Diagnostic modalities and surgical procedures for biliary diseases have been greatly advanced recently. Laparoscopic surgery for gallstone disease and urgent biliary drainage for acute cholecystitis and cholangitis have been widely accepted and the results were improved. In contrast, the prognosis of biliary tract cancer, that is the sixth cause among the cancer death in Japan, is still dismal even the development of diagnostic and surgical procedures because the disease is diagnosed as an advanced stage. In this presidential lecture, changes in molecular biology regulating liver regeneration after hepatectomy in obstructive jaundice frequently associated with bile duct cancer were clarified. Moreover, an importance of the presence of bile in the intestine before surgery in obstructive jaundice was presented. The biliary stent drainage in obstructive jaundice after the assessment of tumor extension is favorable. The surgical procedure and outcome in patients with hilar bile duct carcinoma, distal bile duct carcinoma and gallbladder carcinoma were presented. Finally, I have shown the results of ongoing prospective randomized study on delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy with respect to the reconstruction route.

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Cancer stem cells (CSCs) are the cancer cells which have the unique characteristics of self-renewal and pluripotency, and the critical role for tumor growth and resistance to anti-cancer therapy. Niches interact with CSCs, involving in CSC regulation, tumor invasion and metastasis.
We found that CD13 was a surface marker for CSCs in human liver cancer cell lines and clinical samples, and that CD13+CSCs were associated with a hypoxic marker in clinical hepatocellular carcinoma sample, suggesting that CD13+CSCs have the critical role in tumor growth and resistance to anti-cancer therapy in liver cancers.
We also successfully produced so-called iPC cells in transfecting iPS factors into cancer cell lines. iPC cells acquired higher sensitivity to chemotherapeutic agents and less tumorigenecity than original cell lines. We also established the method to produce iPC cells by direct transfection of the combination of micro RNAs (mir-200c, mir-302s and mir-369s).
Further studies in the field of CSCs are necessary in order to detect early cancer, to regulate CSCs, and to improve the efficacy of anti-cancer therapy.

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The optimal management of patients with concomitant common bile duct (CBD) stones and gallstones is still evolving. Since May 1992 we have begun laparoscopic common bile duct (CBD) exploration as the choice for the management of CBD stones. Laparoscopic CBD exploration is actually categorized into two approaches which are the transcystic approach and choledochotomy. We selected the transcystic approach for patients whose CBD stones were less than 4 in number and smaller than 8 mm in diameter on cholangiograms. Among 515 patients with CBD stones, the transcystic approach was performed successfully in 205 cases. 300 patients underwent laparoscopic choledochotomy which was followed by ductal closure with transcystic drainage in 177, T-tube drainage in 75, primary ductal closure in 31, and others. Ten patients were converted to open surgery. The transcystic approach was associated with short hospital stay and few morbidities. Choledochotomy also had an acceptably low rate of complications and short hospital stay especially with C-tube drainage. Bile leaks occurred more frequently in those with primary ductal closure than in those with transcystic drainage or T-tube drainage. From these results we conclude that laparoscopic management of CBD stones is feasible for almost all cases of CBD stones. In the near future, the procedure should be the choice for CBD stones.

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IgG4-related sclerosing cholangitis (IgG4-SC) is a characteristic sclerosing cholangitis showing the increased level of the serum IgG4, the dense infiltration of lymphocytes and IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. IgG4-SC shows various cholangiographic features similar to those of primary sclerosing cholangitis (PSC), pancreatic cancer, and cholangiocarcinoma. Therefore, it is not easy to discriminate IgG4-SC from those progressive or malignant diseases on the basis of cholangiographic findings alone. The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract provided by the Ministry of Health, Labor, and Welfare of Japan, and the Japan Biliary Association organized a working group consisting of researchers specializing in IgG4-SC. This working group proposed the new clinical diagnostic criteria of IgG4-SC 2012 in order to avoid the misdiagnosis of PSC and malignant diseases as far as possible, after several meetings and the open forum on 17 September 2011 to discuss the tentative proposal.

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Objective: We assessed whether or not ultrasonography with the pulse Doppler method is useful to diagnose arterial infiltration in biliary tract cancer.
Methods: 27 patients with bile duct cancer or gallbladder cancer underwent Doppler ultrasonography pre-operatively. We assumed that an artery could be infiltrated by a tumor if a change in waveform is observed on ultrasonography with the pulse Doppler method, compared with pathological findings (pA).
Results: For microscopic arterial infiltration, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 60.0%, 63.6%, 63.0%, 27.3%, and 87.5%, respectively.
Conclusion: Ultrasonography with the pulse Doppler method is useful for diagnosis of arterial non-infiltration in biliary tract cancer. This method was easier to perform and involved less burden than other modalities.

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A patient with acute cholangitis needs prompt treatment in appropriate institutions that can provide emergency care, because of the high probability of serious complications. Subjects were 138 patients diagnosed as acute cholangitis from April 2007 to September 2010 and we investigated them retrospectively. Age of all patients is average 71 year old, male/female: 86/52. The diagnoses for these patients were common bile duct stone (n=104), malignant biliary stenosis (n=19), stent obstruction (n=7), biliary pancreatitis (n=5), and others (n=3). Primary procedures were drainage (n=90), stone extraction (n=44), stent exchange (n=4). Patients in the group with a severe grade showed significant differences compared with patients with a moderate grade that included thrombocytopenia, a low GPT level, hypoalbuminemia, a high CRP level, and renal dysfunction. Endoscopic nasobiliary drainage (ENBD) placement for drainage is useful because we can examine properties of bile, pathogenic bacteria, and causes after drainage. Since there were deaths among the patients with severe disease despite the implementation of appropriate treatment using ENBD, disease severity carried a high risk for mortality.

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We evaluated clinicopathological features of the surgical cases of pancreaticobiliary maljunction (PBM) with biliary carcinoma in the biliary dilated group and the non-dilated group. Our purpose of this study was to clarify the adequate surgical procedures of PBM without biliary dilatation, especially indication for resection of extrahepatic bile duct. Of these 17 patients, 9 patients in dilated type group and 8 patients in non-dilated group, there were no significant differences between 2 groups in clinicopathological features. We also investigated the frequency of the type of bile duct dilatation, such as cystic, fusiform and non-dilated type, in the patients of PBM with biliary carcinoma. As results, bile duct carcinoma was developed from not only cystic type but fusiform type or non-dilated type bile duct. In conclusion, extrahepatic bile duct should be removed in patients with PBM regardless of the type of bile duct dilatation.

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Transpapillary endoscopic biliary drainage (EBD) is the standard treatment in patients with biliary obstruction. However, transpapillary access to the bile duct is not always possible, especially in patients with duodenal stenosis or difficult cannulation of the bile duct during endoscopic retrograde cholangiopancreatography. Percutaneous transhepatic biliary drainage has been performed in cases of unsuccessful ERCP. ESBD is a new, promising biliary drainage technique for biliary obstruction. However, several issues remain to be solved for its widespread use. The appearance of ESBD is a blessing for both patients and physicians, as it has expanded the choice of biliary drainage methods. Endoscopists should take etiology of biliary obstruction into consideration before selecting a biliary drainage procedure. For establishment of appropriate indications, randomized controlled trials of ESBD versus EBD/PTBD are awaited. Technical standardization of ESBD is expected to be accelerated with the development of dedicated accessories optimal for ESBD.

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Fluorescent cholangiography is a technique that enables real-time identification of the extrahepatic duct during surgery, through visualization of fluorescence of indocyanine green (ICG) in the bile following intrabiliary or intravenous injection. Since this technique first originated in Japan in 2008, it has been clinically used to identify the confluence of the left and right hepatic ducts during hepatectomy, the extrahepatic bile ducts during cholecystectomy, and the site of bile leakage on the raw surface of the liver. Especially, fluorescent cholangiography by intravenous injection of ICG is expected to enhance the safety of laparoscopic cholecystectomy, although the fluorescent imaging system for laparoscopic use has not been available. In the experimental studies, novel fluorescent agents and imaging systems have been actively developed, aiming to visualize the deeply-located bile ducts with fluorescent images of blood vessels on the color images.

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A 70-year-old woman underwent surgical removal of a malignant melanoma on her right arm. Four years after the surgery, computed tomography (CT) showed a mass inside the gallbladder. Trans-abdominal ultrasonography (US) revealed a semipedunculated elevated lesion 30 mm in diameter inside the gallbladder, and color Doppler ultrasonography showed linear vascular flow within the lesion. Contrast-enhanced US using Sonazoid^® showed strong enhancement inside the tumor but poor enhancement on the edge of the tumor. Multiphasic CT revealed a 30 mm large tumor inside the gallbladder with contrast-enhancement from the arterial phase. Endoscopic ultrasonography (EUS) showed hyperechoic layer on the top of the tumor with smooth surface. Contrast-enhanced EUS revealed the similar findings as US, showing strong enhancement only in the center of the tumor. Endoscopic retrograde cholangiography showed a smooth elevated lesion like a submucosal tumor in the body of the gallbladder. She underwent open cholecystectomy, and the pathological diagnosis was metastasis of malignant melanoma.

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Xanthogranulomatous cholecystitis (XGC) is difficult to differentiate from gallbladder carcinoma. We report a case of XGC diagnosed preoperatively by imaging modalities from the onset of its disease. The patient was an 81-year-old man. Initially, the gallbladder wall was slightly thickened and ERC showed normal bile duct but the gallbladder was not visualized. 4 months later, an abdominal ultrasonography (US) showed a thickened gallbladder wall with many gallbladder stones. ERC showed the narrowing of the common hepatic duct and computed tomography (CE-CT) revealed the presence of low density area at the gallbladder bed. Gallbladder carcinoma was suspected and he was refered to our hospital. After admission, ERC showed similar findings but low density area was decreased on CT. The biopsy specimen from the common hepatic duct showed no malignancy and obstructive jaundice was absent. Cholecystectomy was performed under the diagnosis of XGC. The final histological diagnosis was XGC. Since this XGC case is that can be followed-up from the onset of the disease, we herein report a case and review of the literature.

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Two patients (case1: A 60-year-old man and case2: A 63-year-old woman) were admitted to our hospital due to acute cholecystitis. Multiple metallic stent deployment had been performed on them because of unresectable biliary tract carcinoma. Case1 suffered from acute cholecystitis three times during the course. Case2 developed acute cholecystitis under the chemotherapy and PTGBD was difficult because her gallbladder was deviated to dorsal side due to right hepatic lobe atrophy and compensated left lobe hypertrophy with progression of cancer. Endoscopic ultrasonography-guided gallbladder drainage (EUS-GBD) was successfully conducted on these patients and they became outpatient. Although EUS-GBD is technically demanding and potentially hazard, this technique might offer an alternative treatment for acute cholecystitis, especially in the patients with metallic stents deployed due to malignant biliary strictures. To establish this new technique as standard treatment, the results of multicenter studies and the development of new device are warranted.

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A 59-year old man presented to the surgery outpatient department with a diagnosis of cholecystitis and gallbladder stones. Initial blood investigations revealed increased white cell count of 10,800 /μl and C-reactive protein of 8.49 mg/dl. While the hepato-biliary-enzymes were within normal range. Serum CA19-9 was markedly increased (8528 IU/ml). A ¹⁸F-fluorodeoxyglucose-Positron emission tomography (FDG-PET) was performed and demonstrated increased activity of in the thickened wall of the gallbladder, in which an standardized uptake value (SUV) that increases in the late phase compared to that of early phase is generally considered suspicious for malignant disease. Follow up examination revealed decreased serum level of the CA19-9 to the normal range. The patient underwent the laparoscopic cholecystectomy. The gross appearance of the resected gallbladder showed smooth mucus without neither elevated nor ulcerative lesion. And the microscopic examination of pathologic specimen diagnosed adenomyomatosis and chronic cholecystitis. We suggested that, even in the case of which showed increased uptake of FGD-PET, it is necessary for us to take into account of benign gallbladder diseases as well as malignant disease and to decide a therapeutic management.

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Although malignant diseases are common in the patients with hilar biliary stricture, benign diseases sometimes present as malignant biliary stricture and may be difficult for differential diagnosis. In benign hilar bile duct strictures, IgG4-related sclerosing cholangitis (IgG4-SC) is suspected to be more frequent, in addition, some patients with bile duct strictures due to unknown inflammatory change exist. It is necessary to evaluate laboratory data, detailed cholangiography, and obtaining samples from the bile duct stricture for the differential diagnosis. Biopsy is preferable compared to cytology because it is sometimes difficult for differentiation between malignancy and inflammatory change with cytology only. Cholangioscopy may be helpful for correct diagnosis. Because there are some cases with difficult differential diagnosis in spite of detailed examination, it is important to take extra caution in those difficult cases, in which using a removable plastic stent is recommended for the initial biliary stenting.

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