for CA 125 were high in all malignant cysts, low in pseudocysts, and variable in mucinous cystic neoplasms and serous cystadenomas. Levels of Ca 19.9 were nondiscriminatory. Cyst fluid amylase and lipase content were variable but were generally high in pseudocysts and low in cystic tumors. Amylase isoenzyme analysis was useful to differentiate pseudocysts from cystic tumors. Measurement of the relative viscosity in cyst fluid showed high (> serum viscosity) values in 89% of mucinous tumors and low values (< serum) in all pseudocysts and serous cystadenomas (p < 0.01). Cytologic analysis of cyst fluids was of limited value in differentiating pseudocysts from serous cystadenoma, but in seven of eight mucinous tumors provided useful diagnostic information and correctly classified three of five malignant tumors. The authors conclude that cyst fluid analysis can provide a preoperative classification of these diagnostically difficult lesions. The combination of viscosity, CEA, CA 125, and cytology can reliably distinguish malignant cystic tumors and potentially premalignant mucinous cystic neoplasms from pseudocysts and serous cystadenomas. Amylase content with isoenzyme analysis is useful to identify pseudocysts.

The regulation of cell adhesion and motility in human prostate is not well understood. We have previously shown that the endoglin gene is differently expressed during changes in prostate cell adhesion. Endoglin is a transmembrane transforming growth factor b binding protein typically expressed by endothelial cells. In this report we demonstrate that endoglin over expression increases prostate cell attachment, while decreasing migration and invasion. Engineered decreases in endoglin expression have opposite effects. While endoglin exerted only relatively small effects upon cell adhesion, large effects upon cell migration and invasion were observed. Endoglin was shown to localize to focal adhesion plaques, consistent with its role in regulating cell adhesion and motility. Loss of endoglin expression in cancer, as compared to normal prostate, was seen in human prostate cell lines. Suppression of endoglin expression in a panel of normal human prostate cell lines led to cell detachment. Endoglin is identified as a regulator of cell adhesion, motility and invasion in human prostate. Loss of endoglin expression appears to be associated with prostate cancer progression, at least in vitro.

ObjectiveThe purpose of the study was to determine the prevalence of activating K-ras mutations in the pancreas of patients with intraductal papillary mucinous tumors (IPMT) and to analyze their relation to the degree of site-specific histopathologic abnormality.