Covering the Cover

Abstract

In this retrospective cohort study, continuation of low-dose aspirin use was associated with a nearly 3-fold increased risk of recurrent lower GI bleeding, but reduced risk of serious cardiovascular events and death. The US Preventive Services Task Force recently endorsed low-dose aspirin for the prevention of cardiovascular disease and colorectal cancer for certain subgroups. However, aspirin increases the risk of both upper and lower tract gastrointestinal (GI) bleeding. A randomized, controlled trial has shown that early resumption of low-dose aspirin after upper GI bleeding reduces short-term risk of cardiovascular mortality (Figure 1). Comparable data for lower GI bleeding are lacking. Thus, clinicians faced with the challenging decision of whether to recommend resumption of low-dose aspirin in a patient that has had an episode of lower GI bleeding have little data to guide them. In this issue of Gastroenterology (accompanied by an editorial by Deepak Bhatt and Richard Hunt), Chan et al report a retrospective hospital-based cohort study of 295 aspirin users in Hong Kong who experienced an overt lower GI bleed subsequently followed for 5 years. Using prescription data, individuals that resumed low-dose aspirin had a subdistribution hazard ratio for recurrent lower GI bleed of 2.76 (95% CI, 1.26-6.07) compared with individuals who did not resume use. However, low-dose aspirin users had a subdistribution hazard ratio for serious cardiovascular events (including cardiovascular death) of 0.59 (95% CI, 0.37-0.91), and 0.33 (95% CI, 0.17-0.63) for death from other causes. This relatively small observational study has inherent limitations, including potential biases related to differences in the risk factor profile among aspirin users compared with nonusers. Thus, larger, ideally prospective randomized studies remain warranted. Until then, however, these results provide much needed initial data supporting the importance of weighing aspirin’s cardiovascular benefits against the increased risk of recurrent bleeding when deciding whether to resume aspirin after a lower GI bleed. See page 271; editorial on page 222. In a retrospective cohort of 4017 patients who underwent ERCP, rectal indomethacin was associated with reduced odds of post-ERCP pancreatitis. Pancreatitis complicates endoscopic retrograde cholangiopancreatography (ERCP) in an estimated 15%-20% of individuals with sphincter of Oddi dysfunction. However, rates are considerably lower among individuals with malignant biliary obstruction. Several randomized controlled trials composed primarily of patients with sphincter of Oddi dysfunction found that rectal indomethacin significantly reduced the risk of post-ERCP pancreatitis. In contrast, a recent randomized controlled trial of primarily lower risk patients did not observe a benefit. In this issue of Gastroenterology (accompanied by an editorial by Douglas Adler), Thiruvengadam et al report a retrospective cohort of 4,017 patients at University of Pennsylvania who underwent ERCP over a 7-year period. Rectal indomethacin (routinely given in the last 3.5 years of the period) was associated with an odds ratio of 0.35 (95% CI, 0.24-0.51) for post-ERCP pancreatitis overall and 0.17 (95% CI, 0.09-0.32) for moderate to severe post-ERCP pancreatitis. Indomethacin was associated with significant reductions in risk of pancreatitis for patients undergoing ERCP across a range of indications, including relief of malignant obstruction. Although the study has limitations associated with its observational design, the findings do lend additional support for use of rectal indomethacin among a range of patient populations undergoing ERCP. A broader, more definitive recommendation for routine use of rectal indomethacin after ERCP awaits the results of additional clinical trials currently underway. See page 288 and editorial on page 225. A 2-step forward genetic screen in murine HCC identifies oncogenes and tumor suppressors likely driving tumorigenesis. This catalog of potential cancer-causing genes extends our understanding of the pathogenesis of HCC and may lead to new therapies for this devastating disease. Hepatocellular carcinoma (HCC) is a deadly disease and although liver transplantation or surgical resection are curative measures, they can only be used for early stage disease. Identifying new therapeutic strategies are essential to improving outcomes but require a better understanding of the molecular pathogenesis underlying this disease. Although the Cancer Genome Consortium and the Cancer Genome Atlas have cataloged mutations in >500 HCC cases, infrequent mutations dominate these datasets making it difficult to distinguish cancer-causing from bystander mutations. In this issue of Gastroenterology, Kodama et al applied a 2-step forward genetic strategy in a mouse HCC model to identify cancer-causing genes (Figure 2A). The approach combined a sleeping beauty transposon mutagenesis screen coupled to a high throughput pooled short hairpin RNA interference library screen to validate tumor suppressors. This strategy identified 62 tumor drivers including the noncoding RNA, Rian, as well as Hras and Kras, all previously implicated in the pathogenesis of HCC. The secondary short hairpin RNA suppressor screen identified previously known tumor suppressors Aldh2, Ralgapa2, Kif1b, Stk11, and Arid1b in addition to other de novo suppressors. The authors observed the Ral GTPase-activating protein family was frequently mutated in this screen. RalGAPs repress the oncogenic Ral pathway and functional studies confirmed that suppression of this pathway accelerated tumor growth. Animal studies further demonstrated that targeting both the Raf and Ral pathways with sorafenib and RBC8 attenuated tumor growth, suggesting that dual blockade of Ral and Raf may be effective in treating HCC. This study provides an unbiased whole-genome catalog of cancer-causing genes in HCC. Future investigations to understand the functional contribution of these candidate cancer-causing genes are required to further our understanding of the pathogenesis of HCC and potential therapeutic targets. See page 324; editorial on page 231. A new model for studying local recurrence in PDAC identifies natural killer cell recruitment as critical to gemcitabine therapeutic benefit in patients with advanced disease. Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of <5%, with extensive local and neural involvement and early metastasis typically occurring. Even surgical resection in localized disease still leads to 85% recurrence. Thus, new therapeutic modalities and preclinical models are desperately needed. In this issue of Gastroenterology, Gürlevik et al develop a transgenic mouse model which generates focal, resectable PDAC, thereby establishing a tractable model for drug development (Figure 3). This model reproduced many of the histologic features of PDAC, including acinar-to-ductal metaplasia and pancreatitis. Using this model, the authors determined that active AKT2, a serine/threonine kinase frequently activated in PDAC and postulated to drive disease progression, was required for local infiltration, neural invasion, and metastasis. Furthermore, the authors demonstrate that recruitment of natural killer cells, as opposed to CD8+ cells, at the tumor margin underlies the recently determined therapeutic benefit observed with adjuvant gemcitabine chemotherapy. Limitations of this study are that all laboratories may not be able to use this model because it requires surgical expertise, and whether this model can be used to test other therapies has yet to be determined. Notwithstanding, this is the first animal model of resectable pancreatic cancer that closely recapitulates human disease and offers considerable hope as a therapeutic testing platform in pancreatic cancer. This study is highly significant for a cancer that is in great need of studies to define mechanisms of recurrence and test novel therapeutic approaches. See page 338; editorial on page 234. Gemcitabine Activates Natural Killer Cells to Attenuate Pancreatic Cancer RecurrenceGastroenterologyVol. 151Issue 2PreviewWith an overall 5-year survival rate of only 7%, pancreatic ductal adenocarcinoma (PDA) has now eclipsed breast cancer as the third leading cause of cancer death in the United States1 and it is predicted to be second by 2030.2 Despite improvements in surgical and clinical management, the majority of patients with localized PDA who undergo successfully R0 surgical resection (ie, resection followed by absence of cancerous cells seen microscopically at the margins) succumb to recurrent local or distant metastatic disease. Full-Text PDF Rectal Indomethacin Reduces Pancreatitis in High- and Low-Risk Patients Undergoing Endoscopic Retrograde CholangiopancreatographyGastroenterologyVol. 151Issue 2PreviewRectal indomethacin reduces the risk of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Most studies of its efficacy included high-risk cohorts and excluded low-risk patients, including those with malignant biliary obstruction. We investigated the potential of rectal indomethacin to prevent post-ERCP pancreatitis (PEP) in a variety of patients. Full-Text PDF Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer CellsGastroenterologyVol. 151Issue 2PreviewEven after potentially curative R0 resection, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis owing to high rates of local recurrence and metastasis to distant organs. However, we have no suitable transgenic animal models for surgical interventions. Full-Text PDF Concurrent Lower Gastrointestinal Bleeding Risk and Myocardial Ischemic Risk: Resume Aspirin or Not?GastroenterologyVol. 151Issue 2PreviewTeleologically, when there is bleeding, the natural response of the body is to promote clotting. This makes perfect sense if there is external injury that leads to bleeding and the response is also useful for some forms of internal “injury,” such as gastrointestinal (GI) bleeding. However, in those prone to atherosclerosis, the prothrombotic stimulus of bleeding can provoke ischemic events leading to the paradox of patients who are bleeding also being at potentially high ischemic risk.1 This mechanism is less likely to occur in a young healthy person, but in an older patient with established or silent atherosclerosis, myocardial ischemia may occur. Full-Text PDF Risks of Bleeding Recurrence and Cardiovascular Events With Continued Aspirin Use After Lower Gastrointestinal HemorrhageGastroenterologyVol. 151Issue 2PreviewIt is not clear whether use of low-dose aspirin should be resumed after an episode of lower gastrointestinal (GI) bleeding. We assessed the long-term risks of recurrent lower GI bleeding and serious cardiovascular outcomes after aspirin-associated lower GI bleeding. Full-Text PDF Two-Step Forward Genetic Screen in Mice Identifies the Ral Pathway as a Central Drug Target in Hepatocellular CarcinomaGastroenterologyVol. 151Issue 2PreviewA detailed understanding of the genetic background of hepatocellular carcinoma (HCC) will be crucial to developing new therapies aimed at selected targets.1 Given the sparse treatment options of advanced HCC, such progress is needed urgently for this highly prevalent cancer. However, even though the full genomes of roughly 500 HCC samples are now fully available from diverse sequencing efforts and public databases,2–4 the genetics of HCC remains challenging. This is mostly owing to the significant heterogeneity of these tumors and the experimental/diagnostic problem of a lack of disease-free control liver tissue. Full-Text PDF Rectal Nonsteroidal Anti-inflammatory Drugs to Reduce the Rate and Severity of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: Still Grappling With Fundamental QuestionsGastroenterologyVol. 151Issue 2PreviewEven in 2016, with all of our accumulated knowledge about pancreaticobiliary interventions, minimally traumatic cannulation techniques, the role and value of pancreatic duct stents, and the need for adequate training in the performance of endoscopic retrograde cholangiopancreatography (ERCP), post-ERCP pancreatitis (PEP) remains the single most common (and dreaded) complication of the procedure.1–4 PEP still results in significant morbidity among patients undergoing ERCP and is still a cause of occasional mortality, usually in patients who develop severe or necrotizing pancreatitis. Full-Text PDF Two-Step Forward Genetic Screen in Mice Identifies Ral GTPase-Activating Proteins as Suppressors of Hepatocellular CarcinomaGastroenterologyVol. 151Issue 2PreviewHigh-throughput sequencing technologies have identified thousands of infrequently mutated genes in hepatocellular carcinomas (HCCs). However, high intratumor and intertumor heterogeneity, combined with large numbers of passenger mutations, have made it difficult to identify driver mutations that contribute to the development of HCC. We combined transposon mutagenesis with a high-throughput screen of a small-hairpin RNA (shRNA) library to identify genes and pathways that contribute to HCC development. Full-Text PDF