Cholangiocarcinoma (CCA) is a lethal disease, afflicting many thousands the world over. Human CCA develops through a multi-step progression model, preceded by the onset of dysplasia in the cholangiolar ductal epithelium. An animal model of multi-step carcinogenesis in the biliary tree will enable the study of genetic changes in human CCA, and provide an avenue for chemoprevention strategies. We describe an oral thioacetamide (TAA)-induced model of rat CCA that recapitulates the histologic progression of human CCA. Male Sprague-Dawley (SD) rats (n = 170), weighing 350 +/- 20 g, were used in this study. Drinking water with TAA 300 mg/l was administered orally, and the liver was harvested and examined histologically at weekly intervals, beginning at 5 weeks after initiation of TAA. Harvested tissues were formalin-fixed and paraffin embedded for morphologic and immunohistochemical studies. Multifocal bile ductular proliferation with intestinal metaplasia (presence of goblet cells) and increasing histologic atypia (biliary dysplasia) was observed by the 9th week of TAA administration. Biliary cytokeratin (CK19)-expressing invasive intestinal-type CCA with stromal desmoplasia was evident at the 16th week, and by the 22nd week, the yield rate for CCAs had increased to 100%. Invasive CCAs preceded the development of hepatic cirrhosis by at least 4 weeks; the earliest incidence of hepatic fibrosis was observed beginning at 20 weeks post-TAA administration. The progression from normal cholangioles to biliary dysplasia to invasive CCA was accompanied by up-regulation of the proto-oncogenes c-met and c-erbB-2, tyrosine kinase receptors over-expressed in human CCAs. The study was terminated at 6 months, at which time no systemic metastases or deaths were observed. Oral administration of TAA in drinking water to male SD rats provides a reproducible animal model for development of CCA with a high yield rate. In particular, the presence of biliary dysplasia beginning at the 9th week, which progresses to invasive CCA, mimics the multi-step model of human CCA. The TAA rat model may serve as a powerful pre-clinical platform for therapeutic and chemoprevention strategies for human CCA.

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Background Serious complications continue to occur in laparoscopic cholecystectomy (LC). The commonly used indicators of surgical difficulty such as the duration of surgery are insufficient because they are surgeon and institution dependent. We aimed to identify appropriate indicators of surgical difficulty during LC. Methods A total of 26 Japanese expert LC surgeons discussed using the nominal group technique (NGT) to generate a list of intraoperative findings that contribute to surgical difficulty. Thereafter, a survey was circulated to 61 experts in Japan, Korea, and Taiwan. The questionnaire addressed LC experience, surgical strategy, and perceptions of 30 intraoperative findings listed by the NGT. Results The response rate of the survey was 100%. There was a statistically significant difference among nations regarding the duration of surgery and adoption rate of safety measures and recognition of landmarks. The criteria for conversion to an open or subtotal cholecystectomy were at the discretion of each surgeon. In contrast, perceptions of the impact of 30 intraoperative findings on surgical difficulty (categorized by factors related to inflammation and additional findings of the gallbladder and other intra-abdominal factors) were consistent among surgeons. Conclusions Intraoperative findings are objective and considered to be appropriate indicators of surgical difficulty during LC.

CF is a known complication of chronic gallbladder disease that is traditionally considered as a contraindication to LC. Correct preoperative diagnosis of CF demands high index of suspicion and determines the success of laparoscopic management for the subset of patients. The difficult laparoscopic repair is safe and effective in the experienced hands of laparoscopic surgeons.

Background We previously identified 25 intraoperative findings during laparoscopic cholecystectomy (LC) as potential indicators of surgical difficulty per nominal group technique. This study aimed to build a consensus among expert LC surgeons on the impact of each item on surgical difficulty. Methods Surgeons from Japan, Korea, and Taiwan (n = 554) participated in a Delphi process and graded the 25 items on a seven-stage scale (range, 0-6). Consensus was defined as (1) the interquartile range (IQR) of overall responses ≤2 and (2) ≥66% of the responses concentrated within a median AE 1 after stratification by workplace and LC experience level. Results Response rates for the first and the second-round Delphi were 92.6% and 90.3%, respectively. Final consensus was reached for all the 25 items. 'Diffuse scarring in the Calot's triangle area' in the 'Factors related to inflammation of the gallbladder' category had the strongest impact on surgical difficulty (median, 5; IQR, 1). Surgeons agreed that the surgical difficulty increases as more fibrotic change and scarring develop. The median point for each item was set as the difficulty score. Conclusions A Delphi consensus was reached among expert LC surgeons on the impact of intraoperative findings on surgical difficulty.

The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination.Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.

The postoperative intrahepatic remnant rate is very high; 80% by 5 years after resection. The preoperative serum alpha-fetoprotein level and adequacy of the cut margin significantly influenced the recurrence rate.

We report our experience of the surgical treatment of intrahepatic cholangiocarcinoma (ICC) in Taiwanese patients. A total of 162 patients with histologically proven ICC were treated of whom 106 (65. 4%) had associated hepatolithiasis. Patients with hepatolithiasis were in earlier stages than those without hepatolithiasis. Two-thirds of the patients with hepatolithiasis presented with acute cholangitis, and two-thirds of those without hepatolithiasis presented with hepatomegaly. The rate of hepatic resection was 29.6% (48 of 162), and these rates were 31.1% and 26.8% for the patients with and without hepatolithiasis, respectively. Ninety-three percent of the patients with hepatolithiasis underwent common bile duct exploration, compared with 18% of those without hepatolithiasis. The surgical mortality rates were 3.7% (6/162), for all patients, and 3. 8% and 3.6% for patients with and without hepatolithiasis, respectively. The morbidity rate was much higher in the patients with hepatolithiasis (37.7% vs 16.1%). The 1-, 3-, and 5-year survival rates were 35.5%, 20.5%, and 16.5% in the patients with hepatolithiasis and 27.2%, 8.8%, and 7.8% in those without hepatolithiasis. Concomitant hepatolithiasis prevented precise diagnosis preoperatively and precipitated biliary sepsis, which affected resectability and increased postoperative morbidity. Hepatolithiasis per se did not influence long-term survival.