Hodaka Amano

Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment

The only curative treatment in biliary tract cancer is surgical treatment. Therefore, the suitability of curative resection should be investigated in the first place. In the presence of metastasis to the liver, lung, peritoneum, or distant lymph nodes, curative resection is not suitable. No definite consensus has been reached on local extension factors and curability. Measures of hepatic functional reserve in the jaundiced liver include future liver remnant volume and the indocyanine green (ICG) clearance test. Preoperative portal vein embolization may be considered in patients in whom right hepatectomy or more, or hepatectomy with a resection rate exceeding 50%–60% is planned. Postoperative complications and surgery-related mortality may be reduced with the use of portal vein embolization. Although hepatectomy and/or pancreaticoduodenectomy are preferable for the curative resection of bile duct cancer, extrahepatic bile duct resection alone is also considered in patients for whom it is judged that curative resection would be achieved after a strict diagnosis of its local extension. Also, combined caudate lobe resection is recommended for hilar cholangiocarcinoma. Because the prognosis of patients treated with combined portal vein resection is significantly better than that of unresected patients, combined portal vein resection may be carried out. Prognostic factors after resection for bile duct cancer include positive surgical margins, especially in the ductal stump; lymph node metastasis; perineural invasion; and combined vascular resection due to portal vein and/or hepatic artery invasion. For patients with suspected gallbladder cancer, laparoscopic cholecystectomy is not recommended, and open cholecystectomy should be performed as a rule. When gallbladder cancer invading the subserosal layer or deeper has been detected after simple cholecystectomy, additional resection should be considered. Prognostic factors after resection for gallbladder cancer include the depth of mural invasion; lymph node metastasis; extramural extension, especially into the hepatoduodenal ligament; perineural invasion; and the degree of curability. Pancreaticoduodenectomy is indicated for ampullary carcinoma, and limited operation is also indicated for carcinoma in adenoma. The prognostic factors after resection for ampullary carcinoma include lymph node metastasis, pancreatic invasion, and perineural invasion.

Diagnosis of pancreatic cancer

The ability to diagnose pancreatic carcinoma has been rapidly improving with the recent advances in diagnostic techniques such as contrast-enhanced Doppler ultrasound (US), helical computed tomography (CT), enhanced magnetic resonance imaging (MRI), and endoscopic US (EUS). Each technique has advantages and limitations, making the selection of the proper diagnostic technique, in terms of purpose and characteristics, especially important. Abdominal US is the modality often used first to identify a cause of abdominal pain or jaundice, while the accuracy of conventional US for diagnosing pancreatic tumors is only 50-70%. CT is the most widely used imaging examination for the detection and staging of pancreatic carcinoma. Pancreatic adenocarcinoma is generally depicted as a hypoattenuating area on contrast-enhanced CT. The reported sensitivity of helical CT in revealing pancreatic carcinoma is high, ranging between 89% and 97%. Multi-detector-row (MD) CT may offer an improvement in the early detection and accurate staging of pancreatic carcinoma. It should be taken into consideration that some pancreatic adenocarcinomas are depicted as isoattenuating and that pancreatitis accompanied by pancreatic adenocarcinoma might occasionally result in the overestimation of staging. T1-weighted spin-echo images with fat suppression and dynamic gradient-echo MR images enhanced with gadolinium have been reported to be superior to helical CT for detecting small lesions. However, chronic pancreatitis and pancreatic carcinoma are not distinguished on the basis of degree and time of enhancement on dynamic gadolinium-enhanced MRI. EUS is superior to spiral CT and MRI in the detection of small tumors, and can also localize lymph node metastases or vascular tumor infiltration with high sensitivity. EUS-guided fine-needle aspiration biopsy is a safe and highly accurate method for tissue diagnosis of patients with suspected pancreatic carcinoma. (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been suggested as a promising modality for noninvasive differentiation between benign and malignant lesions. Previous studies reported the sensitivity and specificity of FDG-PET for detecting malignant pancreatic tumors as being 71-100% and 64-90%, respectively. FDG-PET does not replace, but is complementary to morphologic imaging, and therefore, in doubtful cases, the method must be combined with other imaging modalities.

Preoperative biliary drainage for biliary tract and ampullary carcinomas

We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for postdrainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned.

Assessment of severity of acute pancreatitis according to new prognostic factors and CT grading.

The assessment of severity at the initial medical examination plays an important role in introducing adequate early treatment and the transfer of patients to a medical facility that can cope with severe acute pancreatitis. Under these circumstances, “criteria for severity assessment” have been prepared in various countries, including Japan, and these criteria are now being evaluated. The criteria for severity assessment of acute pancreatitis in Japan were determined in 1990 (of which a partial revision was made in 1999). In 2008, an overall revision was made and the new Japanese criteria for severity assessment of acute pancreatitis were prepared. In the new criteria for severity assessment, the diagnosis of severe acute pancreatitis can be made according to 9 prognostic factors and/or the computed tomography (CT) grades based on contrast-enhanced CT. Patients with severe acute pancreatitis are expected to be transferred to a specialist medical center or to an intensive care unit to receive adequate treatment there. In Japan, severe acute pancreatitis is recognized as being a specified intractable disease on the basis of these criteria, so medical expenses associated with severe acute pancreatitis are covered by Government payment.

New diagnostic criteria of acute pancreatitis.

Practical guidelines for the diagnosis of acute pancreatitis are presented so that a rapid and adequate diagnosis can be made. When acute pancreatitis is suspected in patients with acute onset of abdominal pain and tenderness mainly in the upper abdomen, the diagnosis of acute pancreatitis is made on the basis of elevated levels of pancreatic enzymes in the blood and/or urine. Furthermore, other acute abdominal diseases are ruled out if local findings associated with pancreatitis are confirmed by diagnostic imaging. According to the diagnostic criteria established in Japan, patients who present with two of the following three manifestations are diagnosed as having acute pancreatitis: characteristic upper abdominal pain, elevated levels of pancreatic enzymes, and findings of ultrasonography (US), CT or MRI suggesting acute pancreatitis. Detection of elevated levels of blood pancreatic enzymes is crucial in the diagnosis of acute pancreatitis. Measurement of blood lipase is recommended, because it is reported to be superior to all other pancreatic enzymes in terms of sensitivity and specificity. For measurements of the blood amylase level widely used in Japan, it should be cautioned that, because of its low specificity, abnormal high values are also often obtained in diseases other than pancreatitis. The cut-off level of blood pancreatic enzymes for the diagnosis of acute pancreatitis is not able to be set because of lack of sufficient evidence and consensus to date. CT study is the most appropriate procedure to confirm image findings of acute pancreatitis. Elucidation of the etiology of acute pancreatitis should be continued after a diagnosis of acute pancreatitis. In the process of the etiologic elucidation of acute pancreatitis, judgment whether it is gallstone-induced or not is most urgent and crucial for deciding treatment policy including the assessment of whether endoscopic papillary treatment should be conducted or not. The diagnosis of gallstone-induced acute pancreatitis can be made by combining detection of elevated levels of bilirubin, transamylase (ALT, AST) and ALP detected by hematological examination and the visualization of gallstones by US.

Is pancreatectomy with arterial reconstruction a safe and useful procedure for locally advanced pancreatic cancer

BACKGROUND/PURPOSE We often encounter unresectable pancreatic cancer due to invasions of the major vessels. Vascular resection for locally advanced pancreatic cancers has an advantage in en block local resection. There are potential cases in which good outcomes can be achieved by arterial resection. METHODS Pancreatectomy (including total pancreatectomy in 15 cases, pancreatoduodenectomy in 7 cases and distal pancreatectomy in one case) was performed in 23 cases of invasive ductal carcinoma of the pancreas, in combination with resection and reconstruction of the hepatic artery in 15 cases, the superior mesenteric artery in 12 cases (there are overlaps) and the portal vein in 20 cases. RESULTS The median operating time was 686 min (416-1,190 min) and the median blood loss was 2,830 ml (440-19,800 ml). This shows that the surgery was highly-invasive. The operative mortality rate was 4.3%. On the basis of the UICC classification, there were 2 cases of Stage IIa, 4 cases of Stage IIb, 9 cases of Stage III, 8 cases of Stage IV, while there were 18 cases (78.3%) of R0 resection. On the other hand, the final histological findings showed that there were 8 cases (34.8%) of M1 (liver and non-regional lymph node metastases), so it is thought that decisions on operative indications should be not be made slightly. As for the overall survival rate, the 1-year survival rate was 51.2% and the 3-year survival rate was 23.1% while the median survival time (MST) was 12 months. As for 15 cases of M0, the 1-year survival rate was 61.9% and the 4-year survival rate was 38.7% while the MST was 16 months. On the other hand, the MST was poor (10 months) in 8 cases of M1, showing that a statistically significant difference was observed depending upon the degree of metastasis (log-rank P = 0.0409). In 18 cases of R0, the 1-year survival rate was 67.2%, the 4-year survival rate 30.2% and the MST 13 months, respectively, while in 5 cases of R1 and R2, the MST was 6 months, showing that there was a statistically significant difference between R0 cases and R1, R2 cases (log-rank P = 0.0002). CONCLUSIONS Further discussion is required concerning surgical indications and significance. However, it is thought that resection is useful only when surgery of R0 has taken place for selected locally advanced pancreatic cancer (M0).

Risk factors for biliary tract and ampullary carcinomas and prophylactic surgery for these factors

Curative resection is the only treatment for biliary tract cancer that achieves long-term survival. However, patients with advanced biliary tract cancer have only a limited prognosis even after radical surgical resection. Thus, to improve the longterm results, the early detection of biliary tract cancer and subsequent cure seem to be essential. The purpose of this study was to review the literature concerning the risk factors for cancerous and precancerous lesions of the biliary tract, and prophylactic surgery for these factors. It has been reported that pancreaticobiliary maljunction (PBM) with bile duct dilatation is a risk factor for gallbladder cancer and bile duct cancer, while PBM without bile duct dilatation is a risk factor for gallbladder cancer. Thus, in the former group, a prophylactic excision of the common bile duct and gallbladder should be recommended, while in the later group, a prophylactic cholecystectomy without bile duct resection may be the appropriate surgical procedure. It has also been reported that primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma. Patients with PSC often develop advanced cholangiocarcinoma with a poor prognosis. In patients with PSC, therefore, strict follow-up should be recommended. Adenoma and dysplasia have been regarded as precancerous lesions of gallbladder cancer. A polypoid lesion of the gallbladder that is sessile, has a diameter greater than 10 mm, and /or grows rapidly, is highly likely to be cancerous and should be resected. Although gallstones seem to be closely associated with gallbladder cancer, there is no evidence of a direct causal relationship between gallstones and gallbladder cancer. Thus, a cholecystectomy is not advised for asymptomatic cholecystolithiasis. Controversy remains as to whether adenomyomatosis of the gallbladder and porcelain gallbladder are associated with gallbladder cancer. With respect to ampullary carcinoma, adenoma of the ampulla is considered to be a precancerous lesion. This article discusses the risk factors for cancerous and precancerous lesions of the biliary tract and prophylactic treatment for these factors.

Management of postoperative arterial hemorrhage after pancreato-biliary surgery according to the site of bleeding: re-laparotomy or interventional radiology

BACKGROUND/PURPOSE Intra-abdominal arterial hemorrhage is still one of the most serious complications after pancreato-biliary surgery. We retrospectively analyzed our experiences with 15 patients in order to establish a therapeutic strategy for postoperative arterial hemorrhage following pancreato-biliary surgery. METHODS Between August 1981 and November 2007, 15 patients developed massive intra-abdominal arterial bleeding after pancreato-biliary surgery. The initial surgery of these 15 patients were pylorus-preserving pancreatoduodenectomy (PPPD) (7 patients), hemihepatectomy and caudate lobectomy with extrahepatic bile duct resection or PPPD (4 patients), Whipples pancreatoduodenectomy (PD) (3 patients), and total pancreatectomy (1 patient). Twelve patients were managed by transcatheter arterial embolization and three patients underwent re-laparotomy. RESULTS Patients were divided into two groups according to the site of bleeding: SMA group, superior mesenteric artery (4 patients); HA group, stump of gastroduodenal artery, right hepatic artery, common hepatic artery, or proper hepatic artery (11 patients). In the SMA group, re-laparotomy and coil embolization for pseudoaneurysm were performed in three and one patients, respectively, but none of the patients survived. In the HA group, all 11 patients were managed by transcatheter arterial embolization. None of four patients who had major hepatectomy with extrahepatic bile duct resection survived. Six of seven patients (85.7%) who had pancreatectomy survived, although hepatic infarction occurred in four. CONCLUSIONS Management of postoperative arterial hemorrhage after pancreato-biliary surgery should be done according to the site of bleeding and the initial operative procedure. Careful consideration is required for indication of interventional radiology for bleeding from SMA after pancreatectomy and hepatic artery after major hepatectomy with bilioenteric anastomosis.

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.

Post-ERCP pancreatitis

Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP). Detailed information about the findings of previous studies concerning post-ERCP pancreatitis has not been utilized sufficiently. The purpose of the present article was to present guidelines for the diagnostic criteria of post-ERCP pancreatitis, and its incidence, risk factors, and prophylactic procedures that are supported by evidence. To achieve this purpose, a critical examination was made of the articles on post-ERCP pancreatitis, based on the data obtained by research studies published up to 2009. At present, there are no standardized diagnostic criteria for post-ERCP pancreatitis. It is appropriate that post-ERCP pancreatitis is defined as acute pancreatitis that has developed following ERCP, and its diagnosis and severity assessment should be made according to the diagnostic criteria and severity assessment of the Japanese Ministry of Health, Labour and Welfare. The incidence of acute pancreatitis associated with diagnostic and therapeutic ERCP is 0.4–1.5 and 1.6–5.4%, respectively. Endoscopic papillary balloon dilation is associated with a high risk of acute pancreatitis compared with endoscopic sphincterotomy. It was made clear that important risk factors include dysfunction of the Oddi sphincter, being of the female sex, past history of post-ERCP pancreatitis, and performance of pancreaticography. Temporary prophylactic placement of pancreatic stents in the high-risk group is useful for the prevention of post-ERCP pancreatitis [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.6–6.4, number needed to treat (NNT) 10]. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the development of post-ERCP pancreatitis (OR 0.46, 95% CI 0.32–0.65). Single rectal administration of NSAIDs is useful for the prevention of post-ERCP pancreatitis [relative risk (RR) 0.36, 95% CI 0.22–0.60, NNT 15] and decreases the development of pancreatitis in both the low-risk group (RR 0.29, 95% CI 0.12–0.71) and the high-risk group (RR 0.40, 95% CI 0.23–0.72) of post-ERCP pancreatitis. As for somatostatin, a bolus injection may be most useful compared with short- or long-term infusion (OR 0.271, 95% CI 0.138–0.536, risk difference 8.2%, 95% CI 4.4–12.0%). The usefulness of gabexate mesilate was not apparent in any of the following conditions: acute pancreatitis (control 5.7 vs. 4.8% for gabexate mesilate), hyperamylasemia (40.6 vs. 36.9%), and abdominal pain (1.7 vs. 8.9%). Formulation of diagnostic criteria for post-ERCP pancreatitis is needed. Temporary prophylactic placement of pancreatic stents in the high-risk group offers the most promise as a means of preventing post-ERCP pancreatitis. As for pharmacological attempts, there are high expectations concerning NSAIDs because they are excellent in terms of cost-effectiveness, ease of use, and safety. There was no evidence of effective prophylaxis with the use of protease inhibitors, especially gabexate mesilate.