Risk Of Gallbladder Cancer Research Articles

3034 Acute Pancreatitis in a Patient With a Choledochal Cyst

INTRODUCTION: Biliary cysts, also called choledochal cysts, are cystic dilatations that may occur singly or in multiples throughout the biliary tree. Cysts may be congenital or acquired and have been associated with a variety of anatomic abnormalities. The incidence of biliary cysts in Western populations has been estimated to be 1:100,000 to 1:150,000. Biliary cysts are associated with an increased risk of cholangiocarcinoma, pancreatic cancer, and gallbladder cancer. Malignancy is more common in patients who are older and in those with Type I and II cysts. As such, surgical resection is necessary. Due to stasis of bile flow in the cyst, other well-known complications include choledocholithiasis and pancreatitis. CASE DESCRIPTION/METHODS: A 35-year old woman presented to the ED with epigastric pain and lipase elevation to 700. She reported a history of a congenital hepatic cyst and previous history of cholecystectomy as a child. Over the last 2 years, she had been admitted to other hospitals for similar complaints. Initial ultrasound of the abdomen revealed common bile duct (CBD) dilatation to 2.3 cm with a filling defect of 1.5 cm. MRCP showed intra- and extra-hepatic dilatation and confirmed evidence of a filling defect in the CBD concerning for multiple intraductal and intracystic stones. The patient was conservatively managed while in the hospital and was discharged with close outpatient follow up. The following week, she underwent a Roux-en-Y hepaticojejunostomy. She was found to have a Type 1c choledochal cyst and an abnormal pancreaticobiliary junction. DISCUSSION: The approach to management of patients with biliary cysts depends on the cyst type. Patients with Type I, II, or IV cysts usually undergo surgical resection of the cysts due to the significant risk of malignancy, provided they are good surgical candidates. Type I and IV cysts should be completely resected with creation of a Roux-en-Y hepaticojejunostomy. The presence of an abnormal pancreaticobiliary junction (APBJ) increases the risk of malignancy, especially gallbladder cancer. Our patient had already had a cholecystectomy as a child. Patient continued to do well post-operatively without recurrence of her symptoms.

1426 Type 1 Choledochal Cyst With Anomalous Pancreaticobiliary Malunion Diagnosed on Cholangioscopy

INTRODUCTION: Choledochal cysts are cystic dilatations found within the intra and/or extrahepatic bile ducts. Untreated choledochal cysts can lead to increased risk for strictures, pancreatitis, cholangitis, gallbladder cancer, cholangiocarcinoma and pancreatic cancer. Early and accurate identification of choledochal cysts is crucial to determine appropriate medical and surgical planning. We present a case of a patient with a type 1 choledochal cyst with anomalous pancreaticobiliary malunion. CASE DESCRIPTION/METHODS: A 42-year-old female with a PMH of a cholecystectomy and known biliary cyst presented with acute onset abdominal pain. MRCP demonstrated a 5.5 cm fusiform dilatation of the common bile duct (CBD). EUS confirmed a CBD dilatation (Figure 1). ERCP with spyglass cholangioscopy showed an abnormal pancreaticobiliary junction with a common channel about 1 cm long leading to two separate openings, one to the CBD/choledochal cyst and another to the pancreatic duct orifice (Figure 2). Fluoroscopy showed contrast filling a dilated cystic structure in the proximal CBD consistent with a choledochal cyst (Figure 3). A 7 French × 7 cm flex stent was deployed into the CBD. Findings were consistent with a type 1 choledochal cyst and an anomalous pancreaticobiliary malunion. Patient underwent ex-lap with resection of the choledochal cyst with roux-en-y hepaticojejunostomy creation, which she tolerated well. DISCUSSION: The Todani classification is based on cyst location and bile duct dilatation. There are 5 types with type 1 as the most common which comprises of 80-90% of all choledochal cysts. Type 1 choledochal cysts involve fusiform dilatation of the entire CBD without any intrahepatic dilatation. Cancer is more common in patients who are older and with type I and IV cysts. These are typically treated with complete cyst resection and Roux-en-Y hepaticojejunostomy. Additionally, 50-80% of patients with choledochal cysts have an anomalous pancreaticobiliary malunion. The KOMI classification is used to classify anomalous pancreaticobiliary malunions into 3 types, which is based on the CBD/pancreatic duct angle and presence of CBD dilation. This case was a KOMI type IIB anomalous pancreaticobiliary malunion given the common hepatic and pancreatic ducts join each other at an acute angle creating a single common channel.

AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review

The purpose of this clinical practice update is to define key principles in the surveillance of hepatobiliary cancers including cholangiocarcinoma, gallbladder adenocarcinoma, and hepatocellular carcinoma in patients with primary sclerosing cholangitis (PSC). The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age. BEST PRACTICE ADVICE 2: Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months BEST PRACTICE ADVICE 3: Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC. BEST PRACTICE ADVICE 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture. BEST PRACTICE ADVICE 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma. BEST PRACTICE ADVICE 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age20. BEST PRACTICE ADVICE 7: The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm. BEST PRACTICE ADVICE 8: Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.

IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction.

To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n=31) and non-associated gallbladder cancers (n=49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P=0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P=0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P<0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.

Cancer risk among patients with type 2 diabetes: A real-world study in Shanghai, China.

The aim of this study was to investigate the risk of 23 common types of cancer among patients with type 2 diabetes (T2D) compared with the general Chinese population. Based on the Shanghai Hospital Link database, 410 191 patients with T2D (age 20-99 years) were identified from July 2013 to December 2016, and were followed-up for cancer incidence until December 2017. In all, 8485 cases of newly diagnosed cancer were identified. The standardized incidence ratios (SIRs) of total cancer were 1.34 and 1.62 among males and females, respectively. Among males with T2D, the risk of cancer of the prostate (highest SIR of 1.86), blood (leukemia, lymphoma), skin, thyroid, kidney, liver, pancreas, lung, colorectum, and stomach was increased significantly. There was a significant decrease in the risk of esophageal cancer. In females with T2D, there were significantly greater risks of cancer of the nasopharynx (highest SIR of 2.33), liver, esophagus, thyroid, lung, pancreas, blood (lymphoma, leukemia), uterus, colorectum, breast, cervix, and stomach. In contrast, there was significantly decrease risk of gallbladder cancer in females with T2D. This study shows significantly increased risks of overall and some site-specific cancers among patients with T2D. We suggest that establishing strategies for regular cancer-specific screening and prevention care among patients with T2D are necessary.

Genetics of gallstone disease revisited: updated inventory of human lithogenic genes.

Gallstone disease is one of the most frequent diseases in gastroenterology and treatment by endoscopy and surgery causes high costs in our health-care systems. Family and twin studies have demonstrated that gallstones are, in part, genetically determined. Here we review all recent genome-wide and phenome-wide studies of gallstones in humans and provide an updated 'inventory of human lithogenic genes.' The largest population attributable risk is conferred by the common variant (p.D19H) of the hepatic and intestinal cholesterol transporter ABCG5/G8. A second ABC transporter, the hepatic phosphatidylcholine translocase ABCB4, increases the risk for gallstone disease, gallbladder cancer and chronic liver diseases in general, whereas the common PNPLA3 risk variant p.I148M decreases gallstone risk. Better understanding of the pathomechanisms of gallstone disease might help to overcome the current invasive treatment of this exceptionally prevalent and economically significant digestive disease by personalized prevention in at-risk patients.

Effects of aspirin and non-steroidal anti-inflammatory drugs on the risk of cholangiocarcinoma: a meta-analysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) can suppress the proliferation of cholangiocarcinoma (CCA) cells in vitro through inhibition of cyclooxygenase-2. However, the effects of aspirin and NSAIDs on the risk of CCA remain unclear. We performed this meta-analysis to assess the risk of biliary tract cancers in patients who take aspirin and/or NSAIDs. A systematic review was conducted utilizing MEDLINE, EMBASE, Cochrane databases from inception through October 2017 to identify studies that assessed the association of aspirin and/or NSAIDs use with risk of biliary tract cancers including CCA, gallbladder cancer and ampulla of Vater cancer. Effect estimates from the studies were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Five observational studies with a total of 9 200 653 patients were enrolled. The pooled OR of CCA in patients with aspirin use was 0.56 (95% CI, 0.32-0.96). Egger's regression asymmetry test was performed and showed no publication bias for the association between aspirin use and CCA with P = 0.42. There was no significant association between NSAIDs use and CCA, with a pooled OR of 0.79 (95% CI, 0.28-2.21). One study showed a significant association between aspirin use and reduced risk of gallbladder cancer with OR of 0.37 (0.17-0.80). However, there was no significant association between aspirin and ampulla of Vater cancer with OR of 0.22 (0.03-1.65). Our study demonstrates a significant association between aspirin use and a 0.56-fold decreased risk of CCA. However, there is no association between the use of NSAIDs and CCA.

Aspirin and statin use and the risk of gallbladder cancer.

243 Background: The risk factors for gallbladder cancer (GBC) are poorly understood and preventive therapeutic options have not been identified. The use of aspirin (ASA) and/or statin has been associated with reduced risk of several gastrointestinal cancers. In this study, we explore if the use of ASA or statin is associated with a reduced risk of GBC. Methods: We identified patients with GBC diagnosed between the years 2000 and 2016 at Mayo Clinic. We identified matched controls in 2:1 fashion for age, gender and country of residence from patients who underwent cholecystectomy at Mayo Clinic. We collected information on co-morbidities and use of statins or ASA by retrospective chart review. We compared baseline characteristics between cases and controls using Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. We used binomial logistic regression to calculate the odds ratio (OR) and 95% confidence intervals (CI) to estimate the association of ASA or statin use with GBC. The logistic regression model included history of cholelithiasis, diabetes, hypercholesterolemia (HCL), hypertension (HTN), hyperthyroidism, hypothyroidism, primary sclerosing cholangitis (PSC), inflammatory bowel disease (IBD), cirrhosis and statin or ASA use as covariates. Results: 633 cases and 1,266 controls were included in our final analysis. The median age at diagnosis of cases and controls was 67 years. The control group had a significantly (p &lt; 0.05) higher proportion of patients with cholelithiasis, HCL, HTN, hypothyroidism and liver cirrhosis compared to the cases. The case group,contrarily, had a significantly higher proportion of patients with PSC and IBD. In univariate analysis, ASA (OR: 0.41; 95% CI: 0.33-0.52) or statin (OR: 0.48; 95% CI: 0.38-0.60) use was associated with a lower risk of GBC (p &lt; 0.001). However, in multivariate analysis, ASA use was associated with a lower risk of GBC (OR: 0.52; 95% CI: 0.41-0.67, p &lt; 0.001) whereas statin use was not (OR: 0.76; 95% CI: 0.56-1.03, p = 0.08). Conclusions: Our study demonstrates that aspirin use is associated with a reduced risk of GBC, whereas statin use is not. Further studies on GBC are needed to confirm these results and to elucidate mechanisms that explain the risk reduction with aspirin.

Menopausal hormone therapy and biliary tract cancer: a population-based matched cohort study in Sweden

Background: This study tested the hypothesis that contemporary menopausal hormonal therapy (MHT) increases the risk of biliary tract cancer. The risk of cancer of the biliary tract (gallbladder and extra-hepatic bile ducts) may be increased following estrogen exposure.Material and methods: This was a nationwide population-based matched cohort study in Sweden. Data from the Swedish Prescribed Drug Register identified all women exposed to systemic MHT in 2005–2012. Group-level matching (1:3 ratio) was used to select women unexposed to MHT from the same study base, matched for history of delivery, thrombotic events, hysterectomy, age, smoking- and alcohol related diseases, obesity, and diabetes. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).Results: Comparing 290,186 women exposed to MHT with 870,165 unexposed, MHT did not increase the OR of biliary tract cancer. The OR of gallbladder cancer was rather decreased in MHT users (OR 0.58, 95% CI 0.43–0.79), but this association became attenuated and statistically non-significant after adjusting for gallstone disease (OR 0.84, 95% CI 0.60–1.15). The OR of extra-hepatic bile duct cancers was 0.83 (95% CI 0.61–1.15). There were no clear differences when the analyses were stratified for estrogen or estrogen/progestogen combinations. MHT increased the risk of gallstone disease (OR 6.95, 95% CI 6.64–7.28).Conclusions: Contemporary MHT does not seem to increase the risk of biliary tract cancer. The decreased risk of gallbladder cancer may be explained by the increased use of surgery for symptomatic gallstones in MHT users.

Circulating inflammatory proteins and gallbladder cancer: Potential for risk stratification to improve prioritization for cholecystectomy in high-risk regions

BackgroundInflammatory proteins could help identify individuals most likely to have gallbladder cancer (GBC) among those waiting for cholecystectomy. MethodsWe analyzed 49 circulating inflammation-related proteins in 144 patients with GBC and 150 patients with gallstones. We calculated age- and sex-adjusted odds ratios (ORs) and 95% CIs for protein quantiles and GBC versus gallstones. Using proteins associated with early GBC (stage 1–2) that were selected in stepwise logistic regression, we created an inflammation score and explored the potential utility for risk stratification. Results26 proteins (53%) had P values for the trend across categories ≤0.001, with associations for a one category increase ranging from 1.52 (95% CI: 1.20–1.94) for CC motif ligand 4 to 4.00 (95% CI: 2.76–5.79) for interleukin (IL)-8. Soluble tumor necrosis factor receptor 2 (sTNFR2), IL-6, sTNFR1, CC motif ligand 20 (CCL20), vascular cell adhesion molecule 1, IL-16, and granulocyte colony-stimulating factor had P values ≤0.001 for early GBC. Of those, IL-6, IL-16, CCL20, and STNFR1 were included in the inflammation score. In a high-risk setting with a pre-test disease risk of 10% (e.g., elderly patients) and using an inflammation score cutoff that provides 90% sensitivity, 39% of patients on the waiting list would be predicted to be positive, and 23% of those would be predicted to have GBC. ConclusionThese results highlight the strong associations of inflammatory proteins with GBC risk and their potential clinical utility. Larger studies are needed to identify the most effective combinations of inflammatory proteins for detecting early GBC and precursor lesions.

Hepato-pancreato-biliary malignancies in patients with connective tissue disorders: a United States population based study from national inpatient sample database (1998–2010)

Background: Patients with connective tissue disorders (CTD) are at increased risk of malignancies, especially lymphoproliferative disorders, both due to chronic inflammatory sequelae and also immunomodulating therapies. The risk of hepato-pancreato-biliary (HPB) malignancies is poorly studied in CTD and this is the first population-based study to estimate this risk. Methods: National Inpatient Database (NIS 1998–2010) was used to identify patients with systemic lupus erythematosus (SLE), discoid lupus (DL), rheumatoid arthritis (RA), juvenile RA, psoriasis, Sjögren's syndrome (SJS), systemic sclerosis (SS) and multiple sclerosis (MS) and demographic data were abstracted. The Standardized Incidence Ratio (SIR) for each malignancy was calculated to assess the true risk. Malignancy data were abstracted and converted to events/year/100,000 and compared against corresponding national incidence rates obtained from Surveillance Epidemiology and End Results (SEER) database. Results: 1,949,776 patients with CTD were identified in NIS database, of whom 4461(0.23%) suffered from at least one HPB cancer. The mean age of CTD patients with cancer was 68.3 years, higher to those without cancer (60.1). The female:male ratio in CTD and HPB cancer was 2.1:1. CTD and HPB cancer was highest in Caucasians. The in-hospital mortality was 7.6% in CTD with HPB cancer, compared to 2.2% in CTD without cancer. Patients with psoriasis are at higher risk of developing any HPB cancer and patients with DL and RA are at increased risk of gallbladder and pancreatic cancer (table). Conclusion: Only three types of CTD are at increased risk for developing HPB malignancies. Advanced age at the diagnosis of HPB cancer in CTD patients might indicate lag phase, which can be utilized with appropriate screening tools for early detection and treatment.Table 1Comparison of demographic characters of patients with connective tissue disorders with and without hepatico-pancreato-biliary malignanciesOverallCTD with HPB malignancyCTD without HPB malignancyN (%)1,949,7764,404 (0.23)1,945,372(99.77)Age60.1 ± 17.368.3 ± 11.760.1 ± 17.3Male: Female1: 3.21: 2.11: 3.2Race Caucasian1,121,648 (57.5)2,692 (61.1)1,118,956 (57.5) African American217,058 (11.1)372 (8.4)216,686 (11.1) Hispanic114,795 (5.9)291 (6.6)114,504 (5.9) Others496,275 (25.5)1050 (23.8)495,225 (25.5)Mortality42,945 (2.2)335 (7.6)42610 (2.2)N; number of patients. Open table in a new tab Table 2Standardized incidence ratio of hepato-pancreato-biliary malignancies in patients with connective tissue disordersGallbladder CaExtrahepatic biliary CaPancreatic CaLiver CaE1.21.912.58.6SLEO0.410.767.464.29SIR34.3139.9159.6749.92DiscoidO2.31.3815.666.45SIR191.9472.72125.3174.99Lupus RAO1.311.6712.955.79SIR109.5188.24103.6267.34Juvenile RAO0.4801.942.92SIR40.49015.5634.23PsoriasisO1.331.9512.9517.89SIR111.04102.63103.56208.09Sjögren's syndromeO1.10.6813.85.79SIR91.6736.01110.4167.4Systemic sclerosisO00.958.735.5SIR050.3169.863.93Multiple sclerosisO0.8450.67.252.07SIR70.4231.535824.09E: Expected events/year/100,000, O: Observed events/year/100,000, SIR = Standardized Incidence Ratio (observed events/expected events × 100). Open table in a new tab N; number of patients. E: Expected events/year/100,000, O: Observed events/year/100,000, SIR = Standardized Incidence Ratio (observed events/expected events × 100).

Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored.

Plasma Helicobacter pylori Antibody Titers and Helicobacter pylori Infection Positivity Rates in Patients with Gallbladder Cancer or Cholelithiasis: a Hospital-Based Case-Control Study

ObjectiveGallbladder cancer is the commonest gastrointestinal cancer in northern Indian women. Some studies have examined the association between Helicobacter pylori infection and gallbladder cancer risk, but findings have been inconsistent. We aimed to examine the association between H. pylori infection and gallbladder cancer in Indian people.Materials and MethodsWe conducted a hospital-based case-control study including 100 gallbladder cancer patients with gallstones who were 32 to 79 years old (cases; 72 women and 28 men), and 100 cholelithiasis patients aged 14 to 75 years (controls; 65 women and 35 men). All patients had a diagnosis of gallbladder cancer or cholelithiasis at the Sanjay Gandhi Post Graduate Institute of Medical Sciences in Lucknow having a high gallbladder cancer incidence in northern India, from May 2014 through July 2017. Plasma samples were collected from all patients before surgical treatment. Plasma H. pylori antibody titer was measured by the latex agglutination method and an autoanalyzer. H. pylori infection was defined as antibody titer ≥10 U/mL. Plasma antibody titers and H. pylori infection positivity rates were compared between cases and controls.ResultsMean plasma antibody titers (standard deviation, range) were 11.1 U/mL (11.6, 0–78) in cases and 13.6 U/mL (23.0, 1–164) in controls. H. pylori infection positivity rates were 41% and 42% in cases and controls, respectively. No significant differences in antibody titers or H. pylori infection positivity rates were found between cases and controls.ConclusionsWe found no evidence of H. pylori infection as an important risk factor for gallbladder cancer in Indian people.

Metagenomics of Microbial Communities in Gallbladder Bile from Patients with Gallbladder Cancer or Cholelithiasis

Salmonella typhi and Helicobacter infections have been shown to increase risk of gallbladder cancer (GBC), but findings have been inconsistent. Other bacterial infections may also be associated with GBC. However, information on microbial pathogens in gallbladder bile of GBC patients is scarce. We aimed to investigate the microbial communities in gallbladder bile of patients with GBC and cholelithiasis (CL). Seven GBC patients and 30 CL patients were enrolled in this study. Genomic DNA was extracted from bile and the V3-V4 region of 16S rRNA was amplified. The sequencing results were compared with the 16S database, and the bacteria were identified by homology searches and phylogenetic analysis. DNA was detected in the bile of three GBC (42.9%; Bolivia, 1; Chile, 2) and four CL patients (13.3%; Bolivia, 1; Chile, 3). Of the 37 patients, 30 (81.1%) were negative and unable to analyze. Salmonella typhi and Helicobacter sp. were not detected in bile from any GBC patients. As the predominant species, Fusobacterium nucleatum, Escherichia coli, and Enetrobacter sp. were detected in bile from GBC patients. Those in bile from CL patients were Escherichia coli, Salmonella sp., and Enerococcus gallinarum. Escherichia coli was detected in bile samples from both GBC and CL patients. Whether the bacteria detected in bile from GBC patients would associated with the development of GBC warrant further investigation.

The risk of incidental gallbladder cancer is negligible in macroscopically normal cholecystectomy specimens

BackgroundCholecystectomy is usually carried out for benign indications. Most perform routine histopathologic examination to detect incidental gallbladder cancer (GBC). MethodsCholecystectomies performed at four hospitals in the Helsinki Metropolitan Area during 2010–2012 were analyzed retrospectively. Patients with preoperative suspicion of neoplasia, active malignancy, or in whom cholecystectomy was performed as a secondary procedure were excluded. ResultsA total of 2034 cholecystectomies were included. In ten patients (0.5%), GBC was identified, each with an associated macroscopic finding, including local hardness (n = 1), a thickened wall (n = 5), acute inflammation and necrosis (n = 1), or suspected neoplasia (n = 3). No GBC was found in macroscopically normal gallbladders (n = 1464). Of the ten patients with GBC, five underwent subsequent liver resection, four had metastatic disease, and one had locally advanced inoperable disease. Three of the five patients who underwent liver resection were alive and disease-free at final follow-up (median 48 months). The remaining seven patients with GBC died of the disease, with a median survival of 14 months (range 10–48 months). ConclusionsRoutine histopathologic examination of a macroscopically normal gallbladder does not improve diagnosis of GBC. A histopathological examination is, however, mandatory when a macroscopic abnormality is present.

Gallbladder polypoid lesions >15 mm as indicators of T1b gallbladder cancer risk

Background and study aimsGallbladder polyps (GBPs) are found in 5–7% of the adult population. However, it is very important to differentiate between benign and malignant polyps to establish an appropriate treatment. The present study aimed to determine the relevance of the 10-mm size criterion and attempted to determine the cut-off diameter of T1b tumours, which requires additional surgical intervention. Patients and methodsCases with GBPs were collected between January 2005 and January 2015. A total of 109 patients were enroled retrospectively. Information on age, sex, ultrasound findings, and blood laboratory tests was reviewed. The 10-mm criterion and T1b tumours were examined. ResultsSixty-nine females and 40 males were included in the study. Patient age was 45±10.7years (range 27–70years). The 10-mm cut-off sensitivity and specificity for predicting malignant polyps was 93.6% and 85.2%, respectively. Fifteen patients had malignant pathologic results, and one patient had GBP <10mm (intraepithelial, 8mm). Two patients had intraepithelial tumours of 12 and 13mm. Twelve malignant patients had T1b tumours with polyp sizes >15mm. ConclusionGallbladder cancer may occur in polyps of <10mm. Larger size and older age were predictors of neoplastic GBPs. We suggest 15mm as the optimal cut-off point to predict T1b cancer.

Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer.

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention.

Presence of Salmonella AvrA in colorectal tumor and its precursor lesions in mouse intestine and human specimens.

Evidence directly supporting an association between Salmonella infection and colorectal cancer in human subjects is sparse. It has been well recognized that Salmonella infection increases the risk of gallbladder cancer. AvrA, a bacterial protein from Salmonella enterica, plays a crucial role in establishing chronic infection. To our knowledge, the presence of the bacterial AvrA has never been studied in human samples. Here, we demonstrated the presence and cellular localization of AvrA in inflamed, colorectal tumor and its precursor lesions, using both animal experimental infection models and human clinical specimens. We performed a newly developed AvrA serological assay and to determine the presence of anti-Salmonella AvrA antibody in chronic infected mouse serum samples. Further, we tested the presence of AvrA gene in healthy human fecal samples, in order to advance etiological studies of Salmonella AvrA in human population. Our study suggests a potential role of this bacterial protein in human colorectal cancer. Moreover, our new serological assay may serve a useful tool to identify individuals at increased risk for colorectal cancer.

Abstract 4729: Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer

Abstract Gallbladder Cancer (GBC) is the most common malignancy of the biliary tract with very high incidence in Northern India, especially around Gangetic belt. Late diagnosis and poor prognosis are the important features of this disease. For improving treatment strategies and outcomes, novel non invasive prognostic biomarkers are needed. Variations in peripheral blood mitochondrial DNA (mtDNA) copy number in various cancers are widely studied but information in relation to gallbladder malignancy is unknown. In this pilot study, we investigated leucocytes mtDNA copy number variation in relation to risk and prognosis of GBC. A total of 300 histologically confirmed or fine needle aspiration cytology proven GBC patients were recruited along with equal number of age and sex matched controls. The mtDNA copy number was measured by real-time polymerase chain reaction through absolute quantification using SYBR green chemistry. We also explore prognostic utility of mtDNA content in relation to overall survival of GBC patients. Statistical analysis was done by Student’s test and survival data was compared using Kaplan Meier method. Two tailed p value less than 0.05 was considered to be significant. We observed high mtDNA content in cases as compared with controls (mean±standard deviation, 1.21±0.88 vs. 1.02±0.76). Higher mtDNA copy number was significantly associated with increased gallbladder cancer risk (p=0.005). In this study, we compared overall survival (OS) for gallbladder cancer patients in relation to mtDNA copy number median value (median, 1.12). Kaplan Meir survival curve predicts decrease in OS (p=0.03, Hazard ratio=2.54; 95% CI = 1.79-5.86) for GBC patients in relation to high mtDNA content (&amp;gt;median) as compared with low mtDNA copy number (&amp;lt;median). This study supports an association between increased mtDNA copy number with susceptibility to gallbladder cancer in this endemic belt. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in relation to gallbladder cancer. Citation Format: Abhijit Chandra, Hasan R. Kazmi, Leena K. Satyam, Saket Kumar. Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4729. doi:10.1158/1538-7445.AM2017-4729

Reproductive factors and gallbladder/bile duct cancer: a population-based cohort study in Japan.

Reproductive/menstrual factors may be involved in the etiology of gallbladder cancer (GBC) and bile duct cancer (BDC). However, the results from previous epidemiological studies have been inconsistent. We investigated the association of reproductive/menstrual factors with the risk for GBC and BDC in a population-based prospective cohort study in Japan. Data on reproductive/menstrual factors were collected through a self-administered questionnaire at baseline. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model. A total of 55 786 women enrolled between 1990 and 1994 were included in the analysis, and 115 GBC and 113 BDC cases were identified, with 944 861 person-years follow-up until 2010. For GBC, irregular and longer cycles were moderately associated with an increased risk [HR=2.12 (95% CI: 1.30-3.47) and HR=1.76 (95% CI: 1.08-2.89), respectively]. This effect tended to be greater in premenopausal than in postmenopausal women. Furthermore, older age at first pregnancy tended to be associated with an increased risk [HR=1.84 (95% CI: 1.03-3.29), P-trend=0.036], whereas increased duration of fertility tended to be associated with a decreased risk [HR=0.59 (95% CI: 0.35-1.01), P-trend=0.055] of GBC. No clear association with BDC was observed. This finding suggests that women with irregular or longer cycles may have an increased risk for GBC and female hormones may play an important role in the etiology of GBC.