CCA In Patients Research Articles

Association between Praziquantel and Cholangiocarcinoma in Patients Infected with Opisthorchis viverrini: A Systematic Review and Meta-Analysis

The liver fluke, Opisthorchis viverrini, and the associated incidence of subsequent cholangiocarcinoma (CCA) are still a public health problem in Thailand, and praziquantel (PZQ) remains the antihelminthic drug of choice for treatment. Evidence in hamsters shows that repeated infection and PZQ treatments could increase the risk of CCA. However, the existing evidence in humans is inconclusive regarding increased risk of CCA with frequency of PZQ intake. To investigate the relationship between number of repeated PZQ treatments and CCA in patients with O viverrini infection. The reviewed studies were searched in EMBASE, MEDLINE, ProQuest, PubMed and SCOPUS from inception to October, 2012 using prespecified keywords. The risk of bias (ROB) of included studies was independently assessed by two reviewers using a quality scale from the Newcastle-Ottawa Scale (NOS). Risk effect of PZQ was estimated as a pooled odds ratio (OR) with its 95% confidence interval (95%CI) in the random-effects model using DerSimonian and Laird's estimator. Three studies involving 637 patients were included. Based on the random effects model performed in two included studies of 237 patients, the association between PZQ treatments and CCA was not statistical significant with a pooled OR of 1.8 (95%CI; 0.81 to 4.16). The present systematic review and meta-analysis provides inconclusive evidence of risk effect of PZQ on increasing the risk of CCA and significant methodological limitations. Further research is urgently needed to address the shortcomings found in this review, especially the requirement for histological confirmation.

Cholangioscopy with narrow-band imaging in patients with primary sclerosing cholangitis undergoing ERCP

Patients with primary sclerosing cholangitis (PSC) have an increased lifetime risk of cholangiocarcinoma (CCA). Detection of localized CCA in patients with PSC may result in curative liver transplantation. Recently, high-resolution per-oral video cholangioscopy (PVCS) has become available and may be useful for evaluating for biliary dysplasia. Narrow-band imaging (NBI) has shown promising results in detecting dysplasia in the esophagus and colon, but its utility in the bile duct is unproven. Evaluate NBI video PVCS in screening for dysplasia in patients with PSC. Prospective case series. Tertiary-care referral center. Patients with PSC undergoing ERCP between December 2008 and July 2010. ERCP with white-light and NBI PVCS and biopsy of suspicious lesions. Dysplasia detection. A total of 30 patients were enrolled. Median follow-up was 319.5 days. Four patients had a final diagnosis of CCA (2 extrahepatic, 2 intrahepatic). NBI visualized the 2 extrahepatic CCAs and allowed determination of tumor margins. The bile duct mucosa by NBI visual appearance in patients with PSC was variable. No correlation with CCA development could be determined. There was a 48% increase in suspicious lesions biopsied with NBI compared with white-light imaging, although NBI-directed biopsies did not improve the dysplasia detection rate. Small sample size, single center, referral bias. NBI allowed visualization of tumor margins in CCA as compared with traditional fluoroscopy-based ERCP. An improvement in dysplasia detection in patients with PSC could not be demonstrated despite an increase in the biopsy rate. Additional experience is needed to assess the utility of NBI in screening for CCA in patients with PSC. ( NCT00951327.).

Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis

The most ominous adverse event of primary sclerosing cholangitis (PSC) is development of cholangiocarcinoma (CCA). There is a wide variation in the reported diagnostic yield of bile duct brush cytology in PSC strictures. To determine the diagnostic utility of biliary brush cytology for CCA detection in patients with PSC. Meta-analysis. Systematic search of PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant studies published up to December 2012. Meta-analysis of diagnostic parameters. A total of 747 patients in studies (both retrospective and prospective) in which histopathologic correlation of CCA was available. Meta-analysis. Construction of 2 × 2 contingency data. Sensitivity, specificity, likelihood ratio, and pooled diagnostic odds ratio. The search yielded 54 studies of which 11, involving 747 patients, were included in our meta-analysis. The pooled sensitivity and specificity of bile duct brushings for a diagnosis of CCA in patients with PSC were 43% (95% confidence interval [CI], 35%-52%) and 97% (95% CI, 95%-98%), respectively. The pooled diagnostic odds ratio to detect CCA was 20.23 (95% CI, 8.75-46.79). The heterogeneity indices of χ(2) statistics, I(2) measure of inconsistency, and the Cochran Q test were 0.156, 14.4, and 30.5%, respectively. Visual inspection of the funnel plot showed low potential for publication bias. Inclusion of low-quality studies, study heterogeneity. Our study suggests that bile duct brushing is a simple and highly specific technique for detection of CCA in patients with PSC. However, the modest sensitivity from bile duct brushing precludes its utility as a diagnostic tool for early detection of CCA in patients with PSC.

Su1367 Does Recurrent Bacterial Cholangitis in Primary Sclerosing Cholangitis Patients Increase the Risk of Cholangiocarcinoma

Patients with primary sclerosing cholangitis (PSC) have a significantly increased risk of developing Cholangiocarcinoma (CCA). The risk factors for the development of CCA in PSC remain unclear. Recurrent cholangitis as a risk factor for CCA in PSC patients is controversial.

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

Purpose: To depict a case of concomitant diagnosis of PSC and cholangiocarcinoma (CCA) in a patient with history of surgically treated UC for 25 years. Methods: A 72-year-old Indian male with history of UC for 25 years and colon cancer s/p proctocolectomy presented with epigastric pain. He was complaining of fevers and chills for 10 days and developed epigastric pain for last 3 days. Pain was 8/10 in intensity, non-radiating, 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 5 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. Results: MRCP showed marked bilobar intrahepatic biliary ductal dilatation with lack of identification of the common hepatic, ERCP showed small filling defects in the CBD and stricture was noted in the distal right hepatic duct proximal to the hilum. Left hepatic duct appeared irregular and dilated likely secondary to PSC. CA-199 was abnormal with a level of 8589 and brush cytology was negative for malignancy. Patient's family opted to continue treatment in India. There, he underwent percutaneous biopsy and PET scan showed CCA with metastasis. Conclusion: PSC is a cholestatic liver disease characterized by multiple fibrotic strictures of the intra- and extrahepatic biliary tree. 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 the 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. In the U.S. and Europe, PSC is the major risk factor associated with the development of CCA, usually leading to death within a few months of diagnosis. 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.

Ultrasound Strain and Strain Rate Imaging of Carotid Artery with the Early Sage of Type 2 Diabetes Mellitus

The objective of this paper is to evaluate the value of ultrasound strain and strain rate imaging in evaluating the motorial characteristics of the early stage of the CCA in patients with type 2 diabetes mellitus (DM2). Fifty patients without vascular complications with type 2 diabetes and fifty healthy volunteers underwent carotid ultrasound are selected as objects in the examinations and the dynamic image was analyzed by the off-line software (syngo Velocity Vector Imaging technology [VVI], Siemens). The results show that Vmax of anterior wall, anterolateral wall and posterolateral wall were higher than those of posterior wall, posteromedial wall, and anteromedial wall (P<0.05). VTTP, Vmax, Smax, and SRmax of corresponding segments had significant differences in study group and control group (P<0.05). From the results, it could be concluded that Velocity Vector Imaging can be used to evaluate the change of common carotid elasticity in early stage of AS in patients with type 2 diabetes. KeywordsUltrasonography; Velocity Vector Imaging; Speckle Tracking; Common Carotid; Atherosclerosis;Diabetes Mellitus

Frequency and prognostic impact of complex chromosomal aberrations in patients with primary myelodysplastic syndromes and del(5q)

Abstract Abstract 1623 Poster Board I-649 Clonal cytogenetic abnormalities are detected in approximately 50% of patients with primary MDS and have a strong impact on disease outcome. More prevalent are unbalanced chromosomal aberrations reflecting a gain or loss of genetic material, whereas balanced rearrangements are rather rare. The most recurrent structural karyotypic abnormality is an interstitial deletion of the long arm of chromosome 5 occurring in 30% of primary MDS cases, either as isolated aberration (10%) or combined with additional cytogenetic changes (20%). An isolated del(5q) is generally associated with a better prognosis, whereas patients with one or more additional chromosomal abnormalities have a significantly shorter overall survival. The worst prognosis is observed in patients with del(5q) occurring in the context of a complex chromosomal aberrations (CCA; 33 abnormalities). Identifications of chromosomal regions involved in CCA in patients with MDS is very important and could yield detection of cryptic, recurrent, prognostically relevant aberrations and identification of candidate genes involved especially in progression of the disease. Detailed molecular cytogenetic analyses of CCA might lead to better understanding of molecular etiology of MDS with its therapeutic consequences. The aim of this study was to assess prognostic relevance of CCA in a cohort of patients with primary MDS and del(5q), to evaluate involvement of specific chromosomes and/or chromosomal regions in CCA and to establish the exact localization of chromosomal breakpoints. During 2002 and 2009, we examined bone marrow samples of 720 adults with MDS. Out of these, a total of 70 patients with primary disease and del(5q) associated with the CCA were identified at the time of initial diagnosis - 32 women (46%) and 38 men (54%), with a median age of 66 years (range 22 - 83). Diagnoses according to the WHO classification were as follows: RA (3%), RCMD (14%), RAEB I (27%), RAEB II (35%), MDS-AML (17%), CMML (3%) and MDS-U (1%). For precise analyses of chromosomal regions and breakpoints involved in CCA, various modifications of molecular cytogenetic techniques were used: FISH with locus specific probes (Abbott Vysis), CGH, mFISH/mBAND (MetaSystems) and/or array CGH (BlueGnome, NimbleGene). In 40 cases, mFISH analyses showed that parts of deleted chromosome 5 were translocated to other chromosomes. Fragmentation of 5q was also frequently found. Interestingly, no patient with monosomy 5 was identified in this study. Even in patients with suspect monosomy 5 detected by conventional cytogenetics, further detailed molecular cytogenetic analyses revealed parts of chromosome 5 material were retained in means of insertions within CCA. The most recurrent partners of del(5q) in unbalanced translocations were chromosomes 12 (23%), 3 (21%) and 17 (21%). The most common chromosome 5 breakpoints were 5q33 (47%), 5q13 (39%) and 5q11 (13%), the most frequently encountered deletion was q13q33 (30%). Except the chromosome 5, most often in CCA involved chromosomes were 17 (53%), 12 (49%), 7 (47%), 3 (43%) and 11 (31%), and the most recurrent breakpoints were at regions 12p11 (16%), 7q11 (10%), 7q21 (9%) and 7p11 (9%). Finding of CCA at diagnosis were associated with poor response to the therapy and short overall survival (median 4 months). Patients were classified into two groups according to the results of molecular cytogenetic analyses: group A (n=30) – del(5q) and additional CCA, and group B (n=40) – deleted chromosome 5 involved in CCA. The shortest overall survival was found in group B (median 3 months versus 5 months in group A). In conclusion, the involvement of specific chromosomes and/or chromosomal regions in CCA associated with del(5q) is nonrandom. Deleted chromosome 5 is very unstable and is often involved in different types of cryptic unbalanced rearrangements (translocation, insertions). Monosomy of chromosome 5, quoted in the literature, does not actually exist in MDS. Patients with del(5q) involved in CCA should be considered as a unique entity with extremely poor prognosis. Supported by grants NR/9227-3, NR/9481-3, MZO VFN2005, MSM 0021620808 and MSM LC535 Disclosures No relevant conflicts of interest to declare.

Frequency and Prognostic Impact of Complex Chromosomal Aberrations in Patients with Primary Myelodysplastic Syndromes and Del(5q).

Abstract 1623Poster Board I-649Clonal cytogenetic abnormalities are detected in approximately 50% of patients with primary MDS and have a strong impact on disease outcome. More prevalent are unbalanced chromosomal aberrations reflecting a gain or loss of genetic material, whereas balanced rearrangements are rather rare. The most recurrent structural karyotypic abnormality is an interstitial deletion of the long arm of chromosome 5 occurring in 30% of primary MDS cases, either as isolated aberration (10%) or combined with additional cytogenetic changes (20%). An isolated del(5q) is generally associated with a better prognosis, whereas patients with one or more additional chromosomal abnormalities have a significantly shorter overall survival. The worst prognosis is observed in patients with del(5q) occurring in the context of a complex chromosomal aberrations (CCA; 33 abnormalities). Identifications of chromosomal regions involved in CCA in patients with MDS is very important and could yield detection of cryptic, recurrent, prognostically relevant aberrations and identification of candidate genes involved especially in progression of the disease. Detailed molecular cytogenetic analyses of CCA might lead to better understanding of molecular etiology of MDS with its therapeutic consequences. The aim of this study was to assess prognostic relevance of CCA in a cohort of patients with primary MDS and del(5q), to evaluate involvement of specific chromosomes and/or chromosomal regions in CCA and to establish the exact localization of chromosomal breakpoints.During 2002 and 2009, we examined bone marrow samples of 720 adults with MDS. Out of these, a total of 70 patients with primary disease and del(5q) associated with the CCA were identified at the time of initial diagnosis - 32 women (46%) and 38 men (54%), with a median age of 66 years (range 22 - 83). Diagnoses according to the WHO classification were as follows: RA (3%), RCMD (14%), RAEB I (27%), RAEB II (35%), MDS-AML (17%), CMML (3%) and MDS-U (1%). For precise analyses of chromosomal regions and breakpoints involved in CCA, various modifications of molecular cytogenetic techniques were used: FISH with locus specific probes (Abbott Vysis), CGH, mFISH/mBAND (MetaSystems) and/or array CGH (BlueGnome, NimbleGene).In 40 cases, mFISH analyses showed that parts of deleted chromosome 5 were translocated to other chromosomes. Fragmentation of 5q was also frequently found. Interestingly, no patient with monosomy 5 was identified in this study. Even in patients with suspect monosomy 5 detected by conventional cytogenetics, further detailed molecular cytogenetic analyses revealed parts of chromosome 5 material were retained in means of insertions within CCA. The most recurrent partners of del(5q) in unbalanced translocations were chromosomes 12 (23%), 3 (21%) and 17 (21%). The most common chromosome 5 breakpoints were 5q33 (47%), 5q13 (39%) and 5q11 (13%), the most frequently encountered deletion was q13q33 (30%). Except the chromosome 5, most often in CCA involved chromosomes were 17 (53%), 12 (49%), 7 (47%), 3 (43%) and 11 (31%), and the most recurrent breakpoints were at regions 12p11 (16%), 7q11 (10%), 7q21 (9%) and 7p11 (9%). Finding of CCA at diagnosis were associated with poor response to the therapy and short overall survival (median 4 months). Patients were classified into two groups according to the results of molecular cytogenetic analyses: group A (n=30) – del(5q) and additional CCA, and group B (n=40) – deleted chromosome 5 involved in CCA. The shortest overall survival was found in group B (median 3 months versus 5 months in group A).In conclusion, the involvement of specific chromosomes and/or chromosomal regions in CCA associated with del(5q) is nonrandom. Deleted chromosome 5 is very unstable and is often involved in different types of cryptic unbalanced rearrangements (translocation, insertions). Monosomy of chromosome 5, quoted in the literature, does not actually exist in MDS. Patients with del(5q) involved in CCA should be considered as a unique entity with extremely poor prognosis.Supported by grants NR/9227-3, NR/9481-3, MZO VFN2005, MSM 0021620808 and MSM LC535 DisclosuresNo relevant conflicts of interest to declare.

Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms

Primary sclerosing cholangitis (PSC) is often complicated by the development of cholangiocarcinoma (CCA). Genetic variation of natural killer cell receptor G2D (NKG2D) has been associated with cancer susceptibility. An important ligand for NKG2D, major histocompatibility complex class I chain-related molecule A (MICA), serves as a marker of cellular stress. The 5.1 allele of the gene encoding MICA has been associated with PSC. In this study, we aimed to investigate the influence of genetic variations in the NKG2D-MICA receptor-ligand pair on the risk of CCA in patients with PSC. Seven single nucleotide polymorphisms (SNPs) covering the NKG2D gene were genotyped in 365 Scandinavian PSC patients and 368 healthy controls with TaqMan technology. Genotype data on the MICA 5.1 variant were available from previous studies. Forty-nine of the PSC patients (13.6%) had developed CCA at the time of study. Two of the NKG2D SNPs were associated with an increased risk of CCA: rs11053781 [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.31-3.29, corrected P (P(c)) = 0.011] and rs2617167 (OR = 2.32, 95% CI = 1.47-3.66, P(c) = 0.0020). Carriership of the MICA 5.1 allele was associated with resistance against CCA (OR = 0.43, 95% CI = 0.20-0.95, not corrected P = 0.032). Our results show that genetic variants of the NKG2D receptor are associated with development of CCA in PSC patients. This suggests that interaction between NKG2D and MICA is involved in protection against CCA in PSC. Patients who are homozygous for the nonrisk alleles are unlikely to develop CCA; this finding could be helpful in identifying PSC patients with a low CCA risk.

Primary Sclerosing Cholangitis and Cholangiocarcinoma

Primary sclerosing cholangitis (PSC), a cholestatic liver disease characterized by fibrosing inflammatory damage of the biliary tree, is a risk factor for cholangiocarcinoma (CCA). Indeed, the prevalence of CCA in patients with PSC ranges from 7 to 13%. The major challenges of CCA in PSC patients relate to lack of methods for early diagnosis and the absence of effective treatment. Early diagnosis of CCA in PSC is delayed because its clinical presentation can mimic benign dominant biliary strictures. Moreover, biliary and serum tests to diagnose development of CCA in PSC are limiting, although the use of advanced cytologic techniques for aneuploidy and chromosomal aberrations are promising in this regard. As a result, current therapies do not extend survival with the exception of protocol liver transplantation available to a selected group of patients. Future studies should emphasize deciphering the sequence of events that transform the inflammatory changes of the biliary tree to cancer. Only then will chemoprevention, early diagnosis, and therapy of CCA in patients with PSC improve.

Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis

Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis

Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.

Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study.

Patients with primary sclerosing cholangitis (PSC) have a significantly increased risk of developing cholangiocarcinoma (CCA). Risk factors for developing such a complication are not well defined. We conducted a multicenter, case-control study to determine the risk factors and possible predictors for CCA in patients with PSC. The demographic, clinical, and laboratory features of 26 PSC patients with CCA diagnosed over a 7-year period at eight academic centers were compared with 87 patients with PSC but no CCA (controls). There was no statistically significant difference in demographics, smoking, signs or symptoms or complications of PSC, indices of disease severity (Mayo Risk score or Child-Pugh score), frequency or duration or complications of inflammatory bowel disease (IBD), frequency of biliary surgery, or therapeutic endoscopy between the two groups. Alcohol consumption was significantly associated with CCA in patients with PSC (odds ratio: 2.95; 95% CI: 1.04-8.3). Serum carbohydrate antigen 19-9 (CA 19-9) was significantly higher in patients with CCA than those without (177 +/- 89 and 61 +/- 58 U/mL, respectively; P =.002). A serum CA 19-9 level > 100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with CCA. In conclusion, alcohol consumption was a risk factor for having CCA in PSC patients. The indices of severity of liver disease were not associated with CCA in patients with PSC. Serum CA 19-9 appeared to have good ability to discriminate PSC patients with and without CCA.

ＣＣＡ投与による慢性関節リウマチの血中・関節液中のリンパ球サブセットの変動

Disodium 4-chloro-2, 2'-iminidibenzoate (CCA) is a drug developed in Japan, and its significant efficacy in rheumatoid arthritis has been demonstrated in multicenter double-blind controlled trials. Since CCA is devoid of direct anti-inflammatory activity, it is suggested that the therapeutic effect of CCA in patients with rheumatoid arthritis may be attributable to improvement of immunological abnormalities that underlie this disease. We investigated changes of lymphocyte subsets in patients undergoing CCA therapy, by assays using OKT3, OKT4, OKT8 and OKIa1 monoclonal antibodies. The T 4 cell subset had no change in blood but showed a tendency to decline in synovial fluid. A significant increase of T 8 cells occurred in blood following CCA therapy while this T cell isubset remained unchanged in synovial fluid. Ia cells decreased significantly in blood whereas they tended to increase in synovial fluid. The drug exerts pharmacological actions that suit the purpose of treatment by way of modulating immunological abnormalities in rheumatoid arthritis.