Citations

The National Heart, Lung, and Blood Institute (NHLBI) convened a conference call working group, consisting of experts in stroke and cerebrovascular biology on January 28, 2005. The purpose of this working group was to develop a prioritized set of recommendations for NHLBI to establish a focused and comprehensive set of research activities in cerebrovascular biology and disease. Three thematic areas of research emerged: (1) molecular and cellular neurobiology of cerebral blood vessels, focusing on genomics and proteomics, neurovascular signaling and cerebrovascular embryogenesis, development and plasticity; (2) resource development, involving the development of new methodological approaches for normal and altered function of the neurovascular unit, collaborative research, and training in cerebrovascular pathobiology; and (3) cerebrovascular diseases and translational approaches, addressing vascular mechanisms of disease, the role of risk factors, importance of biomarkers with the ultimate goal of developing new treatments.

Abstract Tumor-associated eosinophilia has been observed in numerous human cancers and several tumor models in animals; however, the details surrounding this eosinophilia remain largely undefined and anecdotal. We used a B16-F10 melanoma cell injection model to demonstrate that eosinophil infiltration of tumors occurred from the earliest palpable stages with significant accumulations only in the necrotic and capsule regions. Furthermore, the presence of diffuse extracellular matrix staining for eosinophil major basic protein was restricted to the necrotic areas of tumors, indicating that eosinophil degranulation was limited to this region. Antibody-mediated depletion of CD4+ T cells and adoptive transfer of eosinophils suggested, respectively, that the accumulation of eosinophils is not associated with T helper cell type 2-dependent immune responses and that recruitment is a dynamic, ongoing process, occurring throughout tumor growth. Ex vivo migration studies have identified what appears to be a novel chemotactic factor(s) released by stressed/dying melanoma cells, suggesting that the accumulation of eosinophils in tumors occurs, in part, through a unique mechanism dependent on a signal(s) released from areas of necrosis. Collectively, these studies demonstrate that the infiltration of tumors by eosinophils is an early and persistent response that is spatial-restricted. It is more important that these data also show that the mechanism(s) that elicit this host response occur, independent of immune surveillance, suggesting that eosinophils are part of an early inflammatory reaction at the site of tumorigenesis.

AbstractWe have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial pancreatic cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with pancreatic cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident pancreatic cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 (N = 72,700). The mean age ± SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 ± 11.8 and was 65.4 ± 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 ± 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all pancreatic cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(4):704–10)

AbstractBackgroundSolid pseudopapillary neoplasms of the pancreas are rare malignant lesions of the pancreas that typically occur in young women. Large series from any one centre are notably absent in the literature. The aim of this study was to determine long-term outcomes of operative therapy.MethodsThe records of all 14 patients diagnosed with pseudopapillary neoplasms of the pancreas over 17 years were reviewed.ResultsThirteen of the 14 patients were female and the mean age at diagnosis was 30 years. Solid pseudopapillary neoplasm was suspected in only half of these patients before operation. On computed tomography, ultrasonography and/or magnetic resonance imaging, three lesions were solid, three were largely cystic, and five had solid and cystic components. All 14 patients underwent surgical exploration and curative resections were possible in 13, including distal pancreatectomy in nine, pancreaticoduodenectomy in three and resection of a local intraperitoneal recurrence in one patient. After follow-up ranging from 3 months to 20 years, 12 patients were alive, including one who had undergone re-exploration and resection of local and subcutaneous recurrences 9 years previously.ConclusionSolid pseudopapillary neoplasm of the pancreas should be considered in the differential diagnosis of any solid or partly cystic pancreatic mass in women aged less than 35 years. An attempt at en bloc resection without formal lymphadenectomy should be undertaken, including resection of synchronous or metachronous distant metastases.

Abstract B7-H1 participates in T-cell costimulation functioning as a negative regulator of immunity. Recent observations suggest that B7-H1 is expressed by renal cell carcinoma (RCC) tumor cells and is associated with poor prognosis. However, outcome analyses have been restricted to patients with fresh-frozen tissue and limited follow-up. We report the clinical effect of B7-H1 in RCC patients with a median of 10 years of follow-up. Between 1990 and 1994, 306 patients underwent nephrectomy for clear cell RCC and had paraffin tissue available for review. We did immunohistochemistry with anti-B7-H1 and conducted outcome analyses. Among the 306 patients, 73 (23.9%) harbored tumors with B7-H1 expression. Patients with tumor B7-H1 were at a significantly increased risk of both death from RCC [risk ratio (RR), 3.92; P < 0.001] and overall mortality (RR, 2.37; P < 0.001). The 5-year cancer-specific survival rates were 41.9% and 82.9% for patients with and without tumor B7-H1, respectively. In a multivariate model, tumor B7-H1 remained associated with cancer-specific death even after adjusting for tumor-node-metastasis stage, grade, and performance status (RR, 2.00; P = 0.003). In the subset of 268 patients with localized RCC, tumor B7-H1 was significantly associated with metastatic cancer progression (RR, 3.46; P < 0.001) and death from RCC (RR, 4.13; P < 0.001) even after adjusting for stage, grade, and performance status (RR, 1.78, P = 0.036). RCC patients with tumor B7-H1 are at significant risk of rapid cancer progression and accelerated rates of mortality. B7-H1 may function as a key determinant in RCC, abrogating immune responses directed against this immunogenic tumor. (Cancer Res 2006; 66(7): 3381-5)