Cancer Cells in Circulation

Pancreatic cancer cells can be detected in patients’ circulation before tumors are discovered, researchers report in the March issue of Gastroenterology.

Cancer cells have long been believed to acquire metastatic potential after large primary tumors are established. However, many patients undergoing pancreatectomy for chronic pancreatitis are found to have disseminated pancreatic ductal adenocarcinomas (PDAC), even though only precancerous pancreatic intraepithelial neoplasias were detected by histologic analysis.

Furthermore, among patients with small primary tumors (<2 cm) with no evidence of metastatic disease, only 18% survive for 5 years after pancreatectomy—most patients still develop recurrent, metastatic disease. Metastatic cancer cells therefore appear to start spreading before large primary tumors develop.

Andrew Rhim et al. investigated whether pancreas-derived epithelial cells might be detected in blood samples from patients with evidence of only precancerous lesions of the pancreas—with no detectable invasive carcinomas.

They collected and analyzed blood samples from patients with intraductal papillary mucinous neoplasm (IPMNs) or mucinous cystic neoplasms but no evidence for tumors or metastases, along with patients with cytology-confirmed PDAC and no cysts or cancer (positive and negative controls, respectively).

Using microfluidic geometrically enhanced differential immunocapture, they found more than 3 circulating pancreas epithelial cells/mL in blood samples from 7 of 21 patients (33%) with cystic lesions and no diagnosis of cancer (Sendai-criteria negative), 8 of 11 patients (73%) with PDAC, and in 0 of 19 patients without cysts or cancer (controls).

Circulating pancreatic epithelial cells

Circulating pancreatic epithelial cells (red) and leukocytes (green).

Therefore, pancreas epithelial cells from patients with cystic lesions or cancer enter the bloodstream.

Studies are underway to analyze the genetic features of circulating pancreatic endothelial cells from patients with cystic lesions, to see if the cells already have somatic mutations associated with PDAC. It is not clear whether patients with these cells in their circulation all develop tumors.

If the cells are associated with subsequent tumor formation, their detection in blood samples could be a marker of PDAC risk. Rhim et al. are planning studies to follow patients with cysts to determine if number or genomic features of circulating pancreatic cells can predict the development of PDAC.

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In Treating Crohn’s Disease, Earlier is Better

Patients receiving medical therapies when they have more complicated stages of Crohn’s disease (CD) are more likely to require surgery, researchers report in the March issue of Clinical Gastroenterology and Hepatology. The disease is most-effectively treated by drugs at its early, inflammatory stages.

Patients have a 40%–71% risk for requiring intestinal surgery within 10 years of diagnosis of Crohn’s disease. Although many drugs are used to treat this disease, there is controversy over their ability to reduce patients’ need for surgery.


Gordon Moran et al. investigated whether types of Crohn’s disease that patients have when they begin treatment with thiopurines (azathioprine or mercaptopurine) or anti-tumor necrosis factor (TNF) agents affect their need for surgery.

Moran et al. associated the presence of stricturing disease, ileal location, or ileocolonic location at the time patients are first prescribed thiopurines with a need for surgery. However, thiopurines were found to be more likely than other drugs to prevent the need for surgery for patients with only Crohn’s colitis.

Stricturing or penetrating disease at the time of prescription of anti-TNF agents was significantly associated with a need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with prescription of only a thiopurine.

Moran et al. conclude that treatment of Crohn’s disease with thiopurines and/or anti-TNF therapies before the development of complications reduces the risk for surgery. Treatment with these drugs after the development of complicated disease is not as effective—patients are more likely to require intestinal resection. Moran et al. state that the best outcomes are achieved when patients are treated at the early, inflammatory stage of disease development.

Interestingly, surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines or anti-TNF agents. Moran et al. say that there is evidence that the drugs can be effective after the disease course is reset by surgery.

Moran et al. acknowledge that physicians often face the challenge of whether to begin anti-TNF therapy after a complication develops, or to recommend surgery. The authors say that anti-TNF therapy can reduce the inflammatory component of a strictured segment and thereby prevent the need for surgery, or at least reduce the amount of surgery required. Residual inflammation before surgery has been associated with an increased incidence of complications after surgery.

The authors explain that treating patients at a late stage reduces drug efficacy, alters the risk–benefit ratio, and can be more expensive.

In a separate article in the March issue of CGH, Jean–Frédéric Colombel et al. report that among patients with moderate to severe ileocolonic Crohn’s disease who received the anti-TNF agent adalimumab as induction and maintenance therapy, those who achieved ‘deep remission’ (the absence of mucosal ulceration and CD Activity Index scores less than 150) appeared to have better 1-year outcomes (fewer hospitalizations and surgeries, lower rates of dosage adjustment, better quality of life, to be more productive and active, and have lower medical costs) than those who did not.

Similar to the findings of Moran et al., Colombel et al. say that anti-TNF agent therapy earlier in the disease course increases the probability of deep remission.

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How Does an Antibiotic Reduce Symptoms of IBS?

Rifaximin alters the intestinal microbiota to prevent inflammation and visceral hyperalgesia in stressed rats, according to the February issue of Gastroenterology. These findings could explain the ability of this antibiotic to relieve symptoms of irritable bowel syndrome (IBS) in patients.

Rifaximin is a broad-spectrum antibiotic that has been approved by the FDA for traveler’s diarrhea and minimal hepatic encephalopathy. Interestingly, rifaximin also appears to reduce pain and bloating in patients with IBS, but little is known about the mechanisms of this process.

Low-grade mucosal inflammation and increased intestinal permeability are common in patients with functional bowel disorders. Chronic stress contributes to functional bowel disorders and can predispose patients to gastrointestinal infections or induce visceral hyperalgesia. In animal models of visceral hypersensitivity, psychological stress appears to alter gut microbiota and gut barrier function.

Xu et al. therefore used rat models of visceral hyperalgesia to determine how rifaximin affected intestinal microbiota, inflammation, and function. They found that induction of stress, by water avoidance or repeat restraint, led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function.

Oral administration of rifaximin reduced the bacterial load in the intestines of the stressed rats, and altered the composition of bacterial community in the distal ileum (Lactobacillus species became the most abundant, see figure.

Bacterial community composition analyzed with nonmetric multidimensional scaling plots using a θYC distance matrix of operational taxonomic unit−based data. Circles represent distinct bacterial communities identified in luminal contents of terminal ileum of individual rats. Circles that appear larger are closer in the axis not represented and circles that are smaller are farther away in the axis not represented; some circles have been made transparent.

Bacterial community composition analyzed with nonmetric multidimensional scaling plots using a θYC distance matrix of operational taxonomic unit−based data. Circles represent distinct bacterial communities identified in luminal contents of terminal ileum of individual rats. Circles that appear larger are closer in the axis not represented and circles that are smaller are farther away in the axis not represented; some circles have been made transparent.

Rifaximin also prevented mucosal inflammation, barrier impairment, and visceral hyperalgesia in response to chronic stress.

A different antibiotic, neomycin, also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species), but did not prevent intestinal inflammation or induction of visceral hyperalgesia by stress.

The authors propose that development of visceral hyperalgesia is likely, at least in part, mediated by specific interactions between the microbiota and mucosa that lead to inflammation and barrier impairments after exposure to chronic stress.

Preclinical and clinical studies have linked visceral hyperalgesia to increased intestinal permeability. Previous studies have shown that intestinal inflammation induced by chronic stress releases factors such as prostaglandin E2, and activates ion channels in the dorsal root ganglia that innervate the lower gut.

Psychological stressors have been reported to alter bacterial community structure. Studies have shown that the stress can change the bacterial community structure, reducing species richness and diversity, and facilitating susceptibility to bacterial pathogens.

Although rifaximin appears to alter intestinal bacterial communities, leading to a relative abundance of Lactobacillus that prevents mucosal abnormalities and visceral hyperalgesia induced by chronic stress, direct immunomodulatory effects might also be involved. However, the authors provide evidence that the effects of rifaximin observed are not caused by direct anti-inflammatory action on the mucosa.

Several clinical trials have evaluated the efficacy and safety of rifaximin in patients with IBS. A meta-analysis found rifaximin to be more effective than placebo in improving overall symptoms and bloating in IBS. Rifaximin has been estimated to offer an approximate 10% therapeutic gain for patients with IBS—similar to other available IBS therapies.

Xu et al. warn that rodent models have limited predictive value for IBS treatment in humans, and that the experimental design does not indicate that rifaximin treatment is beneficial for the symptomatic patient but rather that rifaximin prophylaxis can be beneficial in preventing a stress-induced flare.

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What are Choledochoceles?

Choledochoceles are cystic dilatations of the intraduodenal portion of the common bile duct. They are often classified as Type III biliary cysts, but have distinct demographic and anatomic features, and a lower risk of malignancy than other types of choledochal cysts. In the February issue of Clinical Gastroenterology and Hepatology, Ryan Law and Mark Topazian discuss how they can be identified and treated.

Choledochoceles are typically diagnosed and managed by gastroenterologists. They are usually first observed as cystic lesions in the duodenum by computed tomography or magnetic resonance imaging. Further information is provided by endoscopic ultrasound or endoscopic retrograde cholangiopancreatography (ERCP), which can distinguish Type A and Type B choledochoceles from duodenal duplication cysts (see figure).

Anatomy of choledochoceles and duodenal duplication cysts. (A) Type A choledochocele. (B) Type B (diverticular) choledochocele. (C) Duodenal duplication cyst.

Anatomy of choledochoceles and duodenal duplication cysts. (A) Type A choledochocele. (B) Type B (diverticular) choledochocele. (C) Duodenal duplication cyst.

Choledochoceles are treated by endoscopic drainage or resection. They have a low risk of malignancy, compared with other types of biliary cysts, but should be evaluated histologically.

Patients with choledochoceles usually present with upper abdominal pain, nausea, and vomiting—different from other types of biliary cysts. Pancreatitis is the most common clinical complication associated with symptomatic choledochoceles and is frequently the event that leads to their identification. Patients often have acute relapsing pancreatitis with multiple discrete episodes due to obstruction of pancreaticobiliary outflow, which increases ductal pressure, or bile reflux into the pancreatic duct.

Choledochoceles and duodenal duplication cysts are usually benign, but some are malignant. The estimated incidence of carcinoma in symptomatic patients with choledochoceles has been estimated at 2.5%. This is in contrast to other types of choledochal cysts, which pose substantial risks for gallbladder carcinoma and cholangiocarcinoma.

Choledochal cysts are uncommon and prevalence varies with region—most are reported in Asia. Choledochoceles frequently develop in people of older age (average 51 years), compared with other choledochal cysts (average 29 years).

Law and Topazian propose that cystic lesions that arise from the intramural bile duct or intra-ampullary common channel, with direct anatomic communication to these ducts, be considered choledochoceles. These may be lined by biliary or enteric mucosa, but do not fuse with the duodenal wall and do not have a muscle layer other than muscularis mucosa.

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Sensitizing Colorectal Tumors to Chemotherapy

Although colorectal tumors with microsatellite instability (MSI) are usually considered to have a poor response to 5-fluorouracil–based chemotherapy, researchers have identified a subset that actually respond well to chemotherapy. These tumors express a dominant-negative form of the chaperone HSP110, according to the February issue of Gastroenterology.

Colorectal cancer (CRC) is a heterogeneous disease; cells of most tumors (80%–85%) have chromosome instability, and significant fraction (15%–20%) have widespread instability at DNA repeats, or MSI. Patients with MSI tumors have better prognoses than those without, but these tumors do not usually respond to 5-fluorouracil–based chemotherapy.

Chaperone proteins such as HSP110 promote the survival of CRC cells. An HSP110 truncation mutant (HSP110DE9) is expressed by some CRC cells with MSI; it is generated from an aberrantly spliced mRNA that results from large deletions of the T17 repeat with intron 8 of the gene that encodes HSP110 (HSPH1). HSP110DE9 interferes with the chaperone activity of HSP110 in a dominant-negative manner to sensitize CRC cells to 5-fluorouracil and oxaliplatin.

Ada Collura et al. investigated whether patients with colorectal tumors that have MSI and also large deletions of the T17 repeat, which cause them to express HSP110DE9, have better responses to chemotherapy than patients without the T17 deletions.

Collura et al. searched for T17 deletions in tumor samples from 329 patients with stage II or III colorectal tumors with MSI, and compared them with patient outcomes. The authors found that most deletions in T17 were biallelic, and resulted in increased ratios of HSP110DE9:HSP110 in tumor samples.

A high percentage of patients (94%) with stage II–III tumors with large HSP110 T17 deletions (≥5 bp) survived for 5 years, relapse-free, after chemotherapy. Among patients with small or no deletions (≤4 bp), only 64% survived for this time period.

Survival analysis of patients with stage II or III colorectal tumors with MSI CRC patients treated with chemotherapy. Patients were classified based on the size of deletion in the T17 intronic repeat.

Survival analysis of patients with stage II or III colorectal tumors with MSI CRC patients treated with chemotherapy. Patients were classified based on the size of deletion (L, long [blue] or S, short [green]) in the T17 intronic repeat.

As expected, because of the chemosensitizing effect of HSP110DE9, deletions in T17 did not affect survival of patients with stage II–III tumors who did not receive chemotherapy.

Collura et al. conclude that patients with large T17 deletions are a minority but nevertheless an important fraction (about 25%) of patients with colorectal tumors with MSI who appear to benefit from 5-FU–based adjuvant chemotherapy. The authors found it particularly interesting that the association between survival and T17 deletion was also significant in a subgroup of patients treated with only 5-fluorouracil.

Collura et al. also showed that tumor mutations in 15 other genes, including some that might play a role in drug response (such as ATR, ATM), had no prognostic significance, indicating the unique role of HSP110 in response to chemotherapy. However, Collura et al. did not assess whether the association between HSP110 T17 deletion and patient survival was independent of other molecular features, such as BRAF mutations or the CpG island methylator phenotype. These genetic features have also been associated patient outcome and colorectal tumor MSI.

The findings of Collura et al. could lead oncologists to reconsider the concept that CRCs with MSI do not respond to 5-fluorouracil–based adjuvant chemotherapy, and increase individualization of treatment of patients with CRC.

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Is There a Way to Prevent Pancreatitis After ERCP?

Aggressive intravenous hydration with lactated Ringer’s solution reduces the incidence of pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP), but is not associated with volume overload, according to a pilot study published in the February issue of Clinical Gastroenterology and Hepatology.



Pancreatitis is the leading complication of ERCP, causing considerable morbidity and even death. Researchers have attempted to reduce post-ERCP pancreatitis with a number of agents (octreotide, corticosteroids, protease inhibitors), but these have not been successful.

Hydration is one of the most important factors in treatment of acute pancreatitis of any etiology. Clinical studies of fluid resuscitation in patients with acute pancreatitis have associated hemoconcentration and decreased systemic perfusion with increased risk of pancreas necrosis and poor outcomes.

James Buxbaum et al. performed a clinical trial to investigate whether aggressive intravenous hydration with lactated Ringer’s solution reduced the incidence of post-ERCP pancreatitis. Patients who were undergoing their first ERCP were randomly assigned to groups that received aggressive hydration with lactated Ringer’s solution (3 mL/kg/h during the procedure, a 20-mL/kg bolus after the procedure, and 3 mL/kg/h for 8 hours after the procedure) or standard hydration with the same solution (1.5 mL/kg/h during and for 8 hours after the procedure).

None of the 39 patients who received aggressive hydration developed pancreatitis after ERCP, compared with 4 of 23 (17%) of patients who received standard hydration. Hyperamylasemia (an excess of the pancreatic enzyme amylase in the blood) developed in 23% of patients who received aggressive hydration vs 39% of those who received standard hydration.

Only 8% of patients who received aggressive hydration experienced increased epigastric pain, compared with 22% of those who received standard hydration. No patients had evidence of volume overload.

Buxbaum et al. say that these findings are important because markers of inadequate fluid resuscitation (increased hematocrit, creatinine, and blood urea nitrogen) are associated with organ failure.

The authors propose that the aggressive fluids act, at least in part, by attenuating pancreatic inflammation. Lactate can stimulate an anti-inflammatory immune response, and lactated Ringer’s solution is less likely than saline to induce metabolic acidosis, which might also account for its protective effects. Furthermore, studies have shown that prophylactic administration of fluids is more effective in preventing tissue damage than administration after pancreatitis has developed.

Buxbaum et al. warn that these results should be interpreted with caution, as this was a pilot study designed primarily to assess feasibility and safety of aggressive hydration and to inform design of future trials.  Larger randomized trials are needed to confirm the findings and determine whether aggressive hydration reduces the severity of post-ERCP pancreatitis, if it does develop.

In an editorial that accompanies the article, B. Joseph Elmunzer says these findings set the stage for larger trials evaluating, in outpatients, a regimen of aggressive fluid delivery followed by a bolus that can be delivered over a reasonable timeframe in the recovery area.

Elmunzer adds that it is important that post-ERCP pancreatitis be defined according to standard consensus criteria, and the impact of aggressive IVFR on moderate and severe post-ERCP pancreatitis be the central focus.

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Are IBD Drugs Safe During Pregnancy?

Researchers find no evidence that inflammatory bowel disease (IBD) during pregnancy, or medical treatment for IBD during pregnancy, increases risk for congenital abnormalities in children. The findings, based on a large database analysis, are published in the January issue of Gastroenterology.

pregnantIBD frequently affects women of reproductive age, and is often managed with medical therapy. The potential teratogenic effects of drugs are an important concern among women with IBD who are pregnant or considering pregnancy. The safety of a number of drugs commonly used to treat IBD has been assessed in small studies of pregnant women, and researchers have not observed large or consistent increases in numbers of congenital anomalies. However, these studies have not completely convinced many people because they included small numbers of exposures.

Guidelines propose that women should not stop taking drugs that keep their IBD in remission for the purpose of becoming pregnant or protecting a pregnancy. However, many women remain fearful about taking these drugs while pregnant.

Lu Ban et al. conducted a large cohort study of pregnant women with IBD and their children using primary care data from the United Kingdom. They collected data on 386,514 children. Of these, 0.4% were born to mothers who had IBD before childbirth (n=1703); 0.2% were born to mothers with Crohn’s disease (n=893).

Ban et al. identified congenital anomalies in 2.7% of children of mothers with IBD and 2.8% of children of mothers without IBD. No increases in heart, limb, or genital anomalies were found in children of women with IBD.

The authors also found no overall excess risk of a major congenital anomaly in children born to mothers with IBD who were treated with azathioprine/6-mercaptopurine, corticosteroids, or 5-aminosalicylate during pregnancy. Among women with IBD who received medical therapy during pregnancy, the adjusted odds ratios of a major congenital anomaly associated with drug use were 0.82 for 5-aminosalicylates, 0.48 for corticosteroids, and 1.27 for azathioprine/6-mercaptopurine.

Interestingly, 31.2% of women discontinued 5-aminosalicylates and 24.6% discontinued azathioprine/6-mercaptopurine during early stages of pregnancy. The authors did not associate cessation of medication with increased risk of IBD flares later in pregnancy, although this does not mean that no risk exists—the power on this subanalysis was limited.

This is the largest study conducted (in terms of the number of women with IBD, number of births, and number of major congenital anomalies) to assess the risks of congenital anomalies among children of women with IBD.

Ban et al. conclude that neither IBD, nor its common medical treatments, are likely to be major risk factors for congenital anomalies. However, this message may not have reached all pregnant women—up to 31% of women stop taking their medication in pregnancy. Although this could increase the risk of flares later in pregnancy, the authors have not observed such an increase.

Ban et al. remind readers that patients should receive appropriate guidance on use of medication before and during pregnancy.

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