1 (edited by PCL1029 Mon, 27 May 2013 10:12:24)

Topic: Bits and Pieces From DDW 2013

Hi, everyone,

Something I have learnt from DDW 2013.            5/23/20913   page 1.

---There are two primary bile acids in human:  cholic  acid and chenoceoxycholic acid.

---The concentration of the bile acids decrease  from 10nM in the jejunum to 0.2 mM in the stool; and the PH increases from 6.5 to 7 likewise.

---bile acids mal- absorption can be resulted in persistent diarrhea.

--- In the hepatocyte(liver cell), LDL facilitated  cholesterol to form bile acids, which through the bile canaliculus circulation into the Ileal enterocyte  for digestion of fats in the small intestines and the majority of the daily production ( about 12-18gms and the amount is meal dependent) will absorb (recycle) back through the portal circulation  into the liver  cells for the next enterohepatic circulation of bile acids. The usage of the bile acids is about 2-3gm each time and fecal excretion is about 0.5gm. In that sense ,that means the daily production of bile acids can be recycle 3-6 times/day.   ---[Bile manufacture ,consumption and transport at  the cellular level ].

(from Wikipedia: The path  of bile flow is as follows: Bile canaliculi → Canals of Hering → interlobular bile ducts → intrahepatic bile ducts → left and right hepatic ducts merge to form → common hepatic duct exits liver and joins → cystic duct (from gall bladder) forming → common bile duct → joins with pancreatic duct → forming ampulla of Vater → enters duodenum.)

-- In other lecture, there are 25 different kinds of bile acids;DHA(a bile acid) decreases ALK phos. in PSC patients and  the use of treatment of omega 3 fatty acid for 6 weeks TENDS to decrease the toxicity of the bile acids.

--- I  talked  one of the  lecture presenter from Thailand about whether he thinks the inflammation process caused by the liver worms and ultimately resulted in CCA is the same as in the western part of the world. He said no,  he believed the  process is different but the outcome is the same.

---On the lighter side, I did discuss one of my ideas with two stent manufacturers (Medi-Globe from Germany and Nanking Medical from China); I suggest to them the molecular structure of the skin of the shark is one of the least liquid flow resistant structure in nature. If the stent manufacturer can coat the inside of either  the metal or the plastic stents with such material, and at each end of the stent coated with antibiotics to digest  or prevent the micro fiber sludge forming, it will substantially prolong the usage of the stents and patients of CCA will require less stent replacements and improve the quality of life of the patients. The research and development adviser for the Medi-Globe from  Achenmuhle ,Germany shows good interest in my design suggestion but the Chinese Nanking Medical may not fully understand what I said in English .

--- I talked to one   GI doctor  who practice in Dallas and treat a lot of patients who have hepatitis B, I questioned him how long should the patient  be on antiviral therapy . he said is between 2-5 years.

---Coffee drinking  may contribute to the decrease of fibrosis formation  in the liver.
---Aspirin, even in low dose(ie:81mg/day)  in relatively long term of treatment( 6-8 years) can prevent many types of cancer including colon CA; aspirin reduces the risk of recurrent ADENOMA in both stage I and II of colon cancer and mets. Vitamin D, and omega 3 Fatty acid have the same effects too in reduction of CRC growth due to their effects as COX-2 inhibitor.--Dr. Andrew Chen from Mass General. Since CCA is also belonging to the class of tumor called Adenoma, therefore aspirin and other NSAID may be of value to try them too. Side effects of aspirin: GI bleeding.

---Using electrostimulation acupuncture pads between the  acupuncture point PC-6 in the forearm rather than using the actual acupuncture needles is effective in treating chemotherapy-induced nausea and motion sickness. patient can do it at home 3-4 times a day and will be more effective in treatment than just once a day. Ask your acupuncturist to elect the proper dose for you after buying the device from the internet.(dose is individualized)

Will be continue...
God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

2 (edited by PCL1029 Fri, 24 May 2013 15:16:10)

Re: Bits and Pieces From DDW 2013


If you don't have time, read #4 and #5 first.

1.A Combined Bile and Urine Proteomic Test Increases Diagnostic Accuracy of Cholangiocarcinoma in Patients With Biliary Strictures of Unknown Origin   10 | 626 |  Jochen Metzger2, et.al
Results: Receiver operating characteristics analysis of proteomic CC-classification of the 87 study patients revealed AUC values of 0.85 . A logistic regression model composed of the bile and urine proteomic classification factors lead to an AUC of 0.96, and 92% sensitivity and 84% specificity at the best cut-off. Most notably only three of the 36 CC patients were false negative and two of the 33 PSC patients were false positive classified. Inclusion of CA19-9 and bilirubin values to the logistic regression model was of minor benefit as indicated by small correlation coefficients and insignificant P values for these serological markers.

Conclusion: A logistic regression model combining the classification factors of bile and urine proteome analysis enables CC-diagnosis with an accuracy > 90% most applicable for patients with biliary strictures of unknown origin referred to endoscopy.
This model substantially improves the diagnosis of CC and may lead to early therapy and improved prognosis.

2.  Malignancy in Biliary Strictures   10:15 | 627 |  Tamas A. Gonda1, Khushboo Munot1, Amrita Sethi1, John M. Poneros1, et.al

Results: 43% of cases were malignant, and 70% of these were distal biliary strictures. Positive cytology diagnoses were made in 16% of cases, excluding them from second-line testing in clinical practice. Negative cytology diagnoses were made in 72% of cases, and no cytologic diagnoses were made in 13% of cases due to paucity of cells. In all cases where cytology was negative or accellular (85%), second-line molecular testing yielded an assessable diagnosis. A diagnosis was assessable in 88% of FISH cases, in 95% mutational profiling cases, and in 100% of cases analyzed with all three tests. FISH identified 1 additional malignancy beyond cytology. Mutational profiling identified 2 additional malignancies beyond cytology and FISH testing. Mutational profiling was ∼30% more sensitive than FISH for detecting malignancy. There was no brush-to-brush variability when DNA from the supernatant of the first or second brushing was analyzed.

Conclusions: Normally discarded, cell-free supernatant fluid collected from cytology brushing of biliary strictures provides sufficient DNA for reproducible mutational profiling. The addition of second-line molecular testing increases the diagnostic yield and sensitivity for detecting malignancy in biliary strictures. Mutational profiling of DNA in cell-free supernatants may help to increase these characteristics in cases where cells are too limited to establish reliable results from cell-based assays, even in our population where a large percentage of distal biliary strictures were evaluated, making sampling especially challenging.
Molecular Analysis Increases the Diagnostic Yield and Sensitivity for
Results .

3. Higher Survival Rate of Patients With Intrahepatic Cholangiocarcinoma Compared to Patients With Extrahepatic Cholangiocarcinoma: a Large Series From Thailand .
  10:30 | 628 |  Sittikorn Linlawan1, Parkpoom Phatharacharukul2, Suebpong Tanasanvimon1 et.al

Three hundred and eighty two males and 258 females at a mean age of 59.8±12.1 years were diagnosed with cholangiocarcinoma. In this study, 216 of 640 patients (33.8%) were diagnosed ICC. We found that ECC patients presented with painless jaundice and cholangitis more often than ICC patients, significantly (80% vs. 4.6%, p<0.001). Demographic data of both groups were not statistically different (Table 1). Baseline serum TB, DB and ALP of ICC patients were statistically lower than those of ECC (TB 1.7±4.6 vs. 16.8±12.2mg/dl, DB 1.0±3.6 vs. 12.8±8.9 mg/dl, ALP 282.5±216.1 vs. 487.3±334.1 U/L, respectively; p<0.01). Serum CEA and AFP were higher in ICC patients than those of ECC patients (CEA 107.3±609.3 vs. 28.7±84.5ng/ml, respectively; p=0.11, AFP 31.5±102.1 vs. 10.2±31.3ng/ml, respectively; p<0.01), in contrast to CA19-9 which was statistically lower in ICC patients (473.5±475.4 vs. 558.5±422.7ng/ml, respectively; p=0.04). Supportive care and selection of treatment were based on clinicians' decision and 20% of them underwent curative surgery. The median survival of patients with ICC and ECC were 51 and 18 months, respectively (Figure 1). Predictors of mortality for the overall group of patients with cholangiocarcinoma were underlying of cirrhosis and HIV infection (hazard ratio, 2.3; 95% CI, 1.2 to 4.3 and 8.0; 95% CI, 2.5 to 26.3; p <0.01, respectively).
Higher survival rate was observed in ICC patients compared to those with ECC and the predictors of mortality were underlying of cirrhosis and HIV infection.

4. A New Staging System for Perihilar Cholangiocarcinoma.
   10:45 | 629 |  Roongruedee Chaiteerakij1, Carlos Romero-Marrero2, Joseph Kaiya1, William S. Harmsen1, Terry M. Therneau1, William Sanchez1, Lewis R. Roberts1, Gregory J. Gores1
CONCLUSIONS: Clinical trials for potential targeted therapies are hampered by the lack of an accurate, non-operative staging system that predicts survival of patients with pCCA. We have developed a staging system based upon clinical and radiologic findings for pCCA which divides patients into four discrete, prognostic stages and should be useful to clinicians and design of clinical trials.

Proposed staging system for perihilar cholangiocarcinoma.

Stage I: No  mass lesion(ML) or unicentricmass (UCM)</=3cm; no mets  ; NO lobar atrophy(LA) and/or vascular encasement(VC); ECOG performance status(ECOG PS)=0-1.
Stage II:   NA ;    no mets; and YES to LA and /or VC; ECOG PS=0-1.
Stage III:  UCM> 3cm; Has perihilar Lymph Nodes ; NA of LA and/or VC; ECOG PS=0-1.
Stage IV:  Has multcentricmass ; has distant lymph node and/or peritonealmetastatsis ; NA of LA and/or VC; and ECOG PS>/=2.

NA, not applicable; ECOG, Eastern Cooperative Oncology Group; LN, lymph node

5. ---Circulating Tumor Cells(CTC) Are Associated With More Advanced Disease in Cholangiocarcinoma.   
11:15 | 631 |  Ju Dong Yang1, Michael B. Campion et.al

Results: The mean age of patients was 61 and 29 (64%) patients were male. CTC were detected in 13 (28%) patients. Patients with CTC tended to have larger tumor size, more tumor nodules, a higher CA19-9 level, increased CEA, lymph node involvement, and metastatic disease compared to patients without CTC. (Table) There was no significant association between CTC and demography (age, gender, and race) or underlying liver dysfunction . There was a trend towards poorer survival in patients with CTC compared to patients without CTC (p=0.09).
Conclusion: CTC are detectable in patients with cholangiocarcinoma. The presence of CTC was associated with tumor burden and metastatic cancer. The prognostic implications of CTC in patients with CCA need further validation in a larger patient group.
Table:                    CTC positive(N=13)        CTC negative(N=32)
Tumor size:                   10.1(6.6-13.6)               2.8(1.6-9.0)
# of Nodules:                    3                                   1
Bilober disease:              69%                               34%
CA 19-9:                      1521(71-6098)              74(34-337)
CEA :                              2.8(4.8-55.4)             2.7(1.8-3.1)
Lymph node                    68%                               31%
Metastasis :                      46%                               6%

God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

Re: Bits and Pieces From DDW 2013

Thanks much, Percy.  I will try to decipher the information later on today.  You give wonderful, scientific reports. So glad that you enjoyed Digestive Week and for everything it had to offer.  Have a safe trip back and rest up before   ASCO, Chicago.
Thanks a bunch,


Re: Bits and Pieces From DDW 2013

Thanks Percy for all the information. The more we know the better masters we are of our treatment plans.


Re: Bits and Pieces From DDW 2013

Thank you Percy and my husband says thank you too!

This Information Is Not Intended Nor Implied To Be A Substitute For Professional Medical Advice. You Should Always Seek The Advice Of Your Physician Or Other Qualified Health Care Provider

Re: Bits and Pieces From DDW 2013

Thank you Percy. I always enjoy reading all your posts.

Re: Bits and Pieces From DDW 2013

Hi Percy,

Many many thanks indeed for all of that information! That is a ton of great information that you have managed to gather there for everyone, thanks so much! I know that you must have been very busy indeed at DDW, but I hope you managed some relaxation time as well!

If Medi - Globe take your stent suggestions on board then they should name their new stent after you!!!

Stay strong my friend,


Any advice or comments I give are based on personal experiences and knowledge and are my opinions only, they are not to be substituted for professional medical advice. Please seek professional advice from a qualified doctor or medical professional.

8 (edited by PCL1029 Fri, 24 May 2013 15:10:56)

Re: Bits and Pieces From DDW 2013

Hi, everyone,

Here are some more lectures that I had attended when they presented their cases. My purpose for this trip is more geared to the understanding of the  ERCP procedures and its development and the property of the bile in hoping to find a better way to manage the problem. some of the abstracts lectures are too long;therefore if you just read the abstract TITLE and its result or CONCLUSION  to understand what the article is all about, I think that will be fine too.
AS a matter of fact, I will cut them short after ASCO2013 ; I think most of you will be happy in that way too, But a few of us may like to know and try to connect the dots for a better understanding and future discovery  to increase the possibility of finding a better treatment and/or cure.

A..   Emid Study: Final Results of a Prospective Bicentric Study Assessing Probe-Based Confocal LASER Endomicroscopy (pCLE). Impact in the Management of Biliary Strictures .

  10:30  | 63  Marc Giovannini, Fabrice Caillol, Erwan Bories, Genevieve M. Monges , France.
Introduction : pCLE is an imaging technology, enabling optical biopsy, or in vivo histology. The definitive results of the EMID study are presented here, comparing optical biopsies with definitive histology.
Patients and Methods : From July 2007 to May 2012, 61 patients with a biliary stricture without any previous histology were included (mean age 67 years old, 26 women, 33 men). Pre-operating imaging findings were available (MRI or scanner). An endoscopic ultrasound (EUS) had to be conducted before the ERCP procedure. The pCLE imaging was done during the ERCP procedure. The pCLE miniprobe was the CholangioFlex (Cellvizio, Mauna Kea Technologies, France). This probe has a 0.96mm diameter, a 55 microns imaging depth, and a 400-fold magnification. It was introduced into a 8.5F double lumen catheter (Cook Endoscopy, or MTW), positioned in the bile duct on a 0.035 inches guide wire. A 2.5ml injection of fluorescein 10 % was necessary to obtain interpretable images.
The pCLE criteria used were the Miami classification criteria (large vessels with double circulation, dark cells aggregates, thick dark bands with irregular branches, epithelium).
Results were compared to definitive histology obtained by biopsy or surgery in case of malignant lesions, and by surgery or 1-year follow-up in case of benign lesions.

Results : Six patients were excluded from the study because no definitive histology was available. There were 41 malignant lesions, 14 benign lesions.The biopsies are the tissue samplings obtained by ERCP or EUS.
19 patients had a biliary stricture without individualized mass on pre-operating imaging findings (6 malignant lesions, 13 benign lesions).

Conclusion : The addition of a pCLE procedure in the diagnostic histological examination of a biliary stricture enables to significantly increase the diagnostic reliability.
Table:                                  Sensitivity          Specificity
   pCLE alone                              58%                  79%
Brushing + Biopsies                    76%                  79%
pCLE+Brushing+biopsies           100%                  71%

* The diagnostic difference regarding the diagnostic reliability is statistically significant (p=0.03).
The biopsies are the tissue samplings obtained by ERCP or EUS.
19 patients had a biliary stricture without individualized mass on pre-operating imaging findings (6 malignant lesions, 13 benign lesions).

B. Regulation of Cholangiocyte Secretion and Bile Formation by the Mechanosensor TRPV4 .

  2:00  | 366  Qin Li, Eduardo Carlin, Charles K. Kresge, Andrew P. Feranchak ,Southwestern Medical School,Dallas,TX.
Mechanosensitive signaling has emerged as a powerful mechanism in the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving ATP release, activation of membrane P2 receptors, and increases in [Ca2+]i. However, the initiating steps translating shear force to regulated membrane transport in cholangiocytes is unknown. TRPV4, a non-selective cation (NSC) channel present in the apical membrane, has been proposed as a potential mechanosensor, though its role in translating shear to cholangiocyte secretion is unknown. Aim: To determine the potential role of TRPV4 in initiating mechanosensitive signaling in response to shear force in cholangiocytes. Methods: Fluid-flow (shear) of isotonic buffer was applied to mouse cholangiocytes cultured in perfusion chambers. Simultaneously, membrane currents and [Ca2+]I were measured via whole-cell patch clamp and ratiometric imaging of Fura-2 loaded cells. ATP release was measured by Luminometry. In some studies, primary cilia were removed via exposure to chloral hydrate. Results: TRPV4 expression was confirmed in both ciliated and non-ciliated cholangiocytes by RT-PCR and immunostaining. Under static (no flow) conditions, only small constitutive NSC currents were measured (4.8 ± 0.2 pA/pF). Exposure to flow (shear of 0.06 dyne/cm2) rapidly increased both [Ca2+]I and membrane NSC currents. Currents reached a maximum of (28 ± 2 pA/pF) within 30 seconds. The magnitude of the NSC currents was proportional to the shear force, reaching a maximum at a shear of 0.12 dyne/cm2. Currents displayed mild outward rectification and a reversal potential of 0 mV (Ecat= 0 mV) and were abolished in the presence of the TRPV4 inhibitors, ruthenium red or HC067047; properties consistent with TRPV4. In additional studies, exposure to the selective TRPV4 activators, 4-α-PDD or GSK-1016790A, under static (no flow) conditions, acutely increased [Ca2+]I, activated NSC currents (with identical properties to the flow-stimulated currents), and stimulated ATP release. Interestingly, non-ciliated cells exhibited flow-stimulated currents and increases in both [Ca2+]I and ATP release. Conclusion: The findings are consistent with a model in which activation of cholangiocyte TRPV4 translates shear force to an acute rise in membrane NSC permeability, [Ca2+]I, and ATP release.

The finding that the signaling complex remained intact in non-ciliated cells, suggests that the ability of TRPV4 to translate shear into membrane transport is independent of the primary cilium. Understanding the role of mechanosensitive transport pathways may provide novel insights to modulate bile flow for the treatment of cholestatic liver disorders. *Studies supported by the NIH NIDDK.

C. Mast Cell Histamine Participates in the Paracrine Regulation of        Cholangiocyte Proliferation
  2:15 367  Laura Hargrove1, Kimberly et.al
1Scott and White Memorial Hospital/Texas A&M HSC/COM, Temple, TX; 2Central Texas Veterans Health Care System, Temple, TX; 3Yamagata University, Yamagata, Japan

Background: Cholangiocyte proliferation is regulated by autocrine and paracrine mechanisms. We have shown that cholangiocytes express histidine decarboxylase (HDC, the key enzyme in histamine synthesis) and vascular endothelial growth factor (VEGF). Histamine increases biliary proliferation and inhibition of HDC decreases hyperplastic and neoplastic biliary growth. Mast cells are the main source of histamine in the body and regulate the functions of numerous cell types by the release of factors like histamine and VEGF. The aim of our study was to determine the paracrine effects of histamine released from mast cells on cholangiocyte proliferation. Methods: In vitro, a co-culture system was used to evaluate the paracrine effect of mast cell histamine on cholangiocyte proliferation. Cholangiocytes and mast cells (non-adherent) were cultured alone (mono-cultures) or in a co-culture system for 3-6 days (1:1 ratio). Histamine levels were reduced (~80%) in cholangiocytes by using a stable transfected HDC shRNA cell line (MSE-HDC) and mast cells were treated with the HDC inhibitor, alpha-methyl-dl-histidine (3 mM), to block mast cell histamine release (MC-HDC). Cholangiocyte proliferation was evaluated by MTT assays. The gene and protein expression levels of HDC and VEGF were measured by real-time PCR and immunoblotting. Histamine release was measured in conditioned medium by ELISA. Results: Loss of histamine (MSE-HDC) reduced cholangiocyte (i) HDC levels and histamine release, (ii) VEGF expression and (iii) proliferation when compared to mock-transfected (MSE-neg) cells. After co-culture with mast cells (containing histamine), cholangiocyte HDC and VEGF levels increased coupled with enhanced histamine release and cholangiocyte proliferation. Further, when mast cells were pre-treated with the HDC inhibitor, alpha-methyl (MC-HDC), mast cell HDC levels and histamine release was decreased compared to control-treated mast cells. Cholangiocyte HDC and VEGF levels were decreased after co-culture with MC-HDC and cholangiocyte proliferation also decreased suggesting that mast cell histamine regulates biliary mitosis.

Summary: We have found that, in addition to an autocrine regulation by cholangiocyte histamine release, cholangiocytes also respond to mast cell histamine release that regulates both biliary proliferation and VEGF levels. Modulation of histamine release from mast cells may be important in the modulation of the homeostasis of the biliary tree.

D.  Glucuronidation: the Ultimate Defense Mechanism Against Bile Acids Toxicity in Cholestatic Diseases 

3:00  | 370  Jocelyn Trottier1, Martin ,et.al     Laboratory of Molecular Pharmacology, Laval University, Faculty of Pharmacy, Québec, QC, Canada; 2Liver Unit, Pomeranian Medical University, Szczecin, Poland

Bile acids (BA) are respectively 9.4-fold (9.4x), 9.3x and 58.8x increased in plasma from cholestatic patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and biliary obstruction (BO). BAs accumulation constitutes a devastating feature of cholestatic diseases. Hepatic glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT)1A3, 1A4, 2B4 and 2B7 enzymes, is viewed as a protective mechanism against BA toxicity. The present study aimed at providing a comprehensive analysis of bile acid glucuronidation and its regulation by the bile acid sensors, FXR and PXR, in the context of cholestatic diseases.
Methods: Eleven BA-glucuronide (G) species were profiled in plasma from 40 healthy donors (controls), 12 PBC, 8 PSC and 17 BO patients using liquid chromatography coupled to mass spectrometry (LC-MS). Human hepatocytes (HH) in primary culture were treated with BAs, the PXR (rifampicin) or FXR (GW4064) agonists, and analyzed for UGT1A3, 1A4, 2B4, and 2B7 mRNA by real-time RT-PCR. Western blotting was used to estimate the content in UGT proteins in livers from controls (n=10), PBC (n=12) and PSC (n=10) donors. The presence of functional PXR response elements (PXREs) within UGT gene promoter regions was analyzed through EMSA and transfection assays. Statistical analyses were performed with the JMP V4.0.2 program.
Results: When compared to controls, plasmas from PBC, PSC and BO donors contained 1.8x, 1.7x and 4.2x higher BA-G levels, respectively. In PBC samples, only CDCA-24G was significantly increased (4x). PSC plasmas exhibited significant accumulation of CDCA-3G (3x), HDCA-24G (4x) and HCA-6G (2x), but were deprived in LCA-24G and DCA-3G. BO samples were significantly enriched in CDCA-3G (5x), CA-24G (88x), LCA-3G (10x), HDCA-24G (2x) and HCA-24G (2x). HH exposed to the BA levels found in BO patients exhibited a strong increase (>4x) in UGT1A3, 1A4 and 2B4 mRNA levels. These genes were also induced in cells exposed to BA levels reflecting PBC and PSC conditions, but at a much lower extent (<1.5x). Accordingly, the UGT proteins contents were comparable in livers from controls, PBC and PSC donors. UGT1A3 (3x), 1A4 (2x) and 2B4 (1.5x) transcripts accumulated in rifampicin-treated HH, while GW4064 only stimulated 2B4 mRNA levels (2x), and 2B7 expression remained stable under all conditions. Functional PXREs were identified in the respective promoter regions of the UGT1A3 (n=4), 1A4 (n=2) and 2B4 (n=1) genes.
Conclusion: By combining clinical investigations to molecular pharmacology analyses, this study highlights the ability of BAs to stimulate their own hepatic glucuronidation in an FXR- and PXR-dependent manner. Such a self-defence mechanism aimed at reducing bile acid toxicity in liver cells is, however, mobilized only under the severe cholestatic conditions observed during biliary obstruction.
E.  Elevated Perioperative Serum CA 19-9 Level Is an Independent Predictor of Poor Outcome in Patients With Resectable Cholangiocarcinoma
Sunday,  8:00AM - 5:00PM  | Su1592  | Location: Orange County Convention Center -
Background: Prognosis of cholangiocarcinoma is still unsatisfactory, and identification of predictive marker of survival after surgical resection is important to establish the perioperative therapeutic strategy for cholangiocarcinoma. Impact of perioerative serum carbohydrate antigen 19-9 (CA19-9) levels on survival of patients with resectable cholangiocarcinoma is still unclear.
Purpose: The purpose of this study was to investigate whether perioerative serum CA19-9 levels can predict survival of patients underwent surgical resection for cholangiocarcinoma.
Methods: One hundred and six patients with cholangiocarcinoma including 33 with intrahepatic, 48 with perihilar and 25 with distal cholangiocarcinoma who underwent surgical resection between 2002 and 2012 were eligible for this study. Preoperative biliary drainage was performed for the patients with obstructive jaundice. Preoperative serum CA19-9 levels were measured after biliary drainage, and postoperative serum CA19-9 levels were measured about 4 weeks after operation. The relationships between clinicopathological factors including perioperative serum CA19-9 levels and overall survival (OS) were analyzed with univariate and multivariate analyses.

Results: Preoperative CA19-9 levels were significantly higher in patients with moderately and poorly differentiated adenocarcinoma than in those with well differentiated adenocarcinoma (P = 0.009), and in patients with UICC stage I/II than those with III/IV (P = 0.008). In contrast, there was no significant difference between postoperative CA19-9 and any other clinicopathological factors. Univariate analysis revealed postoperative adjuvant chemotherapy (P = 0.03), residual tumor factor status (P = 0.01), pathological differentiation (P = 0.02), UICC pT stage (P = 0.009), lymph node metastasis (P < 0.001) and UICC final stage (P = 0.001) were significantly associated with OS. In addition, differences in OS were significant between groups divided on the basis of two preoperative CA19-9 cutoff values (37 and 200 U/ml), and three postoperative CA19-9 cutoff values (37, 100 and 200 U/ml). In multivariate analysis, no postoperative adjuvant chemotherapy (odds ratio [OR], 3.02: 95% confidence interval [CI], 1.54 - 5.89; P = 0.001), lymph node metastasis (OR, 3.96; 95% CI, 1.91 - 8.48; P < 0.001), preoperative CA19-9 (≥200 IU/ml) (OR, 2.27; 95% CI, 1.10 - 4.61; P = 0.03) and postoperative CA19-9 (≥37 IU/ml) (OR, 6.88; 95% CI, 3.36 - 14.41; P < 0.001) were identified as independent predictors for OS.

Conclusion: Perioperative serum CA19-9 levels predict the survival of patients with resectable cholangiocarcinoma, and they may contribute to establishment of new therapeutic strategy, as perioperative treatment can be optimized based on its value.

F. Extended Hepatectomy With Portal and Hepatic Artery Resection for Advanced Perihilar Cholangiocarcinoma .

  Monday,  8:00AM - 5:00PM  | Mo1692  | Minoru Esaki, Kazuaki Shimada, Shutaro Hori, Yoji Kishi, Satoshi Nara, Tomoo Kosuge 
Hepato-biliary pancreatic surgery, National Cancer Center Hospital, Tokyo, Japan

Objectives: The aim of this study was to clarify short- and long-term outcome of extended hepatectomy with portal vein resection (PVR) or hepatic artery resection (HAR) for perihilar cholangiocarcinoma.
Methods: Patients with perihilar cholangiocarcinoma who underwent resection between January 2000 and December 2011 for perihilar cholangiocarcinoma were analyzed retrospectively. Operative variables, mortality, morbidity, and survival were compared among standard resection with no PVR and no HAR (S group), with PVR without HAR (PV group) and with HAR (HA group).
Results: A total 230 patients underwent surgical resection for perihilar cholangiocarcinoma, 172 (75%) in S group, 37 (16%) in PV group, and 21 (9.1%) in HA group were enrolled. Operative time and blood loss were 633minutes and 1415ml in S group, 665 and 2028 in PV group, 775 and 2076ml in HA group, respectively. Those with PV and HA group were significantly more than in those with S group (both P = 0.04). Mortality and more than grade IIIa complications occurred in 4 (2.3%) and 17 (9.9%) patients with S group, in 0 and 5 (14%) with PV group and 0 and 3 (14%) with HA group. The rates of more than Grade IIIa complications were comparable among 3 groups. Overall 5-year survival rate and median survival time were 49% and 47.5 months in S group, 22 and 25.0 in PV group, 21 and 21.4 in HA group. There was significant difference in survival in patients between S and PV, S and HA group, respectively. Especially, patients in HA group with R1 (surgical margin positive) or with severe perineural infiltration were associated with unsatisfactory prognosis, which were not survived for more than 3 years.

Conclusions: PVR and HAR for advanced perihilar cholangiocarcinoma were feasible. It can provide a favorable prognosis in selected patients of advanced perihilar cholangiocarcinoma

G. Tumor Size Does Not Dictate Prognosis After Resection for Hepatocellular Carcinoma. Results From a Large Western Series .

Sunday,  3:30PM - 3:45PM  | 451  Michael D. Kluger1, 2, Andrea Belli2, Alexis Laurent2, Daniel Azoulay2, Daniel Cherqui1, 2
1Division of Hepatobiliary Surgery and Liver Transplantation, New York-Presbyterian Hospital Weill Cornell Medical College, New York, NY; 2Service de Chirurgie Digestive et Hépatobiliaire, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris -Université Paris-Est, Créteil, France

INTRODUCTION: Operative management remains the gold standard approach for hepatocellular carcinoma (HCC). Resection is the preferred treatment in patients without cirrhosis, with transplantation being the best option for decompensated cirrhotics. This study evaluated underlying liver disease, operative factors and histopathological characteristics on overall and recurrence-free survival in 313 patients undergoing liver resection for HCC at a single Western center. METHODS: Patients who underwent liver resection for HCC between 3/89 and 9/10 were studied. Patients were not excluded based on tumor size, extent of fibrosis, or etiology of underlying liver disease. As indications for treatment are mostly based on tumor size, patients were stratified by diameter: < 50 mm, 50-100 mm and > 100 mm. Patients with Child's A cirrhosis, no esophageal varices, and a platelet count ≥100 × 10^9/L were directed toward resection. Kaplan-Meier and Cox regression methodology were utilized. RESULTS: 36% had tumors <50 mm, 36% had tumors 50-100 mm, and 28% had tumors > 100 mm. Patients with larger tumors were more likely to have normal underlying liver parenchyma: 43% > 100 mm, 15% 50-100 mm and 1% < 50 mm (p <0.001). 77% underwent an open and 23% a laparoscopic procedure (p<0.001). Major hepatectomies comprised 56%, anatomic resections 87%, and R0 88% of resections. There was no significant difference in Clavien 3-5 complications among the groups (p=0.78), 16% overall. This rate decreased in the second decade of our experience. For example, the mortality rate between 3/89 and 12/99 was 14%, and 5% through 9/10 (p<0.008). Median overall survival was 60 months, with 1- and 5-year overall survival rates of 76% and 50%. On multivariate analyses, intra-operative transfusion (HR=2.60), cirrhosis (HR=2.42), salvage transplantation (HR=0.23), poorly differentiated tumor (HR=2.04), satellite lesions (HR=1.68), microvascular invasion (HR=1.48), and AFP > 200 (HR=1.53) were significant predictors of survival. Median time to recurrence was 20-months, with 1- and 5-year recurrence-free survival rates of 61% and 28%. By multivariate analyses intra-operative transfusion (HR=2.15), poorly differentiated tumor (HR=1.87), cirrhosis (HR=1.69) and microvascular invasion (HR=1.71) independently impacted recurrence-free survival. CONCLUSION: It is demonstrated that resection is a safe and readily available treatment for any size HCC in properly selected patients in the modern era of liver surgery. Tumor size did not independently impact recurrence or survival on multivariate analyses, whereas tumor histopathology and background parenchyma did. The current investigation adds to a growing body of literature supporting that HCC tumor biology and the condition of the non-tumor parenchyma should be given greater consideration in considering resection in this era of organ shortage.

H. EUS-Guided Biliary Drainage Is Effective, Safe, and Less Costly Than Percutaneous Transhepatic Biliary Drainage in Patients With Distal Malignant Biliary Obstruction and Failed ERCP .
8:00  | Su1567  Ali Kord Valeshabad, Elham Afghani, Vikesh K. Singh, Payal Saxena, Marcia I. Canto, Anthony N. Kalloo, Mouen Khashab .  Johns Hopkins Medical Institute, Baltimore, MD

Background: Endoscopic retrograde cholangiography (ERC) is the method most commonly employed for palliation of malignant biliary obstruction. Percutaneous transhepatic biliary drainage (PTBD) and, rarely, surgical bypass are utilized following failed ERC. Endoscopic ultrasound-guided biliary drainage (EGBD) is an emerging less-invasive alternative following unsuccessful biliary cannulation. EGBD may be a safe alternative technique to PTBD in these instances. However, it is currently unknown how both techniques compare in terms of efficacy, safety and cost. Aims: To compare efficacy, safety, and procedural facility charges of EGBD to PTBD after failed ERCP in patients with malignant distal biliary obstruction. Methods: The endoscopy and billing databases at a tertiary center were searched for patients who underwent PTBD or EGBD for relief of distal malignant biliary obstruction after failed ERC between 1/2002 and 11/2012. At our center, EGBD was instituted in 2/2011 and all patients with failed ERCP were then referred initially for EGBD. EGBD and PTBD groups were compared for technical success (stent placement in desired location), clinical success (relief of biliary obstruction), adverse events, and charges. Adverse events were graded according to the ASGE lexicon’s severity grading system. The groups were compared using the Student’s t- test for continuous variables and the chi-square test for categorical variables. Results: A total of 67 patients (age 66.3yr, male 58%, pancreatic cancer 57%) with failed ERCP subsequently underwent EGBD (n=16) or PTBD (n=51). Baseline characteristics of both groups were equivalent. Technical success was achieved in 14 (87.5%) and 51 (100%) of EGBD and PTBD patients, respectively (p=0.01). Clinical success was more commonly achieved in EGBD group but difference was not statistically significant (100% vs. 92.7%, p=0.30). Rate of adverse events was also equivalent between both groups (25.0% vs. 41.2%, p=0.36). Adverse events were rated as mild (n=2) or moderate (n=2) in the EGBD group and mild (n=9) or moderate (n=12) in the PTBD group. Survival was equivalent between both groups. Reinterventions (stent exchange/upsize/cleaning) were significantly more common in the PTBD group (92.2% vs. 25%, p<0.001). Likewise, number of reinterventions per patient was significantly higher in the PTBD group (5.6 vs. 0.25, p<0.001). Total procedural facility charges ($) (index procedure and reinterventions) was also significantly higher in the PTBD group (9030 vs. 4300, p=0.001).

Conclusion: EGBD and PTBD are both safe and effective techniques for treatment of distal malignant biliary obstruction after failed ERCP. EGBD, however, is associated with significantly less charges due to the need for fewer reinterventions. These intriguing results suggest that EGBD should be the technique of choice for treatment of these patients.

I.  A Multicenter Study on EUS- Guided Expandable Biliary Metal Stent Placement: Choice of Access Route, Direction of Stent Insertion, and Drainage Route  .
8:00  | Su1587  Vinay K. Dhir1, Everson L. Artifon3, Kapil Gupta2, et.al. .1Endoscpy, Baldota Institute of digestive sciences, Mumbai, India; 2Pancreatic and biliary diseases, Cedars-Sinai Medical Centre, Los Angeles, CA; 3Gatrointestinal endoscopy unir, University of Sao Paulo, Sao Paulo, Brazil; 4Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain
Background: EUS-guided expandable biliary metal stent placement (EUS-BD) has emerged as an acceptable alternative in patients with failed ERCP. However there is no consensus over the preferred access route ( point of initial needle puncture; trans-hepatic or extra-hepatic), direction of stent insertion (antegrade or retrograde) or drainage route (the route by which the stent drains to the enteral system; trans-luminal or trans-papillary).
Aims: To compare success and complication rate in patients undergoing EUS-BD via different access routes ,direction of stent insertion, and drainage routes
Study design: Multicentre retrospective study
Patients: Patients who underwent EUS-BD for malignant obstructive jaundice were included.
Methods: Data from four centres was entered in a SPSS data sheet. Details were recorded of the access route, direction of stent insertion ( antegrade being the direction from liver to bile duct and vice versa), and drainage route ( transluminal being choledocho-duodenostomy or hepatico-gastrostomy while transpapillary being antegrade and retrograde( rendezvous) trans-papillary stenting procedures. Details of success and complications were noted. Comparisons were done using Chi square test, Student T test, and stepwise logistic regression
Outcome measures: Success and complication rate with various techniques.

Results: 68 patients (34 males) were analyzed. Median age of the cohort was 66 years (34-95 years). Fifty five patients (81%) had a distal block. Sixty four patients (94%) had previously failed ERCP. EUS-BD was successful in 65 patients ( 95.6%). Complications were seen in 14 patients (20.6%, cholangitis 5, bile leak 4, perforations 2, pneumobilia 2, and bleed 1) and mortality in 3 patients (4.4%, cholangitis 2, perforation 1). The results of various techniques are summarized in the table. Logistic regression analysis showed trans-hepatic access to be the only independent risk factor for complications ( p=0.031, t=2.2).

Conclusions: EUS-BD can be performed with high success rate regardless of the choice of access route, stent direction or drainage route. However the complications appear to be higher in patients following trans-hepatic access, antegrade stent insertion, and in those with proximal block. Extra-hepatic route should be preferred for EUS-guided direct and rendezvous stent placements. Patients with proximal blocks need careful evaluation before EUS-BD.


I.  Effect of Chronic Renal Failure on the Hepatic Expression of Bile Acid Transporters.
   8:00  | Su1680  Gai Zhibo1, Chu Lei2, Jean-Pierre Montani3, Gerd A. Kullak-Ublick1 . 1Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland; 2Department of Nephrology, Shandong University, Jinan, China; 3Physiology of the Dept. of Medicine, Freiburg University, Freiburg, Switzerland

Background. Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high-protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Cyp7a1), despite normal corresponding mRNA levels.
Design and Methods. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the bile acid synthesizing enzyme Cyp7a1 and the bile acid transporters, Ntcp, Bsep, Mrp3, Ost-alpha and OST-beta. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy) or to the sham-operated, placebo-treated normal control group. They were allowed free access to regular rat chow and were analyzed 8 weeks after surgery. Results obtained in CRF rats were compared to those obtained in rats that had undergone uninephrectomy (UNX).

Results. The CRF group exhibited significantly increased plasma cholesterol and bile acid concentrations. Hepatic Cyp7a1 mRNA, and protein levels were almost identical in the two groups. Hepatic Mrp3, Ost-α and Ost-β expression was increased at both the mRNA and protein levels, suggesting increased basolateral efflux of bile acids into basolateral blood. However, no such changes in bile acid transporter expression were observed in kidney. In UNX rats, similar changes in plasma bile acid levels and in the expression of bile acid transporters were found. We hypothesize, that the increase in plasma bile acids is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane.

God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

Re: Bits and Pieces From DDW 2013

Thanks for these Percy. I will have a read of them later on. Hope that you have a safe trip back home!

Any advice or comments I give are based on personal experiences and knowledge and are my opinions only, they are not to be substituted for professional medical advice. Please seek professional advice from a qualified doctor or medical professional.

Re: Bits and Pieces From DDW 2013

This is a wonderful reportage.  If anyone is willing to summarize these reports as they read and understand them, I will be very grateful.  If I get trough some of them, I will be sure to provide a synopsis.

The CA19-9 study is interesting to me since I have always had very low levels.  None of the cancer marker have every shown up on me.  I have ICCA, first diagnosed as a single small tumor in 2009.  It was resected and I was treated with 6 months of gemcitabine.  A routine scan picked up multiple small lesions all over my liver Novemeber 2012, but nowhere else (fingers crossed).  My CA19-9 levels were always normal.  I have been on gen and oxali for six months with stable tumors and the levels are only mildly elevated beyond normal.  We haven't been sure what to make of this, and I always wonder if this is information that would better classify the cancer.

Be well!

Re: Bits and Pieces From DDW 2013

Regina....we will be able to interpret Percy's reports, but it may take a few days.  Percy and I are preparing for the upcoming ASCO meeting in Chicago, but we will try to find some time to go through the Abstracts soon thereafter.

In regards to the tumor markers (CA 19-9) 10% of the Caucasian population lack a specific blood protein hence, they will not show a rise in the marker. It is nothing to worry about, as the Lewis Antigen mainly is used to track response to treatment.  In itself, not much value is given to it.

Patients like you are watched for symptoms and results of scans and blood tests in order to track response to treatments. 


Re: Bits and Pieces From DDW 2013

Thanks for these interesting reports....well done!

13 (edited by PCL1029 Sun, 26 May 2013 20:01:29)

Re: Bits and Pieces From DDW 2013

Hi, Regina,

This is a wonderful reportage.  If anyone is willing to summarize these reports as they read and understand them, I will be very grateful.  If I get trough some of them, I will be sure to provide a synopsis..

For the above comment, I think it is impossible at this moment for me  to link each one and connect the dots to provide you an reasonable answer; it requires full time attention and a smart person to find and solve problem; and I am not able to do so at this time both in time and wisdom.
Since some reports are related to the ERCP procedure; others are relate to the POSSIBLE development of a urine test for CCA in the future; one  study is  related to a proposed new stage for Hilar CCA  ,not for RESECTION purpose but  ONLY proposed for CLINICAL use for determining clinial trial. Each one is unique in itself.

As I mentioned in one of the  message above, I do NOT expect most of you to read through and understand each study in DETAILS. The summation of EACH study is the INDIVIDUAL result or conclusion of each study mentioned at the end or EACH article.

I frankly can say, at this point, all these studies I chose like "the  bile acids at the cellular level";like" the new pCLE ECRP  procedure"; and a lot of the others I did not post are for the purpose of having a better understanding about CCA in general, and hopefully one day, all of these can be connected and make somebody's mind "CLICKS' into  developing a solution to either finding a cure or a better , easier andmore  tolerable treatment. And this is the purpose for me to sitting through  all those presentations besides trying to keep this message board current and up-to-date in the medical knowledge this board can provide to all its members,like you.

I chose these studies because most readers will be interested in the related study subject, such as the  CA19-9 study you are interested in.
Unlike ECCA,  the CA19-9 value is always on the low side, (<37) even when the tumor is 8x6cm that large, as in my case when I had the first resection.

You can have a better idea about this chronic disease by starting with the following message board links first.

http://www.cholangiocarcinoma.org/punbb … 365#p47365

http://www.cholangiocarcinoma.org/punbb … 198#p57198

http://www.cholangiocarcinoma.org/punbb … 365#p47365

God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

14 (edited by PCL1029 Mon, 27 May 2013 23:01:27)

Re: Bits and Pieces From DDW 2013

Hi, Regina,

There are cytologist,oncology ,liver transplant ,OR nurses and other medical professional on this discussion board ,along with some very smart caretakers whose minds are detail oriented,methodological and analytical.
On the other hand, many just like to know the info. in the layman's prospective. Here is part of it in the "easy to know" version

In the meantime. for medical info like these, you can have some practical use right away..
1. If some patient ERCP DX of ECCA is inconclusive, s/he can use pCLE+biopsies+brushing from the ERCP to make a more conclusive DX.
2. or you can add the conclusion of the " CTC are detectable in patients with cholangiocarcinoma" study to confirm the DX of CCA.

BUT be of the fact that , all these are studies were done in large teaching hospitals like John Hopkins or Mayo clinic, Mass General Hospital,therefore if you want the above additional test done, you have to go to the right places to get it. Local community hospital or even large university hospital not specialized in CCA may not have the "research oriented " doctors,techniques and labs to perform such specific  procedure and that is why a lot of GI specialists presented in the presentations of ERCP sessions to learn about the studies and new things and  I  can see some of them are not that  "handy" in handling the device, not to speaking in how to use the devices proficiently . To be considered as a  ERCP proficiency operator, the doctors  have  to performed minimum  of 30 ERCP procedures and 50-60 is desirable to master the technique to become a "specialist" who has enough experience to perform ERCP. So where you can get such GI doctors ,the tools and the lab support? the answer is you must get all of this from the large research hospitals and NO other places. But is it necessary to do all of these or "just to accept the current ERCP Dx practice for ECCA Dx without 100% of certainty?" is easier. I think it is a personal choice at this point.
3. For the bile acids research, I would like to find way to decrease the production of the 12gm /day  bile acids so to relieve the itching and jaundice. I would like to find a way to produce much less concentrated bile acids so they can flow thru the bile ducts easier without clogging too often so the patient do not need to change the stents so often; I would like to,on the cellular genetic level,in the transcriptional phrase using miRNA, to alter some of the 27 kinds of  bile acids genetically into one or two therapeutic agents(like DCA-dicholoacetic acid) to treat ECCA.as of now, this is still in the infant  stage for such of my dream.
4. In another presentation about "thrombosis of the liver diseases" ; you can understand that the chance are high for liver disease patients (including cholangiocarcinoma) to develop DVT,(deep vein thrombosis), portal vein thrombosis(PVT) and PE (pulmonary embolism) .
What choices doyou have and which one is better and how long do you have to be on the medications such as enoxaparin(Lovenox),fondaparinux(Arixtra),Warfarin(Coumadin),and the newer anticoagulants dibigatran(Pradaxa) or rivaroxaban(Xarelto). The answer lies in the patient's choice,  compliance  and doctor's comfort level in using the new drugs(both Xarelto and Pradaxa do not require periodic monitoring of PT/INR like Coumadin does, but there are no antidote for them in case of  bleeding develop; however the half life is relative short and therefore may not require the prolong  treatment of bleeding that is common to  warfarin, which have a long half-life and  required to have Vitamin K as the antidote .
5.As I mentioned before Aspirin provides chemo prevention property, but as a patient,what will you do even if you have an  evidence-based study provide the info to you like this study?--If I want to start, I will talk to my GP on that. The same apply to omega 3 fish oil and vitamin D usage, What will you do? Will you use these info in  your life-time treatment  plan for CCA? Are these studies good enough as evidenced-base study you can trust now.? In my opinion, It won't hurt to try in the dosage range that your GP or doctors recommended. But are all the doctors up-to-date in their knowledge to provide you all the info. you need? My answer: It is the patient's responsibility to fine out .
God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

Re: Bits and Pieces From DDW 2013

For those who really want to dive in and study in details about  cholangiocyte at the cellular level. below is the link.
The reason to start at the cellular level is simple, ASCO last year announced that the future trend of treating cancer is through  genome and genomics on a personalized basis within 10 years.

http://www.nature.com/icb/journal/v86/n … 0837a.html

God bless.

Please know that my personal opinion is not intended nor implied to be a substitute for professional medical advice. If  provided, information are for educational purposes.Consult doctor is a MUST for changing of treatment plans.

Re: Bits and Pieces From DDW 2013

This link offers a good overview to what has been mentioned by Percy:

http://researchadvocacy.org/images/uplo … edBklt.pdf


Re: Bits and Pieces From DDW 2013

Excellent links! Thanks very much to you both for posting them.

Any advice or comments I give are based on personal experiences and knowledge and are my opinions only, they are not to be substituted for professional medical advice. Please seek professional advice from a qualified doctor or medical professional.