44.1

Relationship between Ongoing Participation in Colorectal Cancer Screening and Method of Invitation Alicia Smith, Bronwyn Cadd, Joylene Morcom, Daniel Byme, John Guy, Stephen Cole, Graeme P. Young

Background: As fecal occult blood tests (FOBTs) do riot reliably detect all cancers, methods of increasing the rates of p~.rticipation in repeated screening must be developed in order to maximise the reduction in mortality. Endorsement by primary care practitioner (PCP) improves participation at initial offer (Cole et al, j Meal Screening, 2002 in press), but it is not known if it maintains a higher rate of ongoing participation. Aim: To determine the effect of PCP endorsement on participation rates over three rounds of annual screening based on a fecal immunocbemieal test (FIT) for hemoglobin. Setting: Invatees aged 50-69 years were randomly selected from the patient lists of two urban Adelaide primary care practices Methods: A FIT was offered by mail to 872 invttees in the first round, and subsequently to all who met inclusion criteria, regardless of prior participation status Exclusions: not contactable at address, colonoscopy for any reason in prior five years. Mode of offer varied, from no endorsement or naming of PCP (Endorsed-) to high level endorsement in an invitation letter signed by the PCP (Endorse/+) Subject participation, test positivaty and neoplastic yield were observed across all three screening rounds. Results: Participation at any time throughout the program was signffieantly enhanced by PCP endorsement (see Table). PCP endorsement also maintained the increased rate of participation over the three rounds. Drop-outs (22 % of initial participants in Endorse/- and 17% in Endorse/+ in Round 2) were counterbalanced by new participants entering the program, such that overall participation rates did not fall in subsequent rounds. Overall, 4% (38/952) of tests were positive Significant neoplasms (3 with cancers and 8 with adenomas) were found in all rounds, including in subjects who previously returned negative tests. Conclusions: PCP endorsement maintained improved participation rates across three rounds of screening. Screening programs based on FOBI will be most effecuve in reducing mortality when PCPs are involved in repeated offers. This principle might also apply to screening programs based on other methods.

EndomeJ- Endon~+ P value Year 1 152/447 (3,4%) 1851425 (44%) 0.004 Year 2 152/415 (37%) 182/391 (47%) 0,004 Yur 3 1371355 (39%) 155/330 (47%} 0.027 Any Year 222/447 {50%) 2411425 (57%) 0.037

442

A Prospective Study of Gastric Cancer Development by Endoscopic Follow Up; Risk Ratio Assessment by Serum Pepsinogen and Anti Helicobacter Pylori Antibody Status in 6983 Japanese Subjects Hirotsugu Watabe, Goichi Toga, Yutaka Yamaji, Makoto Okamoto, Haruhiko Yoshida, Takao Kawabe, Ryoichi Wada, Tom Mitsushima, Masao Omata

(Purpose) We previously reported that the combination of serum pepsinogen and anti Helicobacter pylori (H. pylori) IgG antibody was a quite useful marker for the prevalence of gastric cancer in a cross-sectional setting (Yamaji Y. et al. GUT2001;49:335-40). We con/~ucted a prospective, follow up study of a larger cohort by serial endoscopic surveillance We aimed to elucidate the availability of serological test by a combination of serum pepsinogen and H. pylori antibody for the prediction of development of gastric cancer. (Method) Between March 1995 and February 1997, the subjects who paruclpated in our medical health check up program and underwent upper endoscopy were consecutively studied. The subjects wath gastric cancer, peptic ulcer, and past history of surgical resection of stomach were excluded. Finally, a total of 6983 subjects who underwent at least one follow up endoscopy were enrolled into this study. The mean duration of follow up was 4.7 years, and the mean number of endoscopy was 5.1 sessions. Subjects were classified into four groups according to serum pepsinogen and H. pylori antibody at the enrollment Of the total 6983 subjects, 3324 (476 %) were allocated to group A; "normal" pepstnogen and negative for H pylori antibody, 2 t 34 (306 %) to group B; "normal" pepsinogen and positive for H pylori antibody, 1082 (15.5 %) to group C; "low" pepsinogen and positive for H pylori antibody, and 443 (6.3 %) to group D; "low" pepsinogen arid negative for H pylon antibody. Incidence of newly developed gastric cancer and serological status at the enrofimem were analyzed. (Result) Among the 6983 subjects, 43 cases developed gastric cancer during the follow up period. The incidence rate of gasmc cancer was 0.62 % in a whole follow-up period. The incidence per year was O13 %. Of the 43 newly developed gastric cancer eases, 7 cases developed from group A (incidence rate per year: 0.04%), 6 cases developed from group B (0.06%), 18 cases developed from group C (0.35%), and 12 cases developed from group D (0.60%). Hazard ratios (95%C1) matched by age and gender compared with group A were; 1.1 (0 35-3.2) in group B, 5.0 (21-12) in group C, and 71 (2.7-18) in group D. In subjects older than 60 years old, group D had especially high incidence of gastric cancer, 1.7%/year. (Conclusion) Combination of serum pepsinogen and anti H. pylon antibody is a good predictive marker for the development of gastric cancer.

443

Detection of RNA for the CCK-C Receptor in Peripheral Blood: A Predictor for Pancreatic Cancer Alex 1 Fahoury, Wayne B. Stanley, lan S. Zagon, Jill P. Smith

Clinical diagnosis of pancreatic cancer usually requires invasive and expensive radiographic or endoscopic procedures. Blood tests have not been useful for screening and detection of pancreatic cancer in early stages. A novel tumor marker, called the CCK-C (cancer) receptor (CCK-Cr) has recently been characterized. This receptor is associated with pancreatic cancer, and is not found in normal pancreatic tissue. The purpose of this investigation was to determine whether the presence of CCK-Cr RNA in peripheral blood can distinguish popula- tions of patients with pancreatic cancer from control subjects The research protocol was

approved by the Institutional Review Board committee, and all volunteers signed an informed consent. Anticoagulated blood was collected from each subject, and cells were separated from plasma by centnfugation. Red blood cells were lysed with a butler containing NI~CI, KHCO3, and EDTA and total RNA was extracted from the remaining pelleted ceils. RNA was subjected to reverse transcription PCR in the presence of oligonucleotide primers compatible with the sequence for the CCK-Cr. RNA integrity was confirmed by the presence of the housekeeping gene GAPDH. PCR products were analyzed by gel electrophoresls Sixteen of the 17 patients with known adenocarcinoma of the pancreas tested positive for CCK-Cr RNA. Controls included 6 normal volunteer medical students and 12 subjects with other pancreatic disorders including 4 with benign cysts, 3 with chronic pancreatitis, 4 with acute relapsing pancreatitis, and 1 with an islet cell tumor. All 18 control subjects with the exception of one individual with chronic pancreatitis tested negative for CCK-Cr RNA. The sensitivity and specificity of this test for CCK-Cr RNA in blood for predicting pancreatic cancer is 94.1 and 94.4 %, respectively In conclusion, the detection of RNA for the CCK- Cr in peripheral blood is highly associated with the diagnosis of pancreatic cancer. This finding may be of importance as a diagnostic test to distinguish between benign and malignant pancreatic diseases. Supported by NIH grants, R01 CA85713 and K24 CA82303, and a Tobacco Settlement grant.

444

How Much Colorectal Cancer Screening Are We Doing? Estimates From a Population-Based Study kinda Rabeneck, Lawrence Paszat

Background: Colorectal cancer (CRC) incidence and mortality rates in Canada are among the highest in the world. For example, the incidence rates in Ontario are second only to US blacks, and exceed those in US whites. Despite this, there are no population-based studies that estimate the extent of CRC screening in Canada. In the US, the best estimates of CRC screening were obtained from surveys and are not populauon-based. Objectives: To conduct a population-based study to estimate the extent of CRC screening in Ontano, which has a publicly funded universal access health care system and is the largest province (population 11 million) in Canada. Methods: We identified an inception cohort of all residents of Ontario aged 50-59 yr on 1/1/95 without a prior history of CRC or large bowel evaluation by five tests or procedures: fecal occult blood test (FOBT), barium enema, rigid sigmoidoscopy, flexible sigmoidoscopy, and cohinoscopy. We followed these individuals to 12/31/00, identified all tests received, and determined the proportion that had one or more tests or procedures of each type. Data were obtained from: 1) the Canadian Institute for Health Information Discharge Abstract Database, which contains information on all discharges from acute facilities for residents of Ontario; and 2) the Ontario Health Insurance Plan (OH1P) database, which contains information on claims for physicians' services provided to Ontario residents. Results: We identified 982,443 individuals in our inception cohort without prior CRC or targe bowel evaluation. The proportion that had at least one test or procedure was less than 10% for each test. The largest proportion (93%) had at least one FOBT. A larger proportion (14.5%) had at least one non-endoscopic test (FOBT, barium enema) tMn the proportion (6%) that had at least one endoscopic test (rigid sigmoidoscopy, flexible sigmoidoscopy, cohinoscopy). The majority (79.5%) had no test or procedure to evaluate the large bowel. Because we can not determine whether tests were done for screening or for diagnostic work-up, the proportion that had CRC screening must be less than 21.5% Conclusions: There are no published US or Canadian population-based estimates of the extent of CRC screening. We determined that a very low proportion (<21.5%) of screen- eligible 50-59 year old men and women in Ontario were screened for CRC during a 6 year follow-up. Given the strong scientific evidence that supports CRC screening, coupled with national guidelines, it is time for a national CRC screening policy in Canada.

445

Regulated Reorganization of the Actin Cytoskeleton in Motile Pancreatic Tumor Cells by a Dynamin-Cortactin Complex Eugene W. Kmeger, James D. Orth, Hong Cao, Mark A. McNiven

Metastatic pancreatic tumor cells actively remodel the aetin cytoskeleton in response to motogenic stimuli such as EGF. Currently, the mechanism by which this reorganization process is mediated is unclear. The large GTPase dynamin (Dyn2) has recently been implicated in the regulation of the actin cytoskeleton at the leading edge of migrating cells (McNiven et al., JCB 2000). This regulation is believed to be mediated in part by the actin binding, SH3 domain containing protein cortactin that is also a Src substmte. The GOAL of this study was to define the roles of these interacting proteins as mediators of actin cytoskeletal reorganization in growth factor stimulated human pancreatic tumor cells of dncmlar origin (PANCI). Within minutes following stimulation with either PDGF or EGF, PANC1 cells displayed a remarkable coalescence of Dyn2, cortactin, and actin into discrete spots along the leading edge. These puncta moved inward along the dorsal membrane toward the cell center in a "wave" like fashion, with a concomitant disassembly of actin stress fibers. Fluorescence quanritation of polymerized actin levels confirmed that there was an 80% reduction of actin polymer in the cytoplasm following wave migration. Additionalimmunoflu- orescence staining coupled with Western blot analysis showed that wave structures were also comprised of the Arp2/3 complex and the scaffolding protein N-WASp Expression of truncated mutant cortactin and Dyn2 proteins in stimulated cells resulted in a substantial (60%-70%) reduction in wave formation. Importantly, the formation of these structures appears to be essenual for stimulated cells to become polarized and extend a dynamic lamellipodia from the anterior leading edge. Quantitative measurements showed a stmng correlation between the site of wave formation and lamellipodial extension. SUMMARY- These observations suggest that cortactin and Dyn2 function synergistically in a novel, multi- protein complex that assembles in response to growth factor stimulation and mediates the remodeling of actin, and subsequent cell polarization through lamelfipod growth. These findings provide novel insights into the molecular mechanisms by which pancreatic tumor cells initiate the early stages of metastatic migration. Supported by grant RO1 DK56647 to MAM.

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