Didehydroisobenzofuran: A New Reactive Intermediate for Construction of Isoacenofuran.

An efficient generation method of didehydroisobenzofuran, a new heteroaryne species, was developed by bromine/lithium exchange of the dibromoisobenzofuran. The reactive intermediate, thus generated, was trapped by appropriate arynophile to give the [2+2], [2+3], and [2+4] cycloadducts, respectively. Moreover, the reaction could be applied to the syntheses of isoanthracenofurans (anthra[2,3-c]furans), a new class of heteroacenes, with isoelectoronic structure to the corresponding acenoheteroles (anthra[2,3-b]furans).

Ten-year long-term results after non-surgical management of hepatolithiasis, including cases with choledochoenterostomy.

BACKGROUND: Long-term follow-up of non-surgical procedures for the management of hepatolithiasis has been reported, but risk factors for mortality have not been properly evaluated. METHODS: We conducted a retrospective study of the case records of 121 patients with hepatolithiasis who underwent endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy (POCS), percutaneous transhepatic cholangioscopy (PTCS), or conservative treatment at the Department of Gastroenterology of Chiba University Hospital between January 1980 and July 2011. The primary outcome measure was mortality, defined as death due to hepatolithiasis (concomitant liver failure with cholangitis and cholangiocarcinoma). RESULTS: Complete clearance of intrahepatic stones was achieved in 22 (57.8%) of 38 patients by POCS, in 12 (66.7%) of 18 patients by ERCP, and in 10 (52.6%) of 18 patients by PTCS. The remaining 46 patients were treated conservatively. The mean follow-up period was 11.4 ± 7.1 years (range, 0.6-32.8). There were 14 hepatolithiasis-related deaths (11 with cholangiocarcinoma and three from liver failure with cholangitis) during the follow-up periods. Multivariate Cox proportional hazards analysis revealed liver atrophy (P = 0.015; HR = 3.98; 95% CI, 1.30-12.20) and congenital biliary dilatation after biliary-enteric anastomosis (P = 0.036; HR = 4.57; 95% CI, 1.11-18.87) as significant risk factors for mortality. CONCLUSIONS: Analysis of the 10-year long-term results after non-surgical management of hepatolithiasis identified liver atrophy and congenital biliary dilatation as risk factors for mortality. Patients with hepatic lobe atrophy should undergo a hepatectomy, if operable.

Inflammation in background cirrhosis evokes malignant progression in HCC development from HCV-associated liver cirrhosis.

OBJECTIVE: It is accepted that inflammation promotes malignant progression in the development of cancers. Whether, this is true for hepatocellular carcinoma (HCC) remains as an open question. We examined the relationship between the inflammatory histology activity index (HAI) in the background liver cirrhosis (LC) and the histological grading of the HCC in the hepatectomized HCC patients with HCV-associated LC. MATERIAL AND METHODS: Out of 264 HCC patients who underwent curative hepatic resection, 197 had HCV-associated LC. Among them, 52 patients with a small solitary HCC nodule (< 5 cm in diameter) were studied. Inflammation in the background LC was evaluated by modified Knodell's HAI. To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (0-4, each) were estimated. The average HAI was calculated. The grade of malignancy of HCC was determined by WHO classification. RESULTS: The average HAI in the 15 patients with moderately differentiated HCC (4.3 ± 0.8, mean ± SD) was significantly larger than that in 11 patients with well differentiated HCC (3.5 ± 0.6, p = 0.036). The HAI in the 24 patients whose HCC nodules contained poorly differentiated HCC (5.2 ± 1.1) was significantly larger than that in patients with moderately differentiated HCC (p = 0.025). Thus, the HAI order was well differentiated group < moderately differentiated group < poorly differentiated group. CONCLUSIONS: Inflammation in the background non-cancerous cirrhotic portion would evoke malignant progression in HCC development from HCV-associated LC.

Severe inflammation in the background liver cirrhosis correlates with the development of poorly differentiated HCC in HCV-associated liver cirrhosis.

OBJECTIVE: Whether severe inflammation in the background liver cirrhosis might correlate with the development of poorly differentiated human hepatocellular carcinoma (HCC) was studied in hepatitis C virus (HCV)-associated liver cirrhosis. METHODS: Out of 214 HCC patients who underwent curative hepatic resection, 148 patients were HCV-associated liver cirrhosis (LC) patients. Out of these 148, 31 patients with small solitary HCC nodule (diameter ≤ 3 cm) were included in this study. Inflammation in the background LC was evaluated by modified histology activity index (HAI). To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (each 0-4) were estimated. In each case, the average HAI was calculated. The grade of malignancy of HCC was determined by World Health Organization (WHO) classification. RESULTS: The average HAI score in the cirrhotic portion in 17 patients with poorly differentiated HCC (5.21 ± 1.15, mean ± standard deviation (SD)) was significantly larger than that in 14 patients without poorly differentiated HCC (4.05 ± 0.83, p<0.005). The occurrence rate of HCC containing poorly differentiated HCC component in the patients whose HAI was more than 5.0 was 80.0% (12 out of 15), and was significantly higher compared with those in patients whose HAI was less than 5.0 (5 out of 16, 31.3%, p<0.025). In univariate and multivariate analyses for contribution to poorly differentiated HCC development, HAI was the only significant contributor (p=0.011, p=0.012 respectively). CONCLUSION: It is suggested that severe inflammation in the background cirrhosis accelerates the promotion in the HCC development from HCV-associated LC.

[Retroperitoneal metastasis of hepatocellular carcinoma - a case report].

The patient was a 54-year-old man. He was an HBV carrier, and hepatocellular carcinoma (HCC) was detected for the first time in 2000. An operation was performed, but HCC recurred. After repeating the operation and transarterial chemo-embolization (TACE) for the recurrent HCC, a tumor was found in January 2009 on the ventral side of the right kidney, and we thought it was a retroperitoneal metastasis of HCC or peritoneal dissemination. He was enrolled in a trial of systemic chemotherapy, called "S-1 monotherapy for extrahepatic metastasis of HCC", but the tumor seemed progressive. Since he showed no other lesion, he was indicated for surgical resection. Intraoperatively, the tumor was localized between the duodenum and the right kidney, and was covered by the retroperitoneum. Pathological examination of the resected specimen revealed retroperitoneal metastasis of HCC. Intrahepatic recurrence was detected 6 months after the resection. Therefore, he underwent TACE, and he is currently (1 year after surgery) alive without any extrahepatic metastasis. We describe herein this case because retroperitoneal metastasis of HCC is very rare.

[Case of intrahepatic cholangiocarcinoma drained through a fistula of the duodenal bulb].

A 72-year-old woman presented with epigastric discomfort. A low density tumor was found in the hilum and left liver by CT. Since she complained epigastralgia, upper gastrointestinal endoscopy was performed, showing an ulcer in the duodenal bulb, with poorly-differentiated adenocarcinoma seen on a biopsy specimen from the edge of the ulcer. After admission, poorly-differentiated adenocarcinoma cells were also obtained with ultrasound guided aspiration cytology of the liver tumor. We diagnosed intrahepatic cholangiocarcinoma (IHC), and treated with gemcitabine. During chemotherapy, the duodenal ulcer became a fistula, and the liver tumor diminished with bubbles inside it. It was suggested that liquid material of IHC, such as necrotic tissue and mucin, drained to the duodenal bulb during chemotherapy.

Usefulness of peroral cholangioscopy in preoperative diagnosis of intraductal papillary neoplasm of the bile duct.

Surgical resection is considered the first-line treatment of intraductal papillary neoplasm of the bile duct (IPNB). Since some patients with IPNB have an unexpectedly superficially-spreading lesion, preoperative cholangioscopic diagnosis is very useful in determining the extent of resection. We report a patient with IPNB in whom preoperative peroral cholangioscopic evaluation was useful.

Long-term outcome of endoscopic papillotomy for choledocholithiasis with cholecystolithiasis.

AIM: To assess long-term outcome of endoscopic papillotomy alone without subsequent cholecystectomy in patients with choledocholithiasis and cholecystolithiasis. METHODS: Retrospective review of clinical records of patients treated for choledocholithiasis and cholecystolithiasis from 1976 to 2006. Of 564 patients subjected to endoscopic papillotomy and endoscopic stone extraction, 522 patients (279 men, 243 women; mean age 66.2 years) were followed up and predisposing risk factors for late complications were analyzed. RESULTS: The mean duration of follow up was 5.6 years. Cholecystitis and recurrent choledocholithiasis occurred in 39 (7.5%) and 60 (11.5%) patients, respectively. Cholecystitis, including one severe case, resolved with conservative treatment. Recurrent choledocholithiasis was successfully treated endoscopically except in one case. Pneumobilia was found to be a significant risk factor for cholecystitis (P = 0.019) and recurrent choledocholithiasis (P = 0.013). Biliary tract cancer occurred in 16 patients; gallbladder cancer in 13 and bile duct cancer in three. Gallbladder cancer developed within 2 years after endoscopic papillotomy in seven of the 13 patients (53.8%). CONCLUSION: Pneumobilia was the only significant risk factor for cholecystitis and recurrent choledocholithiasis in our study population. As for the long-term outcome, it was unclear whether endoscopic papillotomy contributed to the occurrence of biliary tract cancer.

Endoscopic diagnosis of intraductal papillary mucinous neoplasm of the bile duct.

BACKGROUND/PURPOSE: Intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is considered an uncommon tumor. The purpose of this study was to evaluate the diagnostic utility of endoscopic cholangiography (ERC) with subsequent peroral cholangioscopy (POCS) and/or intraductal ultrasonography (IDUS) for this tumor. METHODS: From December 1991 to November 2006, a retrospective analysis was made of eight patients with IPMN-B. Their clinical features and the endoscopic diagnostic strategy for POCS and IDUS were reviewed. RESULTS: In all the patients, ERC failed to show papillary tumors, due to coexisting mucin or biliary sludge. POCS was carried out after ERC and it showed the presence and locations of papillary tumors in all patients, except for one with a tumor in the peripheral intrahepatic bile duct (B3). IDUS was performed in seven of the eight patients; in five of these patients, intraductal protruding tumors were clearly visualized, whereas flat tumors were not identified in the remaining two patients. In one of the eight patients, endoscopic nasobiliary drainage did not remove the huge amount of mucin. Hence, this patient required subsequent percutaneous biliary drainage. Six of the eight patients underwent surgical treatment; five patients underwent a hepatic resection with or without extrahepatic bile duct resection and one underwent a pancreaticoduodenectomy. Five of the six operated patients are still alive; one patient died of gastric cancer 90 months after the operation (mean follow-up period, 45.3 months). The two remaining patients, who were considered inoperable due to major medical comorbidities, died of liver failure and cholangitis 3 and 6 months, respectively, after stent placement. CONCLUSION: ERC failed to delineate intraductal papillary tumors, due to coexisting mucin. The presence and location of papillary tumors were correctly diagnosed by both POCS and IDUS, but POCS may be better than IDUS to diagnose the extent of the tumor.

The successful use of peroral cholangioscopy for the diagnosis and treatment of the biliary tract lesions and giant bile duct stones in a 76-year-old man.

We encountered a case in whom peroral cholangioscopy was useful for the diagnosis and treatment of irregular biliary tract mucosa and giant bile duct stones. Peroral cholangioscopy seems to improve the diagnosis of biliary tract diseases and allow internal treatment. The proper diagnosis of biliary tract diseases may be further confirmed by the concomitant use of narrow band imaging and this endoscopic technology.

High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis.

Abstract Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (<80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years always > or =80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always <80 IU; n=48; Group B) (p<0.005) during an observation period of 7.9+/-3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.

The usefulness of endoscopic transpapillary procedure in post-cholecystectomy bile duct stricture and post-cholecystectomy bile leakage.

This study was conducted to examine the usefulness of endoscopic transpapillary procedure in post-cholecystectomy bile duct stricture and postcholecystectomy bile leakage. Endoscopic transpapillary procedure was performed in 18 cases of post-cholecystectomy bile duct stricture and 6 cases of post-cholecystectomy bile leakage. In the bile duct stricture cases, the patients were assessed for the stricture by endoscopic retrograde cholangiography (ERC), and then underwent endoscopic sphincterotomy (EST) for tube stent insertion. The stents was replaced every 3 to 6 months, and the treatment was continued until the patients became stent-free. Successful therapy was defined as a stent-free condition without hepatic disorder. In the bile leakage cases, the leakage was located by ERC and EST was performed. Then, endoscopic nasobiliary drainage (ENBD) tube was inserted at the proximal side of the bile leakage, and the therapeutic outcome was defined as successful if disappearance of the leakage was confirmed by cholangiography at a later date. Endoscopic transpapillary procedure was 100% successful in both post-cholecystectomy bile duct stricture cases (18/18) and post-cholecystectomy bile leakage cases (6/6). There was no accident due to the treatment. Restricture occurred in 5.5% (1/18) of the patients, but additional therapy was successful and the stent was removed. Also, there was no accident due to endoscopic transpapillary procedure. Endoscopic transpapillary procedure in postcholecystectomy bile duct stricture and postcholecystectomy bile leakage was demonstrated to be a less invasive, safe, and useful method.

Long-term prognosis of patients with endoscopically treated postoperative bile duct stricture and bile duct stricture due to chronic pancreatitis.

AIM: To compare the outcome of endoscopic therapy for postoperative benign bile duct stricture and benign bile duct stricture due to chronic pancreatitis, including long-term prognosis. METHODS: The subjects were 20 patients with postoperative benign bile duct stricture and 13 patients with bile duct stricture due to chronic pancreatitis who were 2 years or more after initial therapy. The patients underwent transpapillary drainage with tube exchange every 3 to 6 months until being free from the tube. Successful therapy was defined as a stent-free condition without hepatic disorder. RESULTS: Endoscopic therapy was successful in 90% (18/20) of the patients with postoperative bile duct stricture. The stent was removed (stent free) in 100% (20/20) of the patients, but jaundice resolved in only 10% (2/20) of patients while biliary enzymes kept increasing. Restructure occurred in 5% (1/20) of the patients, but after repeat treatment the stent could be removed. In patients with bile duct stricture due to chronic pancreatitis the therapy was successful in only 7.7% (1/13) of the patients; the stent was retained in 92.3% (12/13) of the patients during a long period. Severe acute pancreatitis occurred in 3.0% (1/33) of the patients as an accidental symptom attributable to endoscopic retrograde cholangiopancreatography (ERCP); however, it remitted after conservative treatment. CONCLUSION: Our results further confirm the usefulness of endoscopic therapy for postoperative benign bile duct strictures and good long-term prognosis of the patients.

The usefulness of perfusion-weighted magnetic resonance imaging in advanced pancreatic cancer.

OBJECTIVES: Perfusion-weighted magnetic resonance imaging (MRI) can detect the changes of signal intensity in tumors. We evaluated the prognostic value of perfusion-weighted MRI in patients with advanced pancreatic cancer (PC). METHODS: Perfusion-weighted MRI was performed before treatment on 27 consecutive patients with advanced PC. The American Joint Committee on Cancer (AJCC) stages of patients were as follows (8, stage III; 19, stage IV). Imaging acquisition was continually repeated with echo planar sequence every 2 seconds for 2 minutes after a bolus injection of gadolinium. We made a time intensity curve of PC and calculated the signal ratio (SR) on perfusion-weighted imaging. We assessed the relation between SR and clinical factors including tumor stage, lymph node metastasis, liver metastasis, and so on. Patients were divided into low and high SR group and compared SR with the overall survival. RESULTS: All cases showed transient decreases signal intensity (SR, 6.9-55.7%). These patients were classified into 2 groups at cutoff median SR of 22.0% The high SR group significantly correlated with the higher stage (P=0.03) and the presence of lymph node metastasis (P=0.04). The high SR group had significantly shorter overall survival (P=0.04). CONCLUSIONS: Perfusion-weighted MRI may predict the survival in advanced PC patients.

Clinical evaluation of endosonography-guided biliary drainage for patients with the difficulty with placing of internal drainage.

The methods for non-surgical biliary drainage for the treatment of obstructive jaundice generally include transpapillary one, or endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous one, or percutaneous transhepatic biliary drainage (PTBD). In placing internal drainage, a stent is frequently inserted through the route of the drainage. However, transpapillary approach may be infeasible in patients, if cannulation is difficult, drainage cannot reach the duodenal papilla, and percutaneous approach may be infeasible in patients, if the intrahepatic bile duct is not be expanded. Endosonography-guided biliary drainage (ESBD) is a new method enabling internal drainage of an obstructed bile duct. In this study, the transpapillary ESBD approach was successfully applied to a patient having obstructive jaundice due to cancer of the head of the pancreas during the treatment of ovarian cancer although internal drainage via transpapillary and percutaneous approach was not applicable to this patient. So far, few studies have reported the use of ESBD. Although a large-scale, multicenter study is required to investigate the indications and complications of ESBD, it is no doubt that we have now more treatment options for non-surgical biliary drainage.

Clinical utility of peroral cholangioscopy for mucin-producing bile duct tumor.

BACKGROUND/AIMS: The purpose of this study was to examine the clinical utility of peroral cholangioscopy for mucin-producing bile duct tumor. METHODOLOGY: Peroral cholangioscopy was performed in seven cases of mucin-producing bile duct tumor to decide the course of treatment based on the results. All seven cases were evaluated by peroral cholangioscopy and examined by a transpapillary biopsy. Five out of the seven cases (71.4%) were adequately observed. Because abundant mucin could not be removed in 2 cases (28.6%), one of them underwent PTCS after PTBD, and the other had surgery for EBD insertion without PTBD at the patient's request. A stent was placed by surgery in five out of the seven cases and by a transpapillary method in two cases. RESULTS: Among the five cases that could be evaluated by peroral cholangioscopy, the excised specimens were compared with the findings obtained from peroral cholangioscopy in three cases that underwent surgery, while the results of transpapillary mapping biopsy were compared with the findings obtained from peroral cholangioscopy in two inoperable cases, showing that the evaluation by peroral cholangioscopy agreed with the results of tumor staging in all the five cases. CONCLUSIONS: This study suggested the possibility that the use of peroral cholangioscopy for mucin-producing bile duct tumor could be useful in deciding the course of treatment.

A new approach for diagnosis of hepatolithiasis: magnetic resonance cholangiopancreatography: potential usefulness of dehydrocholic acid (DHCA) administration in the evaluation of hepatolithiasis.

BACKGROUND/AIMS: The aim of this study was to investigate whether exogenous dehydrocholic acid (DHCA) was useful to enhance the delineation of hepatolithiasis. METHODOLOGY: Our study population comprised 9 patients. Magnetic resonance cholangiopancreatography (MRCP) was acquired before and after the administration of DHCA. Two different MRCP snap-shot techniques were applied: thick-slab two-dimensional (2D) (coronal) single shot turbo spin echo T2-weighted sequences and multisection thin-slab, 2D (coronal) single shot turbo spin echo T2-weighted sequences with three-dimensional (3D) maximum intensity projection (MIP) post processing. RESULTS: DHCA provided a better visualization of hepatolithiasis in 8 of 9 cases (88.9%). CONCLUSIONS: It was suggested that administration of DHCA could enhance the delineation of the hepatolithiasis on MRCP images.

Magnetic resonance cholangiopancreatography: potential usefulness of dehydrocholic acid (DHCA) administration in the evaluation of biliary disease.

BACKGROUND/AIMS: The aim of this study was to investigate whether exogenous dehydrocholic acid (DHCA) was useful to enhance the delineation of the biliary tree. METHODOLOGY: Our study population comprised 14 patients. Magnetic resonance cholangiopancreatography was acquired before and after the administration of DHCA. Two different MRCP snap shot techniques were applied: thick-slab two-dimensional (2D) (coronal) single shot turbo spin echo T2-weighted sequences and multisection thin-slab, 2D (coronal) single shot turbo spin echo T2-weighted sequences with three-dimensional (3D) maximum intensity projection (MIP) post processing. Volume rendering was prepared based on the source images, and the pixel size was visually adjusted to the biliary area of MRCP to measure the biliary tree volume. RESULTS: DHCA increased the bile duct volume in 13 of the 14 patients. It provided a better visualization of the biliary tree in 11 patients. The three patients without improvement in visualization included 1 patient with liver cirrhosis secondary to portoenterostomy for congenital biliary dilatation and 2 patients with cholecystectomy who had the bile ducts filled with bile by the time of the administration. CONCLUSIONS: It was suggested that administration of DHCA could enhance the delineation of the biliary tree on MRCP images.

[A resected case of metastatic pancreatic cancer from cecal carcinoma].

A 64-year-old woman underwent an ileocecectomy in July 2002 for ruptured cecal carcinoma, which was a well-differentiated adenocarcinoma, stage II, ss, ly0, v0, n (-). In August 2005, abdominal CT revealed a tumor 20mm in diameter in the pancreatic tail, therefore, a distal pancreatectomy and splenectomy were performed. The pancreatic tumor resembled the moderately differentiated cecal adenocarcinoma, both having p53 and k-ras point mutations in common, and it was diagnosed as a metastasis of the cecal carcinoma.

Magnetic resonance cholangiopancreatography: potential usefulness of dehydrocholic acid (DHCA) administration in the evaluation of anastomotic site.

BACKGROUND/AIMS: The aim of this study was to investigate whether exogenous dehydrocholic acid (DHCA) was useful to enhance the delineation of anastomotic site. METHODOLOGY: DHCA is a cholagogue which produces an immediate effect by acting directly on liver cells. Its choleretic effect is strong, appearing 1 to 3 minutes after intravenous injection, reaching the maximum level in 20 to 30 minutes. Our study population comprised 9 patients. Magnetic resonance cholangiopancreatography (MRCP) was acquired before and after the administration of DHCA. Two different MRCP snap-shot techniques were applied: thick-slab two-dimensional (2D) (coronal) single-shot turbo spin echo T2-weighted sequences and multisection thin-slab, 2D (coronal) single shot turbo spin echo T2-weighted sequences with three-dimensional (3D) maximum intensity projection (MIP) post processing. RESULTS: DHCA provided a better visualization of the anastomotic site in 7 patients (77.8%). The two patients without improvement in visualization of anastomotic site included 1 patient with liver cirrhosis secondary to portoenterostomy for congenital biliary dilatation and 1 patient, who was not eligible for the evaluation because of motion artifact caused by the difficulty of breath holding motion artifact. CONCLUSIONS: It was suggested that administration of DHCA could enhance the delineation of the anastomotic site on MRCP images.