Stuart O. Zimmerman

THE EFFECT OF CELECOXIB, A CYCLOOXYGENASE-2 INHIBITOR, IN FAMILIAL ADENOMATOUS POLYPOSIS

BACKGROUND Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

A Nonlinear Model of Population Dynamics Containing an Arbitrary Number of Continuous Structure Variables

A nonlinear model is presented for the dynamics of a population in which each individual is characterized by its chronological age and by an arbitrary finite number of additional structure variables. The nonlinearities are introduced by assuming that the birth and loss processes, as well as the maturation rates of individuals, are controlled by a functional of the population density. The model is a generalization of the classical Sharpe-Lotka-McKendrick model of age-structured population growth, the nonlinear age-structured model of Gurtin and MacCamy, and the age-size-structured cell population model of Bell and Anderson. Based on a reformulation of the model in terms of a coupled system of equations, the existence for all positive time of unique solutions to the model is proved using a contraction mapping argument. The existence of equilibrium solutions is discussed, and sufficient conditions are proved for the local asymptotic stability of equilibria using results from the theory of strongly continuous...

The relationship between dental disease and radiation necrosis of the mandible

Preirradiation panoramic radiographs of forty-six dentate patients were examined for the presence of significant dental disease. The occurrence of necrosis of the mandible after these patients received radiation therapy was then determined. Evidence of a positive association between dental disease present before radiation therapy and subsequent necrosis of the mandible was found (p = 0.09), leading to a recommendation that significant disease be eradicated before irradiation of oral tissues. Two cases are reported to illustrate the complications that can arise in dentate patients following radiation to the oral cavity. Considerable suffering results from bone necrosis, which can be reduced by careful and rational dental diagnosis and treatment.

Development of an Integrated Biospecimen Bank and Multidisciplinary Clinical Database For Pancreatic Cancer

BackgroundThe integration of biospecimens with reliable clinical data is critical to advance molecular findings from the laboratory to the clinic. We describe the development of an integrated pancreatic tissue bank (PTB) and clinical database for patients with pancreatic cancer and other pancreatic disorders.MethodsA clinical database and PTB were created in 1990 and 2000, respectively, to collect clinical information and biospecimens from patients with suspected or confirmed pancreatic cancer, other pancreatic diseases, and tumors of the duodenum, ampulla of Vater, and distal bile duct. Standard procedures for biospecimen collection and data entry were developed.ResultsFrom 2000 through 2006, the PTB collected 8,061 pancreatic tissue specimens from 620 patients. The most common histologies of pancreatic tumors were pancreatic ductal adenocarcinoma (55.3%) and neuroendocrine carcinoma (16.3%). The biospecimen collection also includes 431 plasma samples, 40 fine-needle aspiration samples, and a tissue microarray containing 85 pancreatic adenocarcinomas and matched normal tissue specimens. The clinical database contains information for 7,647 patients with pancreatic cancer, other pancreatic disorders, and duodenal, ampullary, or bile duct neoplasms. The data are arranged into nine modules: patient, presentation, risk factors, diagnostic imaging, treatment plan, surgery, pathology, postoperative complications, and follow-up.ConclusionsWe have established a pancreatic cancer tissue bank with standardized procedures for collection of biospecimens along with a comprehensive multidisciplinary clinical database. The integrated biospecimen bank and clinical database for pancreatic cancer described here can serve as a model from which other groups may develop similar systems.

Suppression of Delayed and Contact Hypersensitivity Responses in Mice Have Different UV Dose Responses

Although acute exposure to UV radiation suppresses the induction of delayed‐type (DTH) and contact (CHS) hypersensitivity in mice, it is not clear whether the photo‐biological mechanism(s) involved in suppressing these closely related immune reactions is the same. A careful examination of the UV dose responses and wavelength dependencies involved in suppressing CHS and DTH may provide important insights into the mechanisms involved. We compared the UV dose‐response curves for suppressing four closely related immune reactions, local and systemic suppression of CHS to dinitrofluorobenzene, systemic suppression of DTH to Candida albicans and systemic suppression of DTH to alloantigen using three different UV spectra (FS40 sunlamps, Kodacel‐filtered FS40 sunlamps and solar‐simulated light). For each immune response studied, the amount of UVB radiation required to induce 50% immune suppression was lowest when FS40 sunlamps were used, highest with solar‐simulated light and intermediate when Kodacel‐filtered FS40 sunlamps were used, but the differences observed were not statistically significant. The UV dose‐response curves for immune suppression differed significantly depending on the assay used, the site of antigenic sensitization and the antigen used. These findings suggest that the mechanisms by which UV radiation induces immune suppression differ for the four immunological reactions studied.

A mathematical model of the regulation of the G1 phase of Rb +/+ and Rb —/— mouse embryonic fibroblasts and an osteosarcoma cell line

A mathematical model integrating the roles of cyclin D, cdk4, cyclin E, cdk2, E2F and RB in control of the G1 phase of the cell cycle is described. Experimental results described with murine embryo fibroblasts (MEFs), either Rb +/+ or Rb —/—, and with the RB‐deficient osteosarcoma cell line, Saos‐2, served as the basis for the formulation of this mathematical model. A model employing the known interactions of these six proteins does not reproduce the experimental observations described in the MEFs. The appropriate modelling of G1 requires the inclusion of a sensing mechanism which adjusts the activity of cyclin E/cdk2 in response to both RB concentration and growth factors. Incorporation of this sensing mechanism into the model allows it to reproduce most of the experimental results observed in Saos‐2 cells, Rb —/— MEFS, and Rb +/+ MEFs. The model also makes specific predictions which have not been tested experimentally.

Mathematical models for the cellular concentrations of cyclin and MPF

Several mathematical models have been proposed for regulation of the cell cycle in early embryos by cyclin and maturation-promoting factor (MPF). In this paper the previously proposed models for cyclin and MPF activity are analyzed, and the validity of those models based on the mathematical behavior of their solutions and on physical considerations are discussed. In addition, three further models are proposed that exhibit the periodic behavior necessary for modeling the mitotic clock but that do not have certain of the limitations of the other models.

A model for regulation of the cell cycle incorporating cyclin A, cyclin B and their complexes

Abstract. t. A mathematical model for the cell cycle is proposed that incorporates the known biochemical reactions involving both cyclin A and cyclin B, the interactions of these cyclins with cdc2 and cdk2, and the controlling effects of cdc25 and weel. The model also postulates the existence of an as yet unknown phosphatase involved in the formation of maturation promoting factor. The model produces solutions that agree qualitatively with a wide variety of experimentally observed cell‐cycle behavior. Conditions under which the model could explain the initial rapid divisions of embryonic cells and the transition to the slower somatic cell cycle are also discussed.

MDA-Image: An environment of networked desktop computers for teleradiology/pathology

MDA-Image, a project of The University of Texas M. D. Anderson Cancer Center, is an environment of networked desktop computers for teleradiology/pathology. Radiographic film is digitized with a film scanner and histopathologic slides are digitized using a red, green, and blue (RGB) video camera connected to a microscope. Digitized images are stored on a data server connected to the institutions computer communication network (Ethernet) and can be displayed from authorized desktop computers connected to Ethernet. Images are digitized for cases presented at the Bone Tumor Management Conference, a multidisciplinary conference in which treatment options are discussed among clinicians, surgeons, radiologists, pathologists, radio-therapists, and medical oncologists. These radiographic and histologic images are shown on a large screen computer monitor during the conference. They are available for later review for follow-up or representation.

Tools for Study: National Databanking

Some considerations bearing on the creation of a national databank for urotheilal cancer are discussed, including some potential applications of such a resource. A brief discussion of database design issues and caBIG™ serve to highlight the importance of teamwork and semantic interoperability. Finally, some specific data elements are put forward as a starting framework for the design of such a national repository.