Intraductal papillary neoplasm of the bile duct with metachronous development in the downstream bile duct after radical resection.

We report a case of intraductal papillary neoplasms of the bile duct (IPNB) that metachronously developed twice in the downstream bile duct after radical resection. The first lesion was located in the left intrahepatic bile duct, the second lesion in the perihilar bile duct, and the third lesion in the distal bile duct. All lesions were IPNBs with associated invasive carcinoma (pancreatobiliary type). The depth of invasion was to the Glisson's capsule in the first lesion, to the subserosa in the second lesion, and to the fibromuscular layer in the third lesion, without lympho-vascular/perineural invasion and lymph-node metastasis. These were resected radically and had no biliary intraepithelial neoplasia and hyperplasia in the surrounding mucosa. In immunohistochemical examination, each lesion showed a different pattern. Although the downstream occurrence suggests intrabiliary dissemination, the mechanism of these metachronous developments may be multicentric. A literature review revealed that most metachronous cholangiocarcinomas have a grossly papillary appearance and tend to arise downstream. Our findings suggest that IPNB may develop metachronously in the residual bile duct after radical surgery, which may assist in early detection.

Ultrasonographic Features of Nonneoplastic Protrusions in Pancreatic Cysts by Contrast-Enhanced Endoscopic Ultrasound.

OBJECTIVES: Most of the pancreatic cyst protrusions detected by B-mode endoscopic ultrasound (BM-EUS) are nonneoplastic and are not enhanced by contrast-enhanced EUS (CE-EUS) using ultrasound contrast agent (USCA). This study aimed to identify useful findings for distinguishing between neoplastic and nonneoplastic pancreatic cyst protrusions on BM-EUS to facilitate efficient USCA use. MATERIALS AND METHODS: A total of 151 pancreatic cyst protrusions in 119 consecutive patients who underwent CE-EUS were analyzed. We focused on the echo level (hyperechoic/isoechoic/hypoechoic/anechoic), base type (sessile without a basal waist/sessile with a basal waist/pedunculated), surface type (smooth/irregular), and the presence/absence of a hyperechoic surface layer. Enhanced and unenhanced protrusions on CE-EUS were interpreted as neoplastic and nonneoplastic, respectively. RESULTS: Forty-five and 106 protrusions were enhanced and unenhanced, respectively, on CE-EUS performed using USCA. In univariable analysis of predictors of nonneoplastic protrusion on BM-EUS, the following factors were found to be significant: echo level (hypoechoic/anechoic), base type (sessile with a basal waist/pedunculated), a smooth surface, and a hyperechoic surface layer. Of these, only a hyperechoic surface layer remained significant in the multivariable analysis ( P < 0.0001; odds ratio, 40.74; 95% confidence interval, 7.07-387.49). CONCLUSIONS: Pancreatic cyst protrusions with a hyperechoic surface layer on BM-EUS are suggestive of nonneoplastic disease.

Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807.

BACKGROUND: We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer. METHODS: ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates. RESULTS: Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS < 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR < 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS. CONCLUSIONS: ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF.

A resected case of focal autoimmune pancreatitis with pancreatic duct wall thickening representing periductal lymphoplasmacytic infiltrate.

This case revealed that branch pancreatic duct wall thickening by endoscopic ultrasonography represented periductal lymphoplasmacytic infiltrate as a characteristic histopathological finding of autoimmune pancreatitis, which may help in the diagnosis of autoimmune pancreatitis. An 80-year-old man was referred because fluorodeoxyglucose-positron emission tomography for lung cancer indicated abnormal uptake in the pancreatic head. Computed tomography showed an enhanced mass with cystic structures in the pancreatic head. Magnetic resonance cholangiopancreatography revealed mild dilatation of the main pancreatic duct in the pancreatic body with no strictures. Endoscopic ultrasonography demonstrated a lobulated heterogeneous hypoechoic mass in the pancreatic head. A branch pancreatic duct with wall thickening connected the mass to the main pancreatic duct. An intraductal neoplasm filling and spreading into the branch pancreatic duct was considered, and surgery was performed. Histopathologically, the mass consisted of marked inflammatory cell infiltration, storiform fibrosis, and obliterative phlebitis. The branch pancreatic duct with wall thickening revealed a band-like inflammatory cell infiltration with mainly lymphocytes and plasma cells beneath the normal pancreatic duct epithelium. Immunohistological staining revealed abundant IgG4-positive plasma cells (> 10 cells/HPF) in the inflammatory cell infiltration. The definite diagnosis was type 1 focal autoimmune pancreatitis.

An unusual reversible color change in a gastric lesion during real-time endoscopy.

During endoscopy, a light purple flat lesion suddenly appeared at the antrum and the lesion disappeared subsequently. This is an unusual reversible color change that is associated with blood flow, and that must be differentiated from neoplasia.

Usefulness and Limitations of a Serum Screening System to Predict the Risk of Gastric Cancer.

Objective The aim of the present study was to evaluate the effectiveness and limitations of a serum screening system for predicting the risk of gastric cancer. Methods Serum pepsinogen I (PG I)/pepsinogen II (PG II) and Helicobacter pylori (HP) antibody levels were measured. Subjects were classified into four groupsaccording to their serological status (the ABC classification system). The grade of atrophic gastritis was assessed endoscopically. We evaluated gastric cancer detection rates according to the ABC classification system and the endoscopic grade of atrophy. Patients Individuals who underwent esophagogastroduodenoscopy (EGD) in a health check were prospectively enrolled in the present study. Results According to the ABC classification system, the gastric cancer detection rates in groups A, B, C, and D were 0.07% (4/6,105), 0.5% (8/1,739), 0.8% (16/2,010), and 1.1% (3/281), respectively. The gastric cancer detection rates in subjects with no atrophy, closed type (C-type) atrophy, and open type (O-type) atrophy were 0% (0/4,567), 0.2% (4/2,581), and 0.9% (27/2,987), respectively. In group A (HP(-)/PG(-)), the proportions of subjects with no atrophy, C-type atrophy, and O-type atrophy were 71.2%, 22.8%, and 6.0%, respectively. In group A, the gastric cancer detection rates in subjects with no atrophy, C-type atrophy, and O-type atrophy were 0%, 0.07%, and 0.8%, respectively. Conclusion The ABC classification system is useful for predicting the risk of gastric cancer. However, this system was limited in group A, which included individuals with a high risk of developing gastric cancer. An endoscopic diagnosis of atrophy may be more effective than the ABC classification system for predicting the risk of gastric cancer.

Distribution of lanthanum carbonate in the gastric mucosa confirmed by electron microscopy with a magnified endoscopy: a case report and literature review.

We describe the case of a 70-year-old man with diabetic nephropathy undergoing hemodialysis. Four years following hemodialysis, he started taking lanthanum carbonate 1500 mg/day and lansoprazole 30 mg/day. Nine years following hemodialysis, he underwent screening esophagogastroduodenoscopy, which demonstrated the presence of the whitish cobblestone-like mucosa in the gastric corpus and multiple reddish depressed lesions with annular whitish mucosa in the antrum. With magnified narrow-band imaging endoscopy, a yellowish-white substance was observed in the villous structure, and subepithelial vessels were observed on the yellowish-white substance. Biopsies were taken from the whitish cobblestone-like mucosa of the upper corpus, a reddish depressed part of the antrum. Histologically, aggregates of cells containing amphophilic fine granular material were found in the mucosal interstitium. These cells stained positive for CD68 and were identified as histiocytes. Since he had been taking lanthanum carbonate for 5 years, we considered the possibility of histiocyte-mediated phagocytosis of lanthanum. Digital mapping via scanning electron microscopy with energy-dispersive X-ray spectrometry showed the presence of lanthanum and phosphorus in the interstitium and cytoplasm of histiocytes. The white, rough mucosa in the gastric body appeared 6 months following the commencement of lanthanum administration and still exists 3 years and 5 months after discontinuation of lanthanum.

Efficacy and Safety of Adsorptive Granulocyte and Monocyte Apheresis in Elderly and Pregnant Patients With Ulcerative Colitis.

In patients with active ulcerative colitis (UC), adsorptive granulocyte/monocyte apheresis (GMA) is expected to promote remission. We conducted a retrospective cohort study to evaluate the efficacy and safety of GMA in patients with active UC. Twenty-one UC patients including five pregnant or lactating mothers and four elderly patients (aged >60 years) received up to 10 GMA sessions. UC severity was evaluated at baseline and after GMA therapy according to Lichtiger's Clinical Activity Index (CAI). We defined clinical remission as CAI ≤4. Overall, the median CAI score after GMA therapy had decreased from 9 to 4 (P < 0.001). The clinical remission rate was 62%, but in the elderly and pregnant or lactating mothers, the remission rates were 100% and 60%, respectively. No severe adverse effects were seen in this study. Our results may support GMA as an effective and safe treatment for active UC patients, including elderly patients and pregnant cases.

Prediction of the invasion depth of superficial squamous cell carcinoma based on microvessel morphology: magnifying endoscopic classification of the Japan Esophageal Society.

Predicting invasion depth of superficial esophageal squamous cell carcinoma is crucial in determining the precise indication for endoscopic resection because the rate of lymph node metastasis increases in proportion to the invasion depth of the carcinoma. Previous studies have shown a close relationship between microvascular patterns observed by Narrow Band Imaging magnifying endoscopy and invasion depth of the superficial carcinoma. Thus, the Japan Esophageal Society (JES) developed a simplified magnifying endoscopic classification for estimating invasion depth of superficial esophageal squamous cell carcinomas. We conducted a prospective study to evaluate the diagnostic values of type B vessels in the pretreatment estimation of invasion depth of superficial esophageal squamous cell carcinomas utilizing JES classification, the criteria of which are based on the degree of irregularity in the microvascular morphology. Type A microvessels corresponded to noncancerous lesions and lack severe irregularity; type B, to cancerous lesions, and exhibit severe irregularity. Type B vessels were subclassified into B1, B2, and B3, diagnostic criteria for T1a-EP or T1a-LPM, T1a-MM or T1b-SM1, and T1b-SM2 tumors, respectively. We enrolled 211 patients with superficial esophageal squamous cell carcinoma. The overall accuracy of type B microvessels in estimating tumor invasion depth was 90.5 %. We propose that the newly developed JES magnifying endoscopic classification is useful in estimating the invasion depth of superficial esophageal squamous cell carcinoma.

Phase I/II trial of 2-weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807).

We carried out a phase I/II trial of adding 2-weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2-weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2-weekly docetaxel (30 mg/m(2) [dose level (DL)1] or 40 mg/m(2) [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed-dose CF (80 mg/m(2) cisplatin, day 1; 800 mg/m(2) fluorouracil, days 1-5) repeated every 4 weeks. The primary endpoint was dose-limiting toxicity (DLT) in phase I and central peer review-based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty-two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48-75%); median overall survival and progression-free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment-related death in one patient. The 2-weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.

Criteria for non-surgical treatment of perforation during colorectal endoscopic submucosal dissection.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) has recently been applied in the treatment of large colorectal tumors. However, indications for emergent surgery and criteria for conservative treatment of perforation remain unclear. The aim of this study was to clarify the criteria for non-surgical treatment of perforation during colorectal ESD. METHODS: 219 colorectal tumors in 215 patients (136 men and 79 women; median age 69 years) were removed by performing ESD. The procedural outcomes, complications, prognoses, and criteria for non-surgical treatment of perforation were retrospectively analyzed by using our prospectively corrected database. RESULTS: The en-bloc and complete en-bloc resection rates were 92.7% (203/219) and 85.8% (188/219), respectively. The rate of discontinued ESD was 2.3% (5/219). The immediate and delayed perforation rates were 5.0% (11/219) and 0%, respectively. One of these patients required emergent surgery because of a residual lesion and localized peritonitis caused by an unsuccessful closure. The other 10 patients recovered with conservative treatment after successful closure with hemoclips and complete resection. The defects in all patients were successfully closed by using hemoclips. None of the patients had signs of diffuse peritonitis. The other factors, i.e. absence of localized peritonitis, high-grade fever, and acceleration of inflammatory reaction, were not associated with the success or the failure of the non-surgical treatment. CONCLUSIONS: The criteria for non-surgical treatment of perforation caused by colonic ESD were absence of diffuse peritonitis and successful closure.

Bile acid-induced expression of activation-induced cytidine deaminase during the development of Barrett's oesophageal adenocarcinoma.

Activation-induced cytidine deaminase (AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. We recently demonstrated that Helicobacter pylori infection and/or proinflammatory cytokine stimulation triggers aberrant AID expression in gastric epithelial cells, causing mutations in the tumour-suppressor TP53 gene. The findings of the present study provide evidence of ectopic AID expression in Barrett's oesophagus and Barrett's oesophageal adenocarcinoma, a cancer that develops under chronic inflammatory conditions. Immunoreactivity for endogenous AID was observed in 24 of 28 (85.7%) specimens of the columnar cell-lined Barrett's oesophagus and in 20 of 22 (90.9%) of Barrett's adenocarcinoma, whereas weak or no AID protein expression was detectable in normal squamous epithelial cells of the oesophagus. We validated these results by analysing tissue specimens from another cohort comprising 16 cases with Barrett's oesophagus and four cases with Barrett's adenocarcinoma. In vitro treatment of human non-neoplastic oesophageal squamous-derived cells with sodium salt deoxycholic acid induced ectopic AID expression via the nuclear factor-kappaB activation pathway. These findings suggest that aberrant AID expression occurs in a substantial proportion of Barrett's epithelium, at least in part due to bile acid stimulation. Considering the genotoxic activity of AID, our current findings suggest that aberrant AID expression might enhance the susceptibility to genetic alterations in Barrett's columnar-lined epithelial cells, leading to cancer development.

Learning curve for endoscopic submucosal dissection of large colorectal tumors.

BACKGROUND AND AIM: No studies have previously described the learning curve for colonic endoscopic submucosal dissection (ESD). The aim of the present study was to describe the learning curve for ESD of large colorectal tumors based on a single colonoscopist's experience. METHODS: ESD was carried out for 120 colorectal tumors in 115 patients (68 males, median age 70 years). All procedures were carried out by a single experienced colonoscopist. The cases were grouped chronologically into three periods: (1st): cases 1-40; (2nd): cases 41-80; and (3rd): cases 81-120. RESULTS: The learning curve was the changes in proficiency over time. Proficiency was expressed as procedure time per unit area of specimen. In the 1st, 2nd and 3rd periods, the proficiencies were 18.9, 12.6 and 12.9 (min/cm(2) ), respectively. The proficiencies in the 2nd and 3rd periods were significantly shorter than in the 1st period (t-test, P < 0.05). The en-bloc resection rates of the 1st, 2nd and 3rd periods were 92.5% (37/40), 90% (36/40) and 97.5% (39/40), respectively. The en-bloc and R0 resection rates of the 1st, 2nd and 3rd periods were 85% (34/40), 77.5% (31/40) and 92.5% (37/40), respectively. The perforation rates of the 1st, 2nd and 3rd periods were 12.5% (5/40), 5% (2/40) and 5% (2/40), respectively. CONCLUSION: Based on our analysis of the learning curve, approximately 80 procedures must be carried out to acquire skill with ESD for large colorectal tumors. However, approximately 40 procedures were sufficient to acquire skill in avoiding perforations during the ESD procedure.

A comparison of outcomes of endoscopic submucosal dissection (ESD) For early gastric neoplasms between high-volume and low-volume centers: multi-center retrospective questionnaire study conducted by the Nagano ESD Study Group.

OBJECTIVE: Outcomes of endoscopic submucosal dissection (ESD) for early gastric neoplasms at low-volume centers have been unknown, because all previous reports have studied in advanced single centers. The aim of this study was to compare ESD outcomes between high- and low-volume centers. METHODS: A retrospective questionnaire survey was conducted and 30 centers (96.8%) responded. The complete en-bloc resection rate (CERR) and the incidence of complications were analyzed. Early gastric cancer (EGC) was divided into three categories on the basis of pathological diagnosis-standard indication (SI), expanded indication (EI) and out-of-indication (OI). RESULTS: A total of 703 early gastric neoplasms (586 EGCs, 117 gastric adenomas) were treated with ESD from January to December 2005. The institutions that treated more than 30 cases a year were classified as high-volume centers, and those with less than 30 cases, low-volume centers. In SI, the CERRs at high- and low-volume centers were 92.1% and 91.1%, in EI, CERRs were 86.2% and 82.6% and in OI, CERRs were 80.3% and 88.0%. The perforation rates at high- and low-volume centers were 3.6% and 4.7%. The intra-operative bleeding rates at high- and low-volume centers were 0.26% and 0%, while the delayed bleeding rates were 0% and 0.63%. CONCLUSION: There were no significant difference in the outcomes of ESD for early gastric neoplasms between high- and low volume centers.