Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study.

BACKGROUND: Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. METHODS: Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). RESULTS: Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. CONCLUSIONS: Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.

Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct.

We reported previously that intestinal metaplasia in the gallbladder is strongly associated with expression of caudal-related homeobox transcription factor Cdx2. It has been documented that occult pancreatobiliary reflux, even in the absence of pancreaticobiliary maljunction, is associated with elevated risk of biliary malignancy. We ascertained the correlation between intestinal metaplasia in the gallbladder and occult pancreatobiliary reflux. In 196 patients with a normal pancreaticobiliary ductal arrangement who had undergone laparoscopic cholecystectomy, we performed intraoperative cholangiography and measured amylase levels in bile sampled from the gallbladder. The cutoff value for high cystic amylase was defined as a biliary amylase level higher than the normal upper limit of serum amylase (215 IU/L). We also retrospectively reviewed the cholecystectomized tissue specimens to investigate the presence of intestinal metaplasia and expression of Cdx2. Then, we explored the relationship between intestinal metaplasia in the gallbladder and occult choledocho-pancreatic reflux. Intestinal metaplasia was found in 16.8% (33/196) of the gallbladders. The prevalence of choledocho-pancreatic reflux revealed by intraoperative cholangiography was not significantly different between cases with intestinal metaplasia (5/33, 15.2%) and those without (25/163, 15.3%; P = .81). However, in cases with intestinal metaplasia, the rate of high cystic amylase (13/33, 39.4%) was significantly higher compared with cases without intestinal metaplasia (26/163, 16.0%, P = .005). In conclusion, intestinal metaplasia in the gallbladder is significantly correlated with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary ductal arrangement.

Endoscopic thermal ablation therapies for hepatocellular carcinoma: a multi-center study.

AIM: The differing efficacies of radiofrequency ablation and microwave coagulation for hepatocellular carcinoma (HCC) are unknown. Therefore, we performed a multi-center study to assess the factors contributing to survival and local recurrences of HCC among patients with solitary tumors who underwent endoscopic thermal ablation as their primary treatment. METHODS: From six institutions, 391 patients with solitary HCC who were first treated by endoscopic thermal ablation were enrolled in this study and assessed retrospectively. We investigated age, gender, location of tumor, longest diameter of tumor, method of anesthesia, type of endoscope, method of thermal ablation, Child-Pugh classification, the Japan Integrated Staging score and the Cancer of the Liver Italian Program score. Statistical analyses were performed using univariate analysis with log-rank test and multivariate analysis with the Cox proportional hazards model. RESULTS: On univariate analysis, advanced Child-Pugh score, advanced Italian Program score and local recurrences were significant predictors of poor survival. Young age (30 mm) and the use of the thoracoscopic approach were significant predictors for the development of local recurrence. On multivariate analysis, local anesthesia and advanced Child-Pugh score were independent predictors of poor survival. Young age, large tumor, local anesthesia and the use of the thoracoscopic approach were independent predictors for the development of local recurrence. The method of thermal ablation did not influence survival or local recurrence. CONCLUSIONS: Differences in the effect on survival and local recurrence between microwave and radiofrequency were not observed in this retrospective, multi-center study of endoscopic thermal ablation for HCC.

Endoscopic observation of Meckel's diverticulum by double balloon endoscopy: report of five cases.

BACKGROUND AND AIM: Most cases of Meckel's diverticula are asymptomatic, however, some cases presented with gastrointestinal (GI) bleeding. It is often difficult to determine whether Meckel's diverticulum is a source of obscure GI bleeding. Double balloon endoscopy allows endoscopic access to the entire small intestine. The aim of this study was to compare endoscopic findings of three hemorrhagic and two non-hemorrhagic Meckel's diverticula in patients with obscure GI bleeding using this novel technique. METHODS: Between September 2000 and April 2005, 354 enteroscopies, including 162 anterograde and 192 retrograde procedures, were performed on 217 patients at the Jichi Medical University Hospital, Japan, using the double balloon endoscopy system. Five consecutive patients where Meckel's diverticulum was endoscopically observed were selected and analyzed. RESULTS: Double balloon endoscopy enabled direct observation of Meckel's diverticula in all five patients. Surgical procedures were indicated for three patients where double balloon endoscopy discovered ulcers. By contrast, double balloon endoscopy detected other sources of bleeding in the remaining two patients where no ulcers were found in the Meckel's diverticula. CONCLUSION: Endoscopic observation of the ulcers in Meckel's diverticula was important evidence of bleeding in patients with obscure GI bleeding. Other sources of bleeding should be considered when no ulcers are found in the Meckel's diverticula.

Optimal band imaging system can facilitate detection of changes in depressed-type early gastric cancer.

BACKGROUND: The endoscopic diagnosis of depressed-type early gastric cancers is difficult because these cancers manifest as subtle changes in color and shape. The newly developed optimal band imaging (OBI) system can reconstruct the best spectral images derived from ordinary endoscopic images and enhances the mucosal surface without the use of dyes. This imaging technique is based on narrowing the bandwidth of conventional image arithmetically by using spectral estimation technology. OBJECTIVE: Evaluation of the usefulness of the OBI system for identifying the demarcation line of depressed-type early gastric cancers. DESIGN: Prospective study. SETTING: Jichi Medical University in Japan. PATIENTS: Twenty-seven cases with depressed-type early gastric cancer. MAIN OUTCOME MEASUREMENT: Comparative study for the success rate of identifying the demarcation line of depressed-type early gastric cancer by using optimal band images and conventional endoscopic images. RESULTS: Demarcation of the depressed-type early gastric cancer was easily identified by optimal band images without magnification in 26 of 27 cases (96%), because distinct demarcation was observed endoscopically between the reddish images of the cancerous lesion and the yellowish images of the surrounding noncancerous area. With 40-fold magnification of optimal band images, the demarcation was also clearly recognized in all cases. Medical students could point out the demarcation line with significantly greater accuracy by observing the new nonmagnified optimal band images than by the conventional images (P< .0001). LIMITATION: Small sample size. CONCLUSIONS: The new contrasting images of the OBI system can delineate the depressed-type early gastric cancer more easily than conventional endoscopy.

A close relationship between intestinal metaplasia and Cdx2 expression in human gallbladders with cholelithiasis.

We previously reported a case of a human gallbladder with cholelithiasis consisting of intestinal metaplasia with the expression of caudal-related homeobox transcription factor (Cdx2). However, it is unclear how often intestinal metaplasia and Cdx2 expression occur in human, nontumorous gallbladders with cholelithiasis. We studied the incidence of intestinal metaplasia and Cdx2 expression in human gallbladders with cholelithiasis. Gallbladders were resected under laparoscopy from 103 patients with cholelithiasis between September 2003 and March 2005. The mean age of the patients was 59.6 +/- 15.0 years (range, 22-92 years). We retrospectively reviewed these cases to look for the presence of intestinal metaplasia and the expression of Cdx2. In addition, the characteristics of intestinal metaplasia were examined by immunostaining for Muc2, chromogranin A, and serotonin. Intestinal metaplasia was found in 11.7% (12/103) of the gallbladders with cholelithiasis. The mean ages of patients with and without intestinal metaplasia were 60.8 +/- 15.4 and 59.4 +/- 14.9 years, respectively. Cdx2, Muc2, chromogranin A, and serotonin were expressed in 91.7% (11/12), 91.7% (11/12), 83.3% (10/12), and 50.0% (6/12) in intestinal metaplastic mucosa, respectively. Only one case (1.1%) that expressed Cdx2 without intestinal metaplasia did not express Muc2, chromogranin A, and serotonin. We found that 10.7% (11/103) of nontumorous gallbladders resected because of cholelithiasis under laparoscopy revealed intestinal metaplasia with Cdx2 expression.

A case of hepatic pseudolymphoma observed without surgical intervention.

We report a case of liver pseudolymphoma that has been followed up without surgical resection after the diagnosis. A 63-year-old woman with a hepatic hypo-echoic lesion, 16mm in diameter was referred to our hospital. Laboratory data on admission were within normal limits. Serum HbsAg and HCVAb were negative. Abdominal computed tomography revealed an enhanced round lesion at the same location of the liver. Histopathological examination of the biopsy specimen demonstrated aggregation of the small round cells, lacking cytologic atypia or mitotic figures. These cells were B lymphocytes with staining of kappa and lambda light chains at equal frequency. Furthermore, monoclonal band was not detected by the polymerase chain reaction (PCR) method for the position of the third complementarity-determing region (CDR3) in the immunoglobulin heavy chain (IgH). These results suggested that the cells infiltrated in the lesion were polyclonal and benign nature. This case was observed carefully without surgical operation. During the course, Helicobacter pylori were successfully eradicated. Follow-up study after 18 months showed that the diameter of the tumor had decreased from 16mm to 8mm, suggesting no evidence of the malignant transformation.

Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine.

Many transcription factors are involved in the molecular control of intestinal epithelial cell differentiation. We report in this study that the transcription factor Cdx2 functions to define absorptive enterocytes during intestinal epithelial differentiation. Cdx2 is expressed in the villi of the normal small intestine. Intestinal metaplasia, which expresses Cdx2, occurs as a pathological condition in gastric mucosa. We have previously established Cdx2 transgenic mice expressing Cdx2 exclusively in the gastric epithelium. In this study using Cdx2 transgenic mice, we show that Cdx2 plays a key role in the differentiation of intestinal absorptive enterocytes. The gastric mucosa of Cdx2 transgenic mice was morphologically completely changed into intestinal metaplastic mucosa. Absorptive enterocytes had microvilli which were observed by electron microscope. The intestinal metaplastic mucosa of Cdx2 transgenic mice expressed sucrase and peptide transporter PepT1. Disaccharidase and leucine aminopeptidase activities were observed in the intestinal metaplastic mucosa. Glucose and amino acids were absorbed from Cdx2 transgenic mouse stomach with intestinal metaplasia. Finally we generated mice whose intestine was extensively excised. Cdx2 transgenic mice with intestinal metaplasia survived even after extensive intestinal excision. We successfully demonstrated that Cdx2 induced not only morphological but also functional absorptive enterocytes in the intestinal metaplastic mucosa in vivo. Our results suggest that Cdx2 is necessary and sufficient by itself to specify the development of intestinal absorptive enterocytes, whereas other factors which are expressed in the small intestine are not always necessary for the differentiation of functional absorptive enterocytes.

Non-steroidal anti-inflammatory drug-induced small bowel injuries identified by double-balloon endoscopy.

AIM: To clarify clinical features of the NSAID-induced small bowel lesions using a new method of endoscopy. METHODS: This is a retrospective study and we analyzed seven patients with small bowel lesions while taking NSAIDs among 61 patients who had undergone double-balloon endoscopy because of gastro-intestinal bleeding or anemia between September 2000 and March 2004, at Jichi Medical School Hospital in Japan. Neither conventional EGD nor colonoscopy revealed any lesions of potential bleeding sources including ulcerations. Double-balloon endoscopy was carried out from oral approach in three patients, from anal approach in three patients, and from both approaches in one patient. RESULTS: Ulcers or erosions were observed in the ileum in six patients and in the jejunum in one patient, respectively. The ulcers were multiple in all the patients with different features from tiny punched out ulcers to deep ulcerations with oozing hemorrhage or scar. All the patients recovered uneventfully and had full resolution of symptoms after suspension of the drug. CONCLUSION: NSAIDs can induce injuries in the small bowel even in patients without any lesions in both the stomach and colon.

Technical modification of the double-balloon endoscopy to access to the proximal side of the stenosis in the distal colon.

BACKGROUND: The inability to pass endoscopes beyond strictures is a considerable problem in patients with a colonic stricture. METHODS: In patients with bowel obstruction, we have modified the insertion method for double-balloon endoscopy with a long, transnasal decompression tube. OBSERVATIONS: We have succeeded in reaching the proximal side of the stricture from the oral approach across the entire small bowel in a patient. CONCLUSIONS: This modified double-balloon enteroscopy is useful for patients with bowel obstruction in whom a long decompression tube is already placed.

Clinical outcomes of enteroscopy using the double-balloon method for strictures of the small intestine.

AIM: To evaluate the clinical outcome of enteroscopy, using the double-balloon method, focusing on the involvement of neoplasms in strictures of the small intestine. METHODS: Enteroscopy, using the double-balloon method, was performed between December 1999 and December 2002 at Jichi Medical School Hospital, Japan and strictures of the small intestine were found in 17 out of 62 patients. These 17 consecutive patients were subjected to analysis. RESULTS: The double-balloon enteroscopy contributed to the diagnosis of small intestinal neoplasms found in 3 out of 17 patients by direct observation of the strictures as well as biopsy sampling. Surgical procedures were chosen for these three patients, while balloon dilation was chosen for the strictures in four patients diagnosed with inflammation without involvement of neoplasm. CONCLUSION: Double-balloon enteroscopy is a useful method for the diagnosis and treatment of strictures in the small bowel.

Long-term outcomes for patients with solitary hepatocellular carcinoma treated by laparoscopic microwave coagulation.

BACKGROUND: Although many reports on the treatment of hepatocellular carcinoma (HCC) by microwave coagulation have been published recently, none have incorporated data for the long-term therapeutic efficacy of laparoscopic microwave coagulation (LMC). In the current study, the efficacy of LMC was assessed. METHODS: The authors performed LMC under local anesthesia in 69 previously untreated patients with solitary HCCs < or = 4.0 cm in greatest dimension. The maximum diameter for the tumors averaged 22.6 +/- 7.4 mm. Long-time survival rate was evaluated according to the size and histologic grade of the tumor. RESULTS: The 5-year overall cumulative survival rate for the 69 patients was 63.9%. The 5-year overall survival rate for patients with well differentiated HCC was 78.9%, whereas patients with moderately or poorly differentiated HCC had a 5-year overall survival rate of 38.9%. The 5-year cumulative survival rate for patients with HCCs < or = 2.0 cm in diameter was 76.0%, and 56.3% for patients with HCCs >2.0 cm. Twelve patients (17.4%) showed local tumor recurrence during the follow-up period. Local tumor recurrence was observed in 6 of 21 patients with moderately or poorly differentiated HCCs (28.6%) and in 6 of 40 patients with well differentiated HCCs (15.0%). The 3-year cancer-free survival rate for patients with well differentiated HCC was 44.4%, whereas it was 12.2% for patients with moderately or poorly differentiated HCC. CONCLUSIONS: A major factor that influenced outcome in LMC was tumor cell differentiation. LMC procedures were best suited for treatment of well differentiated HCC.

Gastrointestinal angiodysplasia in a patient with type 2 von Willebrand's disease and analysis of exon 28 of the von Willebrand factor gene.

Although the association between gastrointestinal angiodysplasia and von Willebrand's disease has been suggested, molecular mechanisms involved in the formation of angiodysplasia in patients with von Willebrand's disease remained undetermined. We examined exon 28 of the von Willebrand factor gene in a patient with both von Willebrand's disease and recurrent bleeding from angiodysplasia in the duodenum as well as his father's, and found a point mutation, C 3916-->T (amino acid substitution; Arg 543-->Trp), in the A1 domain of the von Willebrand factor gene. This mutation was identical with a previously reported mutation in a patient with von Willebrand's disease complicated with gastrointestinal angiodysplasia.

Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice.

In the progression of chronic gastritis, gastric mucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Many epidemiologic studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence that shows intestinal metaplasia is a precursor lesion of gastric carcinoma, to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice we have previously generated. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying Apc(Min) mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully showed that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.

Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases.

BACKGROUND & AIMS: A specialized system for a new method for enteroscopy, the double-balloon method, was developed. The aim of this study was to evaluate the usefulness of this endoscopic system for small-intestinal disorders. METHODS: The double-balloon endoscopy system was used to perform 178 enteroscopies (89 by the anterograde approach and 89 by the retrograde approach) in 123 patients. The system was assessed on the basis of the rates of success in jejunal and ileal insertion and the entire examination of the small intestine, diagnostic yields, ability to perform treatment, and complications. RESULTS: Insertion of the endoscope beyond the ligament of Treitz or ileocecal valve was possible in all 178 procedures. It was possible to observe approximately one half to two thirds of the entire small intestine by each approach, and observation of the entire small intestine was possible in 24 (86%) of 28 trials. The source of bleeding was identified in 50 (76%) of 66 patients with GI bleeding, scrutiny of strictures was possible in 23 patients, and a tumor was examined endoscopically in 17 patients. Two complications (1.1%) occurred. Endoscopic therapies in the small intestine including hemostasis (12 cases), polypectomy (1 case), endoscopic mucosal resection (1 case), balloon dilation (6 cases), and stent placement (2 cases) were performed successfully. CONCLUSIONS: Double-balloon endoscopy permits the exploration of the small intestine with a high success rate of total enteroscopy. The procedure is safe and useful, and it provides high diagnostic yields and therapeutic capabilities.

Gastrointestinal stromal tumor in the jejunum: diagnosis and control of bleeding with electrocoagulation by using double-balloon enteroscopy.

A 43-year-old man presented with gastrointestinal bleeding. A tumor with central ulceration was observed in the jejunum, with the use of a new enteroscopy system called "double-balloon enteroscopy". Bleeding after biopsy sampling of the tumor was controlled endoscopically by using electrocoagulation. Histological findings of the biopsy specimens were consistent with gastrointestinal stromal tumor, and this was surgically resected. Double-balloon enteroscopy was useful for the diagnosis as well as the control of bleeding in this patient.

Laparoscopic radiofrequency ablation of hepatocellular carcinoma in the caudate lobe by using a new laparoscopic US probe with a forward-viewing convex-array transducer.

BACKGROUND: The use of a new end-fire type laparoscopic US probe with a forward-viewing convex-array transducer allows the caudate lobe of the liver to be accessed. This study evaluated the preliminary results of treatment of hepatocellular carcinoma in the caudate lobe by using this new instrument. METHODS: Three patients with hepatocellular carcinoma in the caudate lobe were selected. A laparoscopic US probe, with a forward-viewing convex-array transducer at the tip and a guide groove for puncture on the back, was used to monitor the position of the radiofrequency ablation needle during the treatment. RESULTS: Ablation was performed without complication in all cases. Complete necrosis of the tumor was confirmed by postoperative CT. At a mean follow-up of 30.3 months, no local recurrence was observed in any patient. CONCLUSIONS: Radiofrequency ablation of hepatocellular carcinoma in the caudate lobe of the liver by using a new laparoscopic US probe with a forward-viewing convex-array transducer at the tip was safe and effective.

Direct observation with double-balloon enteroscopy of an intestinal intramural hematoma resulting in anticoagulant ileus.

In the case presented here, we have succeeded in describing the endoscopic findings of anticoagulant ileus and evaluated the degree of bleeding as well as ischemia through endoscopic observation. We have demonstrated that enteroscopy using the double-balloon method is a useful diagnostic tool in the evaluation of a patient suspected to have anticoagulant ileus.