This Month in Gastroenterology

Abstract

Colorectal cancer (CRC) screening is effective in reducing the incidence of CRC and CRC-related mortality. Nonetheless, many Americans are still not screened for CRC. While colonoscopy and fecal occult blood testing with or with out flexible sigmoidoscopy are the most commonly used CRC screening tools, newer screening modalities are emerging, including computed tomographic colonography (virtual colonoscopy) and fecal DNA testing. Using a decision analytic Markov model of the natural history of colorectal cancer and census data, Ladabaum et al set out to estimate how widespread CRC screening, including the utilization of these new screening modalities, would impact health services demand and national clinical and economic outcomes. Ladabaum et al estimated that screening of 75% of the US population would result in a 17%–54% decrease in CRC incidence and a 28%–60% decrease in CRC-related mortality depending on the screening method used. Widespread screening did increase total annual CRC-related expenditures $0.8–$7 billion compared with the total annual CRC-related expenditures with no CRC screening. This increase was highest when using virtual colonoscopy or fecal DNA testing. These authors also estimated a demand of 8.1 million colonoscopies annually if colonoscopy is used as the screening modality and 1.4–4.7 million if the other modalities are used (Table 1). According to their model, if screening uptake is high, the demand for colonoscopy would increase, even if virtual colonoscopy is a commonly used screening strategy. They predicted our current endoscopic capacity should accommodate these additional colonoscopies presuming a steady state.Table 1National Clinical Outcomes and Expenditures for All Persons 50 Years of Age and Older (75% Uptake of Screening)Natural historyFOBTFSFOBT/FSCOLOF-DNA-baseF-DNA-optimizedVC-baseVC-PickhardtClinical outcomes (cases per year in the United States) CRC incidence144,75592,66381,56173,79066,237119,87486,05778,26669,968 Localized CRC (% of cases)58,215 (40)50,330 (54)37,569 (46)38,215 (52)31,541 (48)57,048 (48)45,038 (52)37,396 (48)33,271 (48) Regional CRC (% of cases)53,843 (37)28,518 (31)28,822 (35)23,644 (32)23,048 (35)41,969 (35)28,148 (33)27,340 (35)24,385 (35) Distant CRC (% of cases)32,697 (23)13,815 (15)15,170 (19)11,931 (16)11,648 (18)20,857 (17)12,871 (15)13,530 (17)12,312 (18) CRC deaths57,90428,93329,17324,19423,01441,62727,43627,00324,341 Deaths from colonoscopy complications2130118639965099101249308National expenditures ($ billions per year in the United States) Base case CRC care8.04.94.53.93.66.54.64.33.8 Testing0.44.25.77.17.48.98.98.28.7 Testing complications0.010.100.100.140.210.040.040.090.10 Total8.49.210.311.211.215.413.512.612.6Sensitivity analysis: CRC care costs reduced by 25% CRC care6.03.73.43.02.74.93.53.22.9 Total6.47.99.210.210.313.812.411.511.7 Open table in a new tab While screening for colorectal cancer is accepted practice in average risk patients age 50 years and older, there have not been studies examining the utility of colorectal cancer screening in older individuals. The decision to pursue colorectal cancer screening in elderly patients with a shorter life expectancy and often increased comorbidity is a complicated and difficult decision. Practitioners must weigh the potential benefits of screening with the risks associated with screening in this population. Because of a lack of evidence regarding colorectal cancer screening in this group of patients, there are no guidelines to assist physicians in determining the appropriateness of screening elderly patients. In this month’s issue, Ko et al aimed to quantify the risks and benefits of different colorectal cancer screening modalities in patients 70–94 years of age with varying health status and life expectancy. These authors examined annual fecal occult blood tests, flexible sigmoidoscopy every 5 years, and colonoscopy every 10 years in a model which estimated the risk of dying of colorectal cancer, the potential mortality reduction with colorectal cancer screening, the number of colonoscopies needed, and the risk for complications related to colonoscopy. The number needed to screen to prevent one death related to colorectal cancer and the number needed to encounter one screening-related complication for each of these 3 screening strategies was calculated. The results varied depending on the screening strategy and the age and life expectancy of the patients screened. The risk of complications associated with screening using colonoscopy was greater than the potential benefit in women 75–79 years of age in poor health, women 85–89 years of age in average health, men 70–74 years of age in poor health, and men 90–94 years of age in good health. In all groups of patients, the estimated mortality reduction from screening was greater than the risk of death secondary to colorectal cancer screening. This study addresses an important issue physicians commonly face when caring for elderly patients. Based on the results of this study, these authors conclude that the potential benefit of colorectal cancer screening must be weighed against the potential risk of complications encountered with colorectal cancer screening on an individual basis, considering an individual’s life expectancy. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly prescribed medications, are associated with significant gastrointestinal-related adverse events. Several evidence-based guidelines have been published to assist physicians in identifying patients prescribed NSAIDs who are at risk for gastrointestinal events and to provide management strategies aimed to prevent these events. This study examines the adherence to these guidelines in the VA population. Abraham et al performed a cross-sectional study of veterans throughout the United States who were prescribed a coxib or a traditional NSAID. Patients prescribed an NSAID were identified through a prescription database and their data were linked to national VA outpatient and inpatient databases, as well as a national VA death file. Patients were categorized as low-risk or high-risk users. Patients were defined as high-risk users if they were older than 65 years of age, had a past history of an upper gastrointestinal event, had concurrent use of anticoagulants or steroids, or were prescribed high-doses of NSAIDs. The primary outcome was adherence, defined as the appropriate prescription of a coxib or the prescription of an NSAID with a gastroprotective agent in high-risk users. There were 707,244 patients prescribed NSAIDs, and of these patients 303,787 were classified as high-risk users. Only 82,766 patients (27.2%) who were considered high-risk were prescribed a regimen adherent to evidence-based guidelines. Adherence did increase in patients with more than one risk factor (41.8% adherence with 3 or more risk factors). Factors predictive of adherence included a history of an upper gastrointestinal event, concurrent use of anticoagulants or steroids, rheumatologic disease, a high Deyo co-morbidity index score, or the concurrent use of low-dose ASA. Prescriptions for ≥ 90 days and high daily doses of NSAIDS were predictive of nonadherence. This large cross-sectional study suggests poor compliance with evidence-based guidelines for the prescription of NSAIDs in high-risk individuals within the VA system. While these authors offer possible explanations for poor compliance with these guidelines, it remains unclear why many high-risk users of NSAIDs are not prescribed regimens which might prevent gastrointestinal-related complications. The poor outcome associated with pancreatic ductal adenocarcinoma is related to resistance of tumor cells to medical therapy, and also to the extent of micro-metastastic disease at the time of diagnosis–estimated to be present in >80% of the patients. The latter is facilitated by the induction of angiogenesis by tumor factors, followed by detachment of the tumor cells from the primary tumor, invasion into lymph and blood vessels, and establishment of metastatic foci elsewhere. The molecular mechanisms involved in metastases of malignant cells are poorly understood, but chemokine receptors on cancer cells and matching chemokines in target organs have been implicated. Chemokines are small molecule cytokines that mediate chemotaxis. For instance, gradients of the chemokine stromal cell derived factor 1α (SDF1α, or CXCL12) are involved in leukocyte homing, but also appear to attract CXCR4 positive tumor cells to specific metastatic sites. It is also notable that cells derived from pancreatic metastases have substantially higher expression levels of CXCR4 than their primary tumor cell counterparts. Thus, the high amounts of CXCL12 expressed by lung and liver may account for preferentially hematogenous spread of pancreatic cancer cells to these regions. This study by Saur et al examines the role of CXCR4 expression in vivo using bioluminescent imaging of targeted metastasis in a mouse model of pancreatic cancer. The investigators used TD-2 cells, derived from the primary pancreatic tumor of a TGFα/p53+/− mouse, that minimally express CXCR4 and display poor metastatic potential. By establishing stable transfection of murine TD-2 pancreatic cancer cells, functional expression of the chemokine receptors, CXCR4 and CCR7, was achieved. As anticipated, native TD-2 cells exhibited poor metastatic potential after tail vein injection. However, CXCR4, but not CCR7 transfected TD-2 cells showed significantly increased in vivo metastatic potential, manifested by liver and lung metastases in nude mice (Figure 1). When mice were treated with the selective CXCR4 inhibitor, AMD 3100, the enhanced metastatic potential of CXCR4 expressing pancreatic cancer cells was blocked. Thus, the study confirms the importance of CXCR4 expression in promoting metastasis of pancreatic cancer cells, a finding that can now be exploited by developing approaches in blocking the CXCL12/CXCR4 axis. β-Catenin/armadillo is the downstream effector of the Wnt/Wingless signaling pathway that regulates cell fate, polarity, differentiation, and apoptosis and is involved in carcinogenesis, as well as embryonic development. In the absence of secreted Wnt ligands, cells maintain low levels of β-catenin protein through phosphorylation by glycogen synthase kinase-3β (GSK-3β) associated with a complex containing Axin/Axil and the APC (adenomatous polyposis coli) gene product. As the majority of colorectal cancers contain mutations in the APC gene or mutations in the β-catenin (CTNNB1) gene, constitutive activation of Wnt signaling occurs and results in the accumulation of β-catenin protein, a process that has oncogenic potential through activation of the T-cell factor (TCF)/lymphoid enhancer factor (LEF)-family transcriptional factors. However, other factors may also be involved in carcinogensis, considering the diverse effects and targets of β-catenin. To examine this issue more closely, this study used a proteomics approach to gain additional insights into the functional properties of nuclear β-catenin. Using immunoprecipitation and mass spectrometry, components of the native β-catenin–containing complex were identified in nuclear extracts from the colorectal cancer cell line, DLD-1. β-Catenin was found to physically interact with fusion/translocated in liposarcoma (FUS/TLS) and various RNA-binding proteins (Figure 2). Sato et al demonstrated that the expression of FUS/TLS was closely associated with the accumulation of β-catenin and with the undifferentiated status of intestinal epithelial cells. When FUS was transiently transfected into cells, β-catenin–stimulated gene transactivation of TCF/LEF was inhibited. When β-catenin was transfected, the splicing pattern of the E1A minigene was affected and a novel splicing variant of estrogen receptor (ER)-β exerting a dominant-negative activity was induced. Thus, aberrations in pre-mRNA splicing induced by accumulated β-catenin protein may play crucial roles in colorectal carcinogenesis, as well as in the regulation of intestinal epithelial cell differentiation and proliferation. Projected National Impact of Colorectal Cancer Screening on Clinical and Economic Outcomes and Health Services DemandGastroenterologyVol. 129Issue 4PreviewBackground & Aims: Colorectal cancer (CRC) screening is effective and cost-effective, but the potential national impact of widespread screening is uncertain. It is controversial whether screening colonoscopy can be offered widely and how emerging tests may impact health services demand. Our aim was to produce integrated, comprehensive estimates of the impact of widespread screening on national clinical and economic outcomes and health services demand. Methods: We used a Markov model and census data to estimate the national consequences of screening 75% of the US population with conventional and emerging strategies. Full-Text PDF Comparing Risks and Benefits of Colorectal Cancer Screening in Elderly PatientsGastroenterologyVol. 129Issue 4PreviewBackground & Aims: In patients with limited life expectancy, the risks of colorectal cancer screening may outweigh the benefits. The aim of this study was to quantify risks and benefits of different screening strategies in elderly patients with varying life expectancies. Methods: We examined risks and benefits of screening in patients aged 70–94 years with differing health status using 3 strategies: annual fecal occult blood tests, flexible sigmoidoscopy every 5 years, or colonoscopy every 10 years. Full-Text PDF National Adherence to Evidence-Based Guidelines for the Prescription of Nonsteroidal Anti-Inflammatory DrugsGastroenterologyVol. 129Issue 4PreviewBackground & Aims: Our objective was to assess adherence to evidence-based guidelines by providers of the Department of Veterans Affairs nationwide. Methods: This was a cross-sectional study among veterans prescribed a nonsteroidal anti-inflammatory drug (NSAID) from January 1, 2002, to December 31, 2002. Prescription data were linked to inpatient and outpatient medical records and death files. The population was characterized as high risk based on the following: age 65 years or older, concurrent corticosteroid or anticoagulant use, history of peptic ulcer, and high average daily dose of NSAIDs. Full-Text PDF CXCR4 Expression Increases Liver and Lung Metastasis in a Mouse Model of Pancreatic CancerGastroenterologyVol. 129Issue 4PreviewBackground & Aims: Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion, and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ-specific pancreatic cancer metastasis in vivo remains unclear. Here, we have studied the role of CXCR4 in vivo using noninvasive imaging of targeted metastasis in a mouse model of pancreatic cancer. Methods: Functional expression of the chemokine receptors CXCR4 and CCR7 was achieved by stable transfection of murine TD-2 pancreatic cancer cells and analyzed by flow cytometry, calcium flux, migration, and proliferation assays. Full-Text PDF β-Catenin Interacts With the FUS Proto-oncogene Product and Regulates Pre-mRNA SplicingGastroenterologyVol. 129Issue 4PreviewBackground & Aims: β-Catenin is a downstream effector of the Wnt signaling pathway and is believed to exert its oncogenic function by activating T-cell factor (TCF)/lymphoid enhancer factor (LEF) family transcriptional factors. However, it is still uncertain whether the diverse effects of β-catenin are caused solely by aberrant gene transactivation. In this study, we used a proteomics approach to obtain further insight into the functional properties of nuclear β-catenin. Methods: The protein assembly of a native β-catenin-containing complex in nuclear extracts from a colorectal cancer cell line, DLD-1, was identified using immunoprecipitation and mass spectrometry. Full-Text PDF