CCA In Patients Research Articles

Detecting Cholangiocarcinoma in the Setting of Primary Sclerosing Cholangitis: Is Biliary Tract Fluorescence InSitu Hybridization Helpful?

Biliary brushing cytology (BB) to detect cholangiocarcinoma (CCA) is integral in the surveillance of patients with primary sclerosing cholangitis (PSC). Since reactive changes can mimic carcinoma, indeterminant results are frequent. Fluorescence insitu hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of CCA. This study evaluates the performance of FISH for detecting CCA in patients with and without PSC. A query of our pathology database for atypical and suspicious BB with concurrent FISH results was performed from 2014 to 2021. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed to identify patients with PSC and CCA. CCA was confirmed by pathology or clinical impression. Of the 65 patients (103 BB) in the PSC cohort, 59 patients (94 BB) without CCA and 6 patients (9 BB) with CCA were identified. 33 non-PSC patients (41 BB) with CCA were included for comparison. Positive FISH was highest in non-PSC patients with CCA (10/41 BB, 24%). Positive FISH was seen in both PSC with (1/9 BB, 11%) and without (2/94 BB, 2%) CCA. FISH positivity was lower than expected and was positive in PSC patients without CCA. These results question the clinical utility of FISH for CCA surveillance in PSC patients.

Involvement of interleukin-1β in high glucose-activated proliferation of cholangiocarcinoma.

Diabetes mellitus (DM) is associated with the increased risk of development and the advancement of cholangiocarcinoma (CCA). High glucose levels were previously shown for upregulating interleukin-1β (IL-1β) in CCA cells with unclear functions. The present study, thus, aimed to investigate molecular mechanisms linking DM to CCA progression, with IL-1β hypothesized as a communicating cytokine. CCA cells were cultured in media with normal (5.6 mM) or high (25 mM) glucose, resembling euglycemia and hyperglycemia, respectively. Expressions of IL-1β and IL-1 receptor (IL-1R) in CCA tissues from patients with and without DM were examined using immunohistochemistry. Functional analyses of IL-1β were performed using siRNA and recombinant human IL-1R antagonist (rhIL-1RA), in which Western blots investigated the knockdown efficacy. BALB/c Rag-2-/- Jak3-/- (BRJ) mice were implanted with CCA xenografts to investigate hyperglycemia's effects on CCA growth and the anti-tumor effects of IL-1RA. CCA tumors from patients with hyperglycemia showed significantly higher IL-1β expression than those from non-DM patients, while IL-1β was positively correlated with fasting blood glucose (FBG) levels. CCA cells cultured in high glucose showed increased IL-1β expression, resulting in increased proliferation rates. Suppressing IL-1β signaling by si-IL-1β or rhIL-1RA significantly reduced CCA cell proliferation in vitro. Anakinra, a synthetic IL-1RA, also exerted significant anti-tumor effects in vivo and significantly reversed the effects of hyperglycemia-induced growth in CCA xenografts. IL-1β plays a crucial role in CCA progression in a high-glucose environment. Targeting IL-1β might, then, help improve therapeutic outcomes of CCA in patients with DM and hyperglycemia.

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile.

Background and AimsPrimary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC.Approach and ResultsDroplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC‐associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77–0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow‐up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA‐PSC ≤ 12 patients, all positive for the biomarkers, included both early‐stage and late‐stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19‐9 levels.ConclusionsUsing highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

Advances in the management of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a primary malignancy of the bile ducts with three anatomically and molecularly distinct entities: Intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. As a result of phenotypic and anatomic differences they differ significantly with respect to management. For each type of CCA there have been significant changes in management over the last several years which will be discussed in this review. Although resection remains the standard of care for all types of CCA, liver transplantation has been established as curative treatment for selected patients with pCCA and is being evaluated for iCCA with early success. With respect to systemic therapy capecitabine is now first line adjuvant therapy for all biliary tract malignancies after curative intent resection. Progress in exploiting the pathologic mutations and molecular abnormalities has also yielded regulatory approval of targeted therapy for CCA in patients with acquired alterations in the fibroblast growth factor receptor. There is also increased consensus in managing malignant biliary obstruction associated with CCA where pre-operative biliary stenting is not beneficial while self-expanding metal stents have been shown to be superior to plastic stents in patients who are not surgical candidates.

Diagnostic power of DNA methylation markers suggestive of cholangiocarcinoma in ERCP-based brush cytology

Accurate differentiation between cholangiocarcinoma (CCA) and benign biliary stricture is of paramount importance. Biliary brush cytology is a simple and safe diagnostic approach that provides relatively high specificity; however, sensitivity is limited. Previous reports indicated the aberrations of DNA methylation in CCA. This study aimed to investigate the diagnostic performance of the methylation index (MI) of HOXA1 and NEUROG1 gene promoters in CCA. Patients with biliary stricture who underwent ERCP with brush cytology in Siriraj Hospital from September 2016 to December 2019 were prospectively enrolled. The MI of HOXA1 (MI_H) and MI of NEUROG1 (MI_N) were determined by quantitative methylation-specific polymerase chain reaction. The diagnostic power for CCA was tested for MI from both genes and serum carbohydrate antigen 19-9 (CA19-9). Sixty-seven patients were included in the study; 41 patients had a final diagnosis of CCA, and 26 patients were determined to have a benign biliary stricture. The results showed that both MI_H and MI_N had higher sensitivity and accuracy (95.1% and 82.3% and 90.2% and 89.5%, respectively) than brush cytology (61.5% and 78.1%) and CA19-9 (69.4% and 77.8%). The combination of brush cytology, both methylation markers, and CA19-9 increased the sensitivity and accuracy to 97.4% and 91.0%. Methylation markers were positive in 5 of 6 patients with confirmed CCA whose cytology and CA19-9 were negative. DNA methylation increased the sensitivity for the diagnosis of CCA; therefore, the use of DNA methylation is promising for diagnosis of CCA in patients with biliary strictures. A future validation study is warranted to assess its role in clinical practice. (Clinical trial registration number: NCT04568512.).

Study of the dynamics of intima media thickness of common carotid artery in elderly patients with ischemic heart disease and diabetes mellitus

Background and Aims: The intima-media thickness of the common carotid artery (IMT CCA) used as a marker of cardiovascular diseases in elderly patients with coronary artery disease (CAD). The aim is to study the dynamics of IMT CCA in patients with coronary artery disease in combination with diabetes mellitus (DM) in comparison with individuals without DM.

Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers.

SummaryCholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.

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.

Incidence and Prognosis of Subsequent Cholangiocarcinoma in Patients with Hepatic Resection for Bile Duct Stones

Cholangiocarcinoma (CCA) often develops after the hepatic resection for hepatolithiasis as well as indwelling it. We studied the incidence and prognosis of subsequent CCA in patients with hepatolithiasis in South Korea. We identified individuals with diagnosed CCA at the time of or after surgery, during 2002-2016, from the Korean National Health Insurance. The incidences and survival rates of subsequent CCA were analyzed and compared with concomitant CCA. The standardized incidence ratios (SIRs) of CCA in this cohort were evaluated in the standard Korean population. All data were stratified by the presence of intrahepatic or extrahepatic CCA, age and sex. Of the 7852 patients with hepatectomy for BDS, 433 (5.84%) had concomitant CCA. Over the 12-year follow-up, 107 of 7419 (1.98%) patients were diagnosed with subsequent CCA. Patients with hepatic resection for BDS revealed higher SIRs for subsequent CCA (12.89, 95% CI 10.96-15.15) in cases of both intrahepatic CCA (13.40, 10.55-17.02) and extrahepatic CCA (12.42, 9.98-15.46). The median survival time for subsequent CCA was 0.87years, while that for concomitant CCA was 2.79years. Having subsequent CCA (HR 2.71, 95% CI 2.17-3.40) and being male (HR 1.28, 1.05-1.57) were related to a shorter survival time. The CCA site and age at CCA diagnosis were not related to prognoses. Subsequent CCA developed in 2% of the patients with hepatic resection for benign BDS until 10years and was associated with poorer prognoses than concomitant CCA. Future studies focused on the long-term surveillance for CCA in such patients are needed.

PO-091 Droplet digital PCR based detection of aberrantly methylated genes in bile identifies cholangiocarcinoma in patients with primary sclerosing cholangitis

IntroductionPatients with primary sclerosing cholangitis (PSC) have up to 20% lifetime risk of developing cholangiocarcinomas (CCAs). Identifying CCA in patients with PSC is, however, complicated and current strategies are suffering from low sensitivity. Consequently, the majority of patients are diagnosed at an advanced, incurable stage of disease, highlighting the need for novel detection methods, which could qualify more patients for curative treatment. In the current study, we aimed at establishing a robust DNA methylation biomarker panel in bile for improved detection of CCA.Material and methodsMore than 300 bile samples (100 µl) from patients with PSC, CCA with and without PSC, and other non-malignant liver diseases were collected during endoscopic retrograde cholangiopancreatography or liver transplantation. All samples were analysed for promoter methylation of selected markers, using highly sensitive droplet digital PCR (ddPCR). In each reaction, an in-house 4-marker control assay was included for normalisation, and an algorithm for automated threshold determination, PoDCall, was applied for increased precision (Pharo et al, Clinical Epigenetics 2018).Results and discussionsPreliminary results indicate that the DNA methylation biomarkers have high accuracy for identifying CCA, particularly among patients with PSC. Interestingly, the markers were able to detect 5/8 PSC patients that later developed CCA, and that were not detected by standard diagnostic tools.ConclusionBy using highly sensitive ddPCR based technology and a robust DNA methylation biomarker panel, CCA can be accurately detected in small volumes of bile from patients with PSC.

Abstract A212: Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model

Abstract Intrahepatic cholangiocarcinoma (iCCA) is a form of deadly malignancy with limited treatment options. Gain-of-function mutations in KRAS are one of the most frequent mutations, found in ~25% of human CCA patients. MEK inhibitors have been developed and show some activity against solid tumors with Ras mutants. However, whether MEK inhibitors are effective against KRas mutant CCAs remains unknown. In the current study, we established a new mouse iCCA model (NICD/KRas) by expressing activated forms of Notch (NICD) and KRas (KRasV12D). We investigated the therapeutic potential of MEK inhibitors in vitro using human CCA cell lines and in vivo using KRasV12/NICD iCCA preclinical model. We found that in general, CCA cell lines with KRas mutations are more sensitive to MEK inhibitor U0126. Treatment of U0126 in KRas mutant CCA cells leads to increased apoptosis and decreased expression of pro-apoptosis gene Survivin. Furthermore, we found that treating KRasV12/NICD tumor-bearing mice with MEK inhibitor PD0325901 (PD901) resulted in stable disease. At molecular levels, PD901 efficiently inhibited p-ERK expression KRasV12/NICD tumor cells, leading to increased apoptosis. In summary, our studies demonstrate that KRasV12/NICD mice represent a novel and useful preclinical model to study KRas-driven CCA development. Our data further support the usefulness of MEK inhibitors for treatment of KRas mutant CCA in patients. Citation Format: Mingjie Dong, Xianqiong Liu, Katja Evert, Kirsten Utpatel, Shanshan Zhang, Li Che, John Gordan, Diego Calvisi, Matthias evert, Yan Liu, Xin Chen. Preclinical efficacy of MEK inhibition in a K-Ras driven cholangiocarcinoma preclinical model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A212.

Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline.

1 ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde cholangiopancreatography (ERCP).Moderate quality evidence, strong recommendation. 2 ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations.Low quality evidence, weak recommendation. 6 ESGE/EASL suggest that, in patients with an established diagnosis of PSC, MRC should be considered before therapeutic ERCP.Weak recommendation, low quality evidence. 7 ESGE/EASL suggest performing endoscopic treatment with concomitant ductal sampling (brush cytology, endobiliary biopsies) of suspected significant strictures identified at MRC in PSC patients who present with symptoms likely to improve following endoscopic treatment.Strong recommendation, low quality evidence. 9 ESGE/EASL recommend weighing the anticipated benefits of biliary papillotomy/sphincterotomy against its risks on a case-by-case basis.Strong recommendation, moderate quality evidence.Biliary papillotomy/sphincterotomy should be considered especially after difficult cannulation.Strong recommendation, low quality evidence. 16 ESGE/EASL suggest routine administration of prophylactic antibiotics before ERCP in patients with PSC.Strong recommendation, low quality evidence. 17 EASL/ESGE recommend that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion.Strong recommendation, moderate quality evidence. 19 ESGE/EASL recommend ductal sampling (brush cytology, endobiliary biopsies) as part of the initial investigation for the diagnosis and staging of suspected CCA in patients with PSC.Strong recommendation, high quality evidence.

Cost utility of ERCP-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis

Cholangiocarcinoma (CCA) is a leading cause of morbidity and mortality in patients with primary sclerosing cholangitis (PSC). Although several ERCP-based diagnostic modalities are available for diagnosing CCA, it is unclear whether one modality is more cost-effective than the others. The primary aim of this study was to compare the cost-effectiveness of ERCP-based techniques for diagnosing CCA in patients with PSC-induced biliary strictures. We performed a cost utility analysis to assess the net monetary benefit for accurately diagnosing CCA using 5 different diagnostic strategies: (1) ERCP with bile duct brushing for cytology, (2) ERCP with brushings for cytology and fluorescence in situ hybridization (FISH)-trisomy, (3) ERCP with brushings for cytology and FISH-polysomy, (4) ERCP with intraductal biopsy sampling, and (5) single-operator cholangioscopy (SOC) with targeted biopsy sampling. A Monte Carlo simulation assessed outcomes including quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were also performed. SOC with targeted biopsy sampling, as compared with ERCP with brushing for FISH-polysomy, produced an incremental QALY gain of .22 at an additional cost of $8562.44, resulting in a base case ICER of $39,277.25. Deterministic and probabilistic sensitivity analyses demonstrated that diagnosis with SOC was cost-effective at conventional willingness-to-pay thresholds of $50,000 and $100,000. SOC was the most cost-effective diagnostic strategy. SOC with biopsy sampling is the most cost-effective diagnostic modality for CCA in PSC strictures.

A Case of Concomitant Diagnosis of PSC and Cholangiocarcinoma (CCA) in a Patient With History of Surgically Treated UC for 25 Years

A 72 year old Indian male with history of UC for 25 years and colon cancer s/p proctocolectomy presented with epigastric pain, fevers and chills for 10 days for last 3 days. Pain was 8/10 in intensity, nonradiating, sharp, and was associated with decreased appetite. He denied any nausea, vomiting, diarrhea or constipation or weight loss. His LRTs showed cholestatic picture, of note for past five years they were within normal range. A CT scan of abdomen showed intrahepatic biliary ductal dilatation the transition to normal-caliber at the porta hepatis and a questionable filling defect at the point of transition within the CBD. A stone or mass could not be excluded. Surgey said no intervention needed at this time. MRCP showed marked bilobar intrahepatic biliary ductal dilatation with normal caliber distal CBD concerning for obstructing stricture or neoplasm. ERCP showed small filling defects in the CBD, likely due to choledocholithiasis. A stricture was noted in the distal right hepatic duct proximal to the hilum. Left hepatic duct appeared irregular and dilated likely secondary to PSC and gallbladder was normal. CA-199 was abnormal with a level of 8589 and brush cytology was negative for malignancy. Patient was informed of high suspicion of biliary ductal tumor and was given the option to seek treatment at a specialized biliary center. He opted to continue treatment in India. There, he underwent percutaneous biopsy and PET scan showed CCA with metastasis. PSC is a cholestatic liver disease characterized by multiple fibrotic strictures of the intra- and extrahepatic biliary tree. Although PSC is generally slow progressive, it is refractory to therapy, and frequently results in advanced liver cirrhosis. CCA is the most feared complication of PSC and the occurrence of CCA leads to a poor prognosis for PSC patients. The prevalence of CCA in patients with PSC is reported to be approximately 7-15% in USA. The average follow-up period between PSC and CCA diagnosis is relatively short (2.6 to 3.5 years). Also, PSC patients with IBD are less likely to develop CCA. Although most PSC patients die from liver failure or cholangitis-associated sepsis, some die from CCA, which occasionally accompanies the natural course of PSC. In the US and Europe, PSC is the major risk factor associated with the development of CCA and rapidly complicates PSC, usually leading to death within a few months of diagnosis. Patients with PSC have a 10-15% lifetime risk of developing CCA. The highest risk is in newly diagnosed patients within the first year, and thereafter, the incidence of CCA is about 1% per year. Unlike CCA without PSC, it is difficult to diagnose CCA in patients with PSC because PSC itself shows similar diffuse radiographic findings of bile duct derangement, and brush cytology and biopsy often fail to detect cancer cells because of the desmoplastic nature of CCA.

Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis.

The tumor microenvironment (TME) includes numerous non-neoplastic cells such as leukocytes and fibroblasts that surround the neoplasm and influence its growth. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are documented as key players in facilitating cancer appearance and progression. Alteration of the macrophage (CD68, CD163) and fibroblast (α-SMA, FSP-1) cells in Opisthorchis viverrini (Ov)-induced cholangiocarcinoma (CCA) was here assessed using liver tissues from an established hamster model and from 43 human cases using immunohistochemistry. We further investigated whether M2-activated TAMs influence CCA cell migration ability by wound healing assay and Western blot analysis. Macrophages and fibroblasts change their phenotypes to M2-TAMs (CD68+, CD163+) and CAFs (α-SMA+, FSP-1+), respectively in the early stages of carcinogenesis. Interestingly, a high density of the M2-TAMs CCA in patients is significantly associated with the presence of extrahepatic metastases (p=0.021). Similarly, CD163+ CCA cells are correlated with metastases (p=0.002), and they may be representative of an epithelial-to-mesenchymal transition (EMT) with increased metastatic activity. We further showed that M2-TAM conditioned medium can induce CCA cell migration as well as increase N-cadherin expression (mesenchymal marker). The present work revealed that significant TME changes occur at an early stage of Ov-induced carcinogenesis and that M2-TAMs are key factors contributing to CCA metastasis, possibly via EMT processes.

Total serum bile acid as a potential marker for the diagnosis of cholangiocarcinoma without jaundice.

Diagnosis of cholangiocarcinoma (CCA) is difficult when patients do not show jaundice. The aim of this study was to examine the feasibility of using the total serum bile acid (TSBA) level as an aid for the diagnosis of CCA in patients without jaundice. For this purpose, TSBA of the following groups were measured using a Beckman Synchron CX4 clinical chemistry analyzer: 60 cases of CCA with total serum bilirubin ≤2 mg/dL (low total bilirubin group, LTB); 32 cases of CCA with total serum bilirubin >2 mg/dL (high total bilirubin group, HTB); and 115 healthy controls. Liver function parameters such as serum cholesterol, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were also examined. The results showed that the TSBA of both LTB and HTB groups of the CCA patients were significantly higher than that of the healthy controls. Also, significant correlation was observed between TSBA and total bilirubin levels in the HTB group of CCA patients. However, no such correlation was seen in the LTB group. The cut-off value of TSBA was determined for the LTB group of CCA patients using the receiver operating characteristic curve analysis, and it was 6.05 μmol/L with the sensitivity and specificity of 46.7% and 84.4%, respectively. In addition, the ALP level was correlated well with the TSBA level and ALP in HTB group was significantly higher than that of LTB group. Moreover, the combination of high TSBA and high ALP levels gave higher specificity up to 97.4%. TSBA might be useful for the diagnosis of CCA patients without jaundice.

Volatile organic compounds in bile for early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis: a pilot study

The diagnosis of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC) is particularly difficult. The role of volatile organic compounds (VOCs) for diagnosis of CCA in patients with PSC is not known. Our aim was to identify potential VOCs in the headspaces (gas above the sample) in bile that may predict CCA in patients with PSC. Prospective cross-sectional study. Referral center. A total of 32 patients undergoing ERCP for PSC and for CCA complicating PSC. ERCP, bile aspiration. Selected ion flow tube mass spectrometry was used to analyze the concentration of 22 prevalent VOCs in bile samples. Logistic regression analysis was performed to build a predictive model for diagnosis of CCA. Levels of several compounds (ethanol, acrylonitrile, acetonitrile, acetaldehyde, benzene, carbon disulfide, dimethyl sulfide, 2-propranolol) were significantly different in patients with CCA complicating PSC compared with those having PSC (P< .05). By using receiver operating characteristic curve analysis, we developed a model for the diagnosis of CCA adjusted for age and sex based on VOC levels of acrylonitrile, 3-methyl hexane, and benzene. The model (2.3239*log [acrylonitrile]+ 0.9871*log [3-methyl hexane]+ 0.8448*log [benzene])< -0.12 identified the patients with CCA (area under the curve [AUC]= 0.89), with 90.5% sensitivity and 72.7% specificity (P= .02). Sample size. The measurement of VOCs in biliary fluid may be useful to diagnose CCA in patients with PSC. A larger study with a longitudinal study design is required to confirm our pilot observations to diagnose CCA early in patients with PSC. ( NCT01565460.).

Endoscopic ultrasound in the diagnosis of cholangiocarcinoma as the etiology of biliary strictures: a systematic review and meta-analysis.

Background and aim: Extrahepatic cholangiocarcinoma (CCA) typically presents as biliary strictures. Endoscopic ultrasound (EUS)-fine needle aspiration (FNA) may contribute to the diagnosis of CCA as the etiology of extrahepatic biliary strictures. Our aim was to study the uselfulness of EUS-FNA in diagnosing CCA as the etiology of biliary strictures.Patients and methods: In this meta-analysis, PUBMED and EMBASE databases were examined to find studies published to April 2014 where diagnostic correlation of CCA was available. Studies reporting only “positive for malignancy” were included in our analysis. The main outcome measurements were sensitivity, specificity and likelihood ratio.Results: Six studies were included, covering 196 patients. The overall pooled sensitivity and negative likelihood ratio (LR-) of EUS-FNA for diagnosis of CCA were 66% [95% confidence interval (CI) 57–74%] and 0.34 (95% CI 0.26–0.43), respectively. In five studies (146 patients), where a mass lesion was detected during EUS, the pooled sensitivity and LR- of EUS-FNA for diagnosis of CCA were 80% [95% CI 72–87%] and 0.20 (95% CI 0.13–0.28), respectively. In the 49 patients with a negative brush cytology, the pooled sensitivity and LR- of EUS-FNA for diagnosis of CCA were 59% [95% CI 44–73%] and 0.41 (95% CI 0.27–0.56), respectively.Conclusions: Our study suggests that EUS-FNA is useful in the evaluation of CCA as the etiology of biliary strictures. EUS-FNA may improve the diagnosis of CCA in patients with negative cytology and no mass on cross-sectional imaging.

Trends in Pre-Liver Transplant Screening for Cholangiocarcinoma among Patients with Primary Sclerosing Cholangitis

Background: Cholangiocarcinoma (CCA) is the most common hepatobiliary malignancy complicating primary sclerosing cholangitis (PSC). Unfortunately, timely diagnosis of CCA in PSC patients remains challenging. Aim: To investigate the strategies among liver centers regarding pre-transplant screening for CCA in patients with PSC. Methods: An online survey was returned from 46 US transplant centers, inquiring on the frequency of screening, the use of specific tests, or tactical approaches to high-grade dysplasia (HGD) or CCA. Results: Most centers screen their PSC patients for CCA prior to orthotopic liver transplantation (OLT) (89%). Serum carbohydrate antigen 19-9 and magnetic resonance cholangiopancreatography are first-line screening tools (93 and 84% respectively). Endoscopic retrograde cholangiopancreatography with biliary brushings is routinely performed in only 30% of the centers. In the case of HGD, 61% would choose close monitoring. In the event of non-resectable CCA, 37% have an OLT protocol, 33% resort to palliative treatment and the remaining 30% make an outside referral. Finally, half the participating centers perform CCA surveillance among their listed PSC patients every 6 months. Conclusion: Screening for CCA among PSC patients prior to OLT varies greatly among centers. Serum carbohydrate antigen 19-9 and magnetic resonance cholangiopancreatography are widely used. HGD warrants surveillance rather than intervention among most experts. Protocolized chemoradiation followed by OLT has yet to become a widely accepted approach. The very poor survival of PSC patients who develop CCA underlines the importance of an effective and universally accepted screening process that will aid in its earlier detection.

Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis

Patients with primary sclerosing cholangitis (PSC) are at risk of developing cholangiocarcinoma (CCA). Fluorescence in situ hybridization (FISH) may aid diagnosis of CCA. To determine the diagnostic utility of FISH for CCA detection in patients with PSC. Meta-analysis. Tertiary-care medical center. Patients in studies where histopathologic correlation of CCA was available; 2 × 2 contingency data were constructed. Database search and review of study findings. Sensitivity, specificity, likelihood ratio, and pooled diagnostic odds ratio. The search yielded 8 studies, involving 828 patients who could be included in our meta-analysis. The pooled sensitivity and specificity of FISH for diagnosis of CCA in patients with PSC were 68% (95% confidence interval [CI], 61%-74%) and 70% (95% CI, 66%-73%), respectively. The pooled positive likelihood ratio was 2.69 (95% CI, 1.84-3.97), and the negative likelihood ratio was 0.47 (95% CI, 0.39-0.58). The pooled diagnostic odds ratio was 7.24 (95% CI, 3.93-13.36). For FISH polysomy (6 studies, n = 690), the pooled sensitivity and specificity of FISH were 51% (95% CI, 43%-59%) and 93% (95% CI, 91%-95%), respectively. The heterogeneity indices of I(2) measure of inconsistency was 45.9%. Visual inspection of the funnel plot showed low potential for publication bias. Inclusion of low-quality studies. Our study suggests that FISH polysomy is highly specific; however, limited sensitivity of FISH highlights that better markers are required for early detection of CCA in PSC.